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Work Husbands I am not sure were the title came from, but it was there when I started. I imagine someone once coined it to reflect the intense relationship that sometimes can develop when you have two who work together often. I mean, we do face life and death situations and other times traumatic events. You see each other at the best, and worst of times. Sometimes it’s fun and laughter, and other times there’s arguments. I mean, we are hired for our Type A personalities. In any event, that is the title given to those we closely work with. I have had two work husbands and one work wife. It is not a reflection of me and my ability to get along, or not, with partners (escorts as we call them.) Rather, it is indicative of the nature of turn over from the front-line Primary Response Unit (PRU) to other units, and then back. PRU is the first place we start, and it is always the place we come back to, for most officers. But in between, there are lots of places and opportunities for officers to go for six months, two years , five years and sometimes beyond. Cops on bikes, on the internet, in Tavis, in sex crimes, in homicide and many, many other areas. Some may stay for their careers in a squad, but for many, the majority, they will return to the PRU. I work with a bunch of boys mostly. Little boys. Don’t kid yourself, they really are still eight to ten years old, just taller. They like to fart and gas each other out, and laugh about it. They laugh at the word ‘boobie’ and they punch, kick and wrestle with each other. Many mothers of young boys would recognize this behaviour. And when they do grow up and behave like adults, they can be extremely moody and difficult to get along with. I mean, with us all being A-Type Personalities, we take charge, we want to do it our own way and we all think we are right. Needless to say, there’s sometimes a lot of arguing going on lol! There is nothing happy and easy about sitting next to a moody guy, especially if you and him have different ideas about how radio calls should be handled. It just makes for a long and stressful shift. I have to say, I have never lived as an adult with a male and I really have empathy for all those wives and girlfriends. I don’t know how you all do it! I came from an environment, the exact opposite, where for over fifteen years, my employment consisted solely of working with females. As hard as people think it is to work in an all female workplace, there is no greater challenge than sitting next to one of those said moody guys in the confined space of a car for ten hours. I think the job is hard enough, without all the personality interplay underlying a shift. I much prefer to be with someone with whom I have the same philosophy and approach to the job and someone who will make me laugh and have a good time. It helps with the hard times on the job. So, I’ll introduce you to my present work husband, (and he picked his screen name) Ralph. He’s a tall, big lug, with a heart of gold for his family and he is as loyal as they come. We don’t always see eye-to-eye on radio calls. Actually, often we are at odds, but he makes me laugh. He comes into work, and no matter what is happening, he puts on a game face and out we go. There is no moodiness, no grumpiness, just a person with a good sense of humour. Most of the time. My job is to entertain him and make him laugh. Cause if we are not enjoying ourselves, we won’t want to work together. And as for those times when he wants to do something the wrong way, I argue with him until he does it the right way. Right Ralph? He doesn’t complain, talk about anyone behind their back or bitch about them not doing their job. I do. Or I try to. But that’s where men and women are different. He just becomes quiet and drifts off somewhere else, not even listening. He will absolutely, flat out refuse to answer if he doesn’t want to. ‘Don’t you think they should have backed up the Sargent?” I ask, which befalls upon silence, as if I didn’t even say anything. But still I’ll try. “What did you think of that move by Spanky?” I’ll ask. Crickets. Crickets. I look at him driving, cause he’s always driving, and his eyes are blank. Nothing there. I mean NOTHING. He just goes there, to that nothing place where he is absent from the world. And he continues to ignore me. I say he always drives cause he can’t stand giving up the control of the car. The odd time when I get assertive and decide I want to be in control, he quickly goes to his car and pulls out his bike helmet. “Really? Put that thing away. You look like a knob sitting in the scout with that helmet on!” And he thinks he’s funny. But he is truly an annoying passenger and he isn’t even sitting in the back seat. First, it’s the path I’ve chosen to get to our destination. Wrong. Then there’s that finger, the one that signals the turns, the directions, whether to use lights and sirens, and even a lane change. When he flashes it near my face, I have only one defence – bite it! I’ve almost got him lol. Then of course, is the yelling and screaming. Like really? Like a little girl. If I’m within three feet of anything he starts to hyperventilate. His sharp intake of breath, trying to slam the brakes on where he sits, and the covering of his eyes, all while sometimes shrieking to his horror. I am not exaggerating here. He really is a drama queen. Then lastly is the arrival. The car is too close to the curb, too far from the curb, should be in the middle of the road, no in the driveway, heck turn around and face the other way. Wrong. And I actually thought that by driving I would have more control. Wrong. I found out he does get grumpy sometimes. Remarkably it is every time I drive! And he calls Sue the Goddess. This is because, he says, she tolerates me.You see, he often just looks at me and says “Duct tape,” which is his solution to dealing with me. Duct tape for my mouth when I talk too much. Duct tape me to the seat when I want to get out and chase. Duct tape me to the spot so he won’t loose me. And the worse of all, duct tape my hands to the steering wheel when I’m driving. You see I talk with my hands and he always insists that there be a least ONE hand on the steering wheel at all times. He’s so annoying! So he has duct tape to deal with our interpersonal dynamics and he just shakes his head and calls Sue The Goddess. So, I sit, mostly in the passenger seat, and do my due diligence. I keep him happy, healthy and fed. I accomplish this by entertaining him, keeping him with a coffee in the hand and making sure he gets his yummy Schwarma from his favourite restaurant. And I try to show him what a good passenger does. Pay attention here Ralph! I sit there quietly and let him drive at whatever speed and take whatever path he wants to take. But most importantly, I make sure he doesn’t miss his wife. You see, he needs consistency. And as he says “I’m a good little trained monkey” and I want to ensure he doesn’t mess this up. So I let him know about the 20-80 rule. He is right only 20% of the time and wrong 80% of the time. When he comes out of his nothing zone, that vacuous place where all time and matter stop, I take great delight in telling him many times throughout the shift when he is wrong. He says it’s just like being at home. Right! He complains that I talk too much. I admit, I get excited when we’ve been on days off and I have so much news to tell him. I am animated and hyper and I talk on and on and he just smiles, nods and laughs a little, occasionally reminding me to breathe. That’s usually when he tells me he has duct tape in his duty bag, just for me. But I know the truth. He secretly enjoys my entertainment AND he hates the silence. If I stop talking for three minutes, he checks to make sure I have a pulse, and then starts whistling. He can’t stand the silence but he wont admit it. And he whistles the All In The Family TV series theme. Of course you know by Edith’s part, being tone deaf, I just have to break in with my horrible rendition of her singing. And then we start laughing, and making strange noises at each other as we go to yet another 911 call. And if it’s lights and sirens on the way, he will usually scare me with his driving and I start laughing hysterically in my fear.You see, when I’m afraid, like on rides or in speeding cars, I don’t scream. I laugh. Hysterically sometimes. As we make our way, me non-stop laughing, I always imagine having to try and explain this in court, as everything is being recorded. “Officer, it seems you found it hysterically funny going to this very serious call for emergency service. Can you explain what you found so funny?” “Yes, you see my escort scared me with his driving and I laugh when I am scared. But he was also poking my side tickling me so I would laugh all the more and embarrass myself. And yes, he does that even while going lights and sirens, Your Honor.” So as far as work husbands go, he’s a good one. I think I’ll keep him for awhile. But we won’t tell him that. | Mid | [
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MICHAEL KELLY SJ. Understanding challenges the church in Asia faces. The Church in Asia can absorb and replicate its hierarchical, tiered cultural surrounds, or leave behind the clericalist conception of the Church, as a tightly run top-down organisation. It lies at the intersection of local hierarchical cultures and the culture of the church fostered by Rome before Vatican II. The calm confidence of Cardinal Oswald Gracias that the church in Asia will avoid or at least manage a Left-Right divide in the church’s hierarchy is an optimistic political review of our prospects. But the challenges and divisions the churches of Asia face are both far more obvious and much more complex than a simple political analysis will reveal. The use of “Left” and “Right” as political descriptors lost any meaning — even when applied to theological positions — with the fall of the Berlin Wall (1989) and the end of the Cold War. That signaled the end of full-blown ideologies as the controlling ideas that shaped societies, economies and polities. Moreover, political descriptors are quite inappropriate to describe the way the church lives and changes. The Catholic Church is not a political society but a faith community and faith communities have cultures, not political ideologies, to sustain them. The area where the church in Asia will face challenges is already well defined and is the fruit of a long history. To put it briefly, the challenge lies at the intersection of local hierarchical cultures and the culture of the church fostered by Rome for 150 years before Vatican II. From a Catholic point of view, the church today operates on two cultural agendas — the vision of the church outlined at Vatican II and the operational agenda of the church that operated for the previous 150 years and that Vatican II sought to reform. Until the Council, the multi-tiered, hierarchical church had initiative and authority come down from the top. The council redefined that and outlined a view of the church as the People of God who are served by clerics. In Asia, embracing that change is further complicated. Local cultures influence the shape of Catholic cultures in various countries. Local cultures are quite distinct and are appropriated in very identifiable ways. It may be said to be inculturation. Sometimes it is. Frequently though, it’s more the unexamined integration and accommodation of a local culture to fill out how Catholic life as proposed and led from Rome is lived. Most Asian cultures are hierarchical. In many Asian cultures — unlike most countries in the West now — the clergy and religious hold revered and highly respected places. In the West, clerics and bishops do not enjoy the trust and respect they once did. This follows the disasters of clerical sexual abuse and its mishandling by bishops. But in most of Asia, and just as Buddhist monks and Islamic Imams hold sway in Buddhist and Islamic cultures by virtue of their status, Catholic clerics and Religious still enjoy a special status in Catholic cultures across the region. There is an almost automatic and involuntary respect and deference accorded bishops and priests that long ago disappeared in the U.S., Canada, Western Europe, Australia and New Zealand. Unfortunately, it’s not very far from an “automatic and involuntary respect” accorded to clerics to the creation and maintenance of a clerical culture that is self-protective, presumptuous and excluding. And in some countries and cultures, there are extra elements that intensify the problem, with the Indian caste system being the most obvious instance. Caste still plays a hefty role in how Catholic life is lived in the Subcontinent. And how does the post Vatican II church proposed by Pope Francis address these circumstances? He goes so far as to say that there is an “illness” at the heart of the church destroying the faith and he calls it clericalism. As he told the Jesuits at their October General Congregation in Rome: “Clericalism, which is one of the most serious illnesses that the church has, distances itself from poverty. Clericalism is rich. If it is not rich in money, it is rich in pride. But it is rich: there is in clericalism an attachment to possessions. “Clericalism does not allow growth, it does not allow the power of baptism to grow. The grace and evangelizing power of the missionary expression comes from the grace of baptism. And clericalism controls this grace badly and gives rise to dependencies, which sometimes have whole peoples in a state of very great immaturity. I remember the fights that took place when I was a student of theology or a young priest and the base ecclesial communities appeared. Why? Because the laypeople began to have strong leadership, and the first ones who felt insecure were some of the priests. I am generalizing too much, but I do this on purpose: if I caricature the problem it is because the problem of clericalism is very serious.” Clericalism is alive and well in Asian Church cultures because it fits so neatly with the hierarchical cultures where the Catholic faith has been planted in Asia. In thrives in hierarchical cultures and naturally fits with an elitism that occurs in the exclusive clerical club. As well, that has fitted neatly with the way of being a Catholic priest and bishop that has been endorsed by Roman decrees and directives for the last 35 years. Moreover, the Vatican has operated in a centralist, authoritarian way under the last two popes. The effect of the centralism and authoritarianism has been to neutralize imagination and local initiative as Cardinal Gracias acknowledged of the FABC in his ucanews.com interview. It has been comparatively dormant for two decades. Moving from a tiered, command and control method of governance by Rome to a People of God — engaged and responsive, operating in servant mode, as proposed in the theology of the church at Vatican II — is an unfamiliar place for many in leadership roles in the Catholic Church. And that’s where the divide in the church among European and North American bishops is already emerging — between those who see themselves as repeater stations for “orthodoxy,” waiting to be told what to think and do, and those who see themselves as leaders and servants of a local community in a worldwide church. When head office asks what people are thinking and believing away from the center, many in the peripheries are puzzled. They’ve never been asked before and often don’t know what they think. They thought it was up to Rome to tell them what to think. That will be where the divide will emerge in Asia — not between “Left” and “Right.” It will be between those who see their mission and ministry as something they get from the Vatican — they want to be told what to think and say — and those who see themselves as the Roman authorized leaders of local faith communities that make the Church Catholic. The church in Asia can absorb and replicate its hierarchical, tiered cultural surrounds or leave behind the clericalist conception of the church, as a tightly run, top down organization. The hallmark of a post-conciliar church is the development of an open and inclusive community that fosters local initiatives before it imposes central rulings. Listening (or not) to that local voice and allowing it to be heard (or not) will be where the divisions emerge in Asia. Father Michael Kelly SJ is executive director of ucanews.com and based in Thailand. This article first appeared in UCANews on 29 November, 2016. Father Michael Kelly is an Australian Jesuit who directed the Catholic Church's news feature and commentary service, UCA News, 2008-2018. He is the publisher of the English editions of La Croix International and La Civilta Cattolica, the 170 year old Jesuit publication of the Italian Jesuits. 1 Response to MICHAEL KELLY SJ. Understanding challenges the church in Asia faces. “The church in Asia can absorb and replicate its hierarchical, tiered cultural surrounds or leave behind the clericalist conception of the church, as a tightly run, top down organization. The hallmark of a post-conciliar church is the development of an open and inclusive community that fosters local initiatives before it imposes central rulings.” | High | [
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Q: "Clone" a RenderTarget2D? I see that some XNA resources implement ICloneable (namely the Effect class) but textures don't. I have encountered a situation where I need to make a complete copy of a RenderTarget2D texture and use it as inputs for two separate rendering effects. One effect will change the contents of the RenderTarget2D so I can't pass it to the other effect, which is why I need two copies. Can you "clone" or deep copy a RenderTarget2D in an easy way? My current work around is that I wrote a copy function that sets a new render target, uses a simple effect to just re-draw the contents of the target to be copied to into a quad and return the new render target. But seems like a lot of work around simply to create a copy. A: I guess textures don't implement ICloneable for a good reason: it would be too easy to accidentally cause a FPS sink. One might think, XNA stores texture resources in the managed memory pool, so when someRt.GetData() gets called, texture data seems to be already there for locking, which should be fast, right? Not really, since getting actual data requires the driver to flush all commands in queue, wait for GPU to process them, and then send fresh data back for reading. Chances are, if you're going to do your thing on a per-frame basis, it will be better to just render twice. But if you want to clone a texture once in while, a simple way of deep cloning is to walk through mipmap levels and clone them one by one: static RenderTarget2D CloneRenderTarget(RenderTarget2D target) { var clone = new RenderTarget2D(target.GraphicsDevice, target.Width, target.Height, target.LevelCount > 1, target.Format, target.DepthStencilFormat, target.MultiSampleCount, target.RenderTargetUsage); for (int i = 0; i < target.LevelCount; i++) { double rawMipWidth = target.Width / Math.Pow(2, i); double rawMipHeight = target.Height / Math.Pow(2, i); // make sure that mipmap dimensions are always > 0. int mipWidth = (rawMipWidth < 1) ? 1 : (int)rawMipWidth; int mipHeight = (rawMipHeight < 1) ? 1 : (int)rawMipHeight; var mipData = new Color[mipWidth * mipHeight]; target.GetData(i, null, mipData, 0, mipData.Length); clone.SetData(i, null, mipData, 0, mipData.Length); } return clone; } | High | [
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--- abstract: 'The value-at-risk of a delta-gamma approximated derivatives portfolio can be computed by numerical integration of the characteristic function. However, while the choice of parameters in any numerical integration scheme is paramount, in practice it often relies on ad hoc procedures of trial and error. For normal and multivariate $t$-distributed risk factors, we show how to calculate the necessary parameters for one particular integration scheme as a function of the data (the distribution of risk factors, and delta and gamma) *in order to satisfy a given error tolerance*. This allows for implementation in a fully automated risk management system. We also demonstrate in simulations that the method is significantly faster than the Monte Carlo method, for a given error tolerance.' address: 'Saxo Bank A/S, Philip Heymans Allé 15, DK-2900 Hellerup, Denmark' author: - Johannes Vitalis Siven - Jeffrey Todd Lins - 'Anna Szymkowiak-Have' bibliography: - 'BibJohannesSiven.bib' title: 'Value-at-Risk Computation by Fourier Inversion with Explicit Error Bounds' --- value-at-risk, delta-gamma approximation, Fourier inversion, characteristic function, error bounds Introduction ============ Value-at-risk calculations of large derivatives portfolios are an important part of risk management in many financial institutions. The calculations are often performed by the Monte Carlo method and can be very time consuming — the main bottleneck is the repricing of the portfolio for different simulated market scenarios, in particular when the portfolio contains exotic contracts that can only be priced with finite difference schemes or even simulations. A common way to speed up computations is to consider a delta-gamma approximation of the portfolio: the change in the portfolio value over a fixed time horizon is approximated by the quadratic function $$\Delta V = \delta ' \Delta S + \frac{1}{2} \Delta S' \Gamma \Delta S,$$ where $\Delta S$ is a vector of changes in the underlying risk factors, and $\delta$ and $\Gamma$ are the usual first and second order sensitivities. These are typically available “for free” since most often they are already computed internally for hedging purposes. Under certain assumptions on the distribution of the risk factors $\Delta S$, the characteristic function $\phi(u) = \mathbb{E}[e^{iu\Delta V}]$ has a closed form expression. One can write the cumulative distribution function as $$\label{eq:integral} \mathbb{P}(\Delta V \leq x) = \frac{1}{2} - \int_{-\infty}^\infty \frac{\phi(u)}{2\pi i u}e^{iux}du,$$ and several authors have proposed to compute the value-at-risk by evaluating this (or some related) integral numerically, thus avoiding Monte Carlo simulations in the value-at-risk computations, see [@Rouvinez] and [@DuffiePan]. In this paper, we describe in detail how to perform this computation, taking into account that the parameters in the numerical integration scheme must be chosen as a function of the data (that is, the distribution of the risk factors, and $\delta$ and $\Gamma$). Any numerical integration scheme involves choosing certain parameters and for a particular case it is typically not hard to find suitable parameters by trial and error. This might not be good enough in an automated system: one would like the parameters to be calculated as an internal part of the algorithm, preferably with a guaranteed upper bound on the numerical error. There is substantial literature on Fourier series methods for computing tail probabilities, see the extensive reviews by [@AbateWhitt] and [@FourierReview], and the references therein. Explicit error bounds are however rare: we use a result from [@HughettBounds], which allows for computing the probability in Equation (\[eq:integral\]) *with a guaranteed upper bound $\varepsilon$ on the error*, where $\varepsilon> 0$ is specified by the user. To apply the result, one must find certain constants that bound the behavior of $\phi$ and the cumulative distribution function. We show how to compute these constants as a function of the data when the risk factors (i) are normally distributed, and (ii) have a multivariate $t$-distribution. [@GlassermanVaR] derive a closed form expression for the characteristic function in the latter, heavy-tailed case. We also perform some simulation experiments, where the Fourier method is benchmarked against the Monte Carlo method. This is an important comparison to make, since the Monte Carlo method is much faster for the delta-gamma approximated portfolio than for the original portfolio (it avoids the pricing bottleneck), and it is easy to understand and implement. The paper is organized as follows. In Section 2, we review the delta-gamma approximation and recall the closed-form expressions for the characteristic functions in the case of normally and multivariate $t$-distributed risk factors. In Section 3, we state the result from [@HughettBounds] on how to perform the numerical integration with explicit error bounds, and discuss how to choose the necessary parameters. Section 4 contains numerical experiments, and Section 5 concludes. The delta-gamma approximation of a portfolio {#sec:deltagamma} ============================================ In this section we define the delta-gamma approximation of a portfolio, and give the closed form expressions for the characteristic function under two different assumptions on the distribution of the risk factors. Let $S = (S_1,\ldots,S_p)'$ denote a vector of $p$ risk factors to which a portfolio is exposed, and let $\Delta S$ denote the change in $S$ from the current time 0 to the end of the horizon $\Delta t$. Let $V(S,t)$ denote the value of the portfolio at time $t$ and risk factors $S$. The delta-gamma approximation to the change $V(S+\Delta S,\Delta t) - V(S,0)$ in the portfolio value is given by $$\begin{aligned} \Delta V:= \theta \Delta t + \delta ' \Delta S + \frac{1}{2} \Delta S' \Gamma \Delta S,\end{aligned}$$ where $$\theta = \frac{\partial V}{\partial t}, \qquad \delta_i = \frac{\partial V}{\partial S_i},\qquad \Gamma_{ij} = \frac{\partial^2 V}{\partial S_i\partial S_j},\qquad i,j = 1,\ldots, p,$$ and all partial derivatives are evaluated at $(S,0)$. The aim is to compute VaR$_\gamma$, the level-$\gamma$ value-at-risk of $\Delta V$, under certain assumptions for the distribution of $\Delta S$. The level-$\gamma$ value-at-risk is defined as the $\gamma$-quantile of the distribution of $\Delta V$: $\mbox{VaR}_\gamma := P^{-1}(\gamma)$, where $P(x) := \mathbb{P}(\Delta V \leq x)$ is the cumulative distribution function of $\Delta V$. Without loss of generality, we look only at the case $\theta = 0$: if $\mathbb{P}(\Delta V - \theta \Delta t \leq x) = \gamma$, then $\mathbb{P}(\Delta V \leq x + \theta\Delta t) = \gamma$. In the case of normally distributed risk factors $\Delta S$, the characteristic function of $\Delta V$ is known on closed form. \[Cf\] Assume that $\Delta S \sim \mathcal{N}(0,\Sigma)$ for some positive definite matrix $\Sigma$. Let $\lambda_1,\lambda_2,\ldots,\lambda_p$ be the eigenvalues of $\Sigma \Gamma$, and let $\Lambda$ be the diagonal matrix with these eigenvalues on the diagonal. There is a matrix $C$ satisfying $CC'= \Sigma$ and $C'\Gamma C =\Lambda$. Let $b = C'\delta$. Then the characteristic function corresponding to $P$ is given by $$\phi(u) = \mathbb{E}[e^{iu\Delta V}]= e^{-\frac{1}{2}\sum_{j = 1}^pb_j^2\frac{u^2}{1 - i\lambda_j u}} \prod_{j = 1}^p(1-i\lambda_j u)^{-1/2}, \mbox{ for }u\in \mathbb{R}.$$ The moment generating function is given by $\psi(u) = \phi(-iu)$ provided $u \lambda_j < 1$ for $j= 1,\ldots,p$. This result is certainly not new, but the proof is constructive and useful for implementation.[^1] We give a proof in the Appendix. [@GlassermanVaR] relax the assumption of normal risk factors and look at a heavy-tailed distribution for $\Delta S$. They assume that $\Delta S$ has a multivariate $t$-distribution with degrees-of-freedom parameter $\nu$: the density of $\Delta S$ is given by $$f_{v,\Sigma}(x) = \frac{\Gamma(\frac{1}{2}(p+\nu))}{(\nu\pi)^{p/2}\Gamma(\frac{1}{2}\nu)|\Sigma|^{1/2}}\left(1 + \frac{1}{\nu}x'\Sigma^{-1}x \right)^{-\frac{1}{2}(p+\nu)}, \qquad \mbox{for }x\in \mathbb{R}^p,$$ for some positive definite matrix $\Sigma$. Here, and only here, $\Gamma(\cdot)$ denotes the gamma-function; elsewhere throughout the paper, $\Gamma$ is the matrix of second order sensitivities in the delta-gamma approximation of the portfolio. All the marginal distributions of $\Delta S$ are $t$-distributions with degrees-of-freedom parameter $\nu$. [@GlassermanVaR] show that, given $x \in \mathbb{R}$, $P(x) = \mathbb{P}(\Delta V \leq x) = F_x(0)$, where $F_x$ is another distribution function, and derive a closed form expression for the characteristic function corresponding to $F_x$. \[tCf\] Denote the eigenvalues of $\Sigma \Gamma$ by $\lambda_1,\lambda_2,\ldots,\lambda_p$ and let $\Lambda$ be the diagonal matrix with these eigenvalues on the diagonal. There is a matrix $C$ satisfying $CC' = \Sigma$ and $C'\Gamma C = \Lambda$. Let $b = C'\delta$. Then $P(x) = F_x(0)$, where the characteristic function corresponding to the distribution $F_x$ is given by $$\phi(u) = (1 -2\xi(u))^{-\nu/2} \prod_{j = 1}^p (1-i\lambda_j u)^{-1/2},$$ with $$\xi(u) = -\frac{iux}{\nu} - \frac{1}{2\nu}\sum_{j = 1}^pb_j^2\frac{u^2}{1 - i\lambda_j u}.$$ The moment generating function is given by $\psi(u) = \phi(-iu)$, provided $\lambda_j u < 1$ for $j= 1,\ldots,p$ and $\xi(-iu) < \frac{1}{2}$. [@GlassermanVaR] also consider a generalized copula model, where the marginal distributions of $\Delta S$ are $t$-distributions with possibly different degrees of freedom. The generalization comes down to modifying $\delta$ and $\Gamma$ in a straight forward way, and it applies here too. Calculating VaR$_\gamma$ by Fourier inversion ============================================= Let $F$ denote the cumulative distribution function for some continuous distribution, and let $\phi$ denote the corresponding characteristic function. Assume that $\phi$ is known on closed form, but that $F$ is unknown. For a fixed $x\in \mathbb{R}$, [@HughettBounds Theorem 10] tells us how to compute $F(x)$ with desired accuracy by numerical integration of $\phi$. In this section we recall that result and discuss how to apply it in the setting of the previous section for computing VaR$_\gamma$. \[ErrBounds\] Suppose (i) that there exists constants $A$ and $\alpha >1$ such that $F(-y) \leq A|y|^{-\alpha}$ and $1-F(y)\leq A|y|^{-\alpha}$ for all $y>0$, and (ii) that there exist constants $B$ and $\beta> 0$ such that $|\phi(u)|\leq B|u/2\pi|^{-\beta}$ for all $u\in \mathbb{R}$. Then, for constants $0<l<2/3$, $T>0$ and $N>0$, the distribution function $F(x)$ may be approximated by the truncated Fourier series $$g(x) := \frac{1}{2} + 2\sum_{k = 1}^{N/2-1}\textrm{Re}\left(G[k]e^{i2\pi k x/T}\right),$$ where Re$(\cdot)$ denote the real part, and $$G[k] := \frac{1-\cos(2\pi l k)}{i2\pi k}\phi(-2\pi k/T).$$ The approximation error on the interval $|x|\leq l T/2$ is bounded by $$|F(x) - g(x)| \leq \frac{2BT^{\beta}}{\pi}\zeta(\beta + 1,N/2) + AT^{-\alpha}L_1(l,\alpha),$$ where $\zeta$ denote the Hurwitz zeta function[^2] and $$L_1(l,\alpha) := (l/2)^{-\alpha} + 2\zeta(\alpha,1 - \frac{1}{2}l) + \zeta(\alpha,1 + \frac{1}{2}l) +\zeta(\alpha,1 - \frac{3}{2}l).$$ Furthermore, for any $D>0$ and $\varepsilon> 0$, choosing $l$, $T$ and $N$ such that $$\begin{aligned} 0<l< \frac{2}{3} \ & \mbox{and}& \ l^\alpha L_1(l,\alpha)\leq 2^{\alpha+1},\\ T\geq \frac{D}{l} \ &\mbox{and}& \ T \geq \frac{2}{l}\left( \frac{3A}{\varepsilon}\right)^{1/\alpha},\end{aligned}$$ and $$\qquad N \geq 2 + 2T\left( \frac{6 B}{\varepsilon\pi \beta}\right)^{1/\beta}$$ suffices to guarantee that $|F(x) - g(x)|\leq \varepsilon$ for every $|x|\leq D/2$. It is always possible to choose $l$ to meet the given conditions. The conditions on $l$, while complicated, involve only the value of $\alpha$. It is thus feasible to precompute the smallest possible values of $l$, for selected values of $\alpha$, using a numerical zero-finding algorithm. Table 1 give the optimal values of $l$ for selected values of $\alpha$. \[rem:computeVaR\] Using Theorem \[ErrBounds\], it is straight forward to compute VaR$_\gamma$ both in the case of normally and multivariate $t$-distributed risk factors. For normally distributed risk factors, take $\phi$ from Proposition \[Cf\] and look for a solution to $g(x) = \gamma$ with any standard zero-finding method. For multivariate $t$-distributed risk factors we similarly look for a solution to $g_{x}(0)= \gamma$, where $g_x(0) = g(0)$ is calculated from Theorem \[ErrBounds\] with $\phi$ from Proposition \[tCf\], where $\phi$ depends on $x$. In both cases we end up with $x^*$ such that $|P(x^*) - \gamma|\leq \epsilon$. Theorem \[ErrBounds\] takes as input parameters $A$ and $\alpha$, related to the unknown distribution function $F$, and $B$ and $\beta$, related to the known characteristic function $\phi$. The rest of this section discusses how to choose these parameters in the setting of Section \[sec:deltagamma\]. How to choose $A$ and $\alpha$ {#chooseA} ------------------------------ The computational effort in using Theorem \[ErrBounds\] is essentially proportional to $(3A/\varepsilon)^{1/\alpha}$, so ideally $A$ and $\alpha>1$ should minimize this quantity subject to $$\label{constr} F(-y)\leq A|y|^{-\alpha} \mbox{ and } 1 - F(y)\leq A|y|^{-\alpha} \mbox{ for all }y>0,$$ where $F = P$ for normal risk factors, and $F = F_x$ for the multivariate $t$-distribution. This problem might be difficult to solve, since the constraints involve the unknown distribution function $F$. It is however not important to find a truly optimal solution: it suffices to make $(3A/\varepsilon)^{1/\alpha}$ as small as possible with little computational effort. If the moment generating function $\psi$ corresponding to $F$ is finite in a neighborhood of zero,[^3] one can use *Chernoff’s bounds*, see [@Chernoff]: $F(-y)\leq e^{-uy}\psi(-u)$ and $1 - F(y)\leq e^{-uy}\psi(u)$ for all $y$ and all $u > 0$. A sufficient condition for $A$ and $\alpha$ to satisfy the constraints (\[constr\]) is thus that $A y ^{-\alpha}\geq \tilde{\psi}(u)e^{-uy}$, for all $y> 0$ and some $u > 0$, where $$\tilde{\psi}(u):=\max\{\psi(u),\psi(-u)\}.$$ Consider for a moment $u> 0$ as given, and assume that $\tilde{\psi}(u)<\infty$. The following proposition gives the solution to the optimization problem $$\label{eq:Asubopt} \min_{A> 0,\alpha > 1} \left( \frac{3A}{\varepsilon}\right)^{1/\alpha} \qquad \mbox{s.t. } A y ^{-\alpha}\geq \tilde{\psi}(u)e^{-uy},\mbox{ for all $y> 0$.}$$ \[prop:Aopt\] The solution to the optimization problem (\[eq:Asubopt\]) is given by $\alpha(u) := \log (3\tilde{\psi}(u)/ \varepsilon)$ and $A(u):= \tilde{\psi}(u)e^{-\alpha(u)}(\alpha(u)/u)^{\alpha(u)}$. The minimal function value is $\log (3 \tilde{\psi}(u)/ \varepsilon )/u$. The proof is found in the Appendix. A tractable way of computing a (suboptimal) minimizer of $(3A/\varepsilon)^{1/\alpha}$ that satisfies the constraints (\[constr\]) is to take $A = A(u^*)$ and $\alpha = \alpha(u^*)$, where $u^*$ solves $$\label{eq:Aopt} \min_{u> 0} \log(3\tilde{\psi}(u)/\varepsilon)/u.$$ This is a one dimensional optimization problem that can be solved with standard methods. \[rem:Aopt\] For normal risk factors, the optimization problem (\[eq:Asubopt\]) needs to be solved only once. The resulting $A$ and $\alpha$ can be used to compute $P(x)$ for any $x\in \mathbb{R}$. For the multivariate $t$-distribution, $P(x) = F_x(0)$, so the optimization problem needs to be solved once for each $x$, each time using the moment generating function corresponding to $F_x$. How to choose $B$ and $\beta$ {#chooseB} ----------------------------- The computational effort in using Theorem \[ErrBounds\] is essentially proportional to $(6B/\pi\varepsilon \beta)^{1/\beta}$, so for fast computations one would like to choose $B$ and $\beta$ that minimize this quantity, subject to $|\phi(u)|\leq B|u/2\pi|^{-\beta}$ for all $u$. In the general case, solving this problem comes down to analyzing the characteristic function. For the two special cases of normally and multivariate $t$-distributed risk factors, we have the following bounds. The proof is found in the Appendix. \[CfBounds\] Let $\lambda_1,\ldots,\lambda_p$ be the eigenvalues of $\Sigma \Gamma$, and let $I$ denote any subset of $\{1,\ldots,p\}$. Let $\beta_I := |I|/2$ and $B_I := (2\pi)^{-\beta_I}\prod_{j\in I}|\lambda_j|^{-1/2}$. If $\phi$ is given either by Proposition \[Cf\] or Proposition \[tCf\], then $|\phi(u)| \leq B_I |u/2\pi|^{-\beta_I}$. A tractable strategy for choosing $B$ and $\beta$ is to solve $$\label{Iopt} \min_I \left(\frac{6B_I}{\pi\varepsilon\beta_I}\right)^{1/\beta_I},$$ where $\beta_I$ and $B_I$ are defined in Proposition \[CfBounds\], and the minimum is taken over all the subsets of $\{1,\ldots,p\}$. \[prop:Iopt\] Let $\{j_1,\ldots,j_p\}$ be an ordering of $\{1,\ldots,p\}$, such that $|\lambda_{j_1}|\geq |\lambda_{j_2}|\geq \cdots \geq |\lambda_{j_p}|$. Denote $I_k := \{j_1,\ldots,j_k\}$ for $k = 1,\ldots,p$, and let $I$ denote a solution to the optimization problem (\[Iopt\]). Then $I = I_k$ for some $k \in \{1,\ldots,p\}$. \[rem:Bopt\] By Proposition \[prop:Iopt\], the optimal subset $I$ (and thus $\beta_{I}$ and $B_{I}$) can be found by computing $(6B_{I_k}/\pi\varepsilon\beta_{I_k})^{1/\beta_{I_k}}$ for $k = 1,\ldots,p$ and choosing the minimum. Note that this needs to be done only once, even in the case of multivariate $t$-distributed risk factors — although $\phi$ depends on $x$, the optimal parameters $B_I$ and $\beta_I$ do not. A large scale numerical experiment ================================== In this section the value-at-risk for a large, simulated options portfolio is calculated with two different methods: (i) the Fourier method from the previous section, and (ii) the Monte Carlo method. The results are then compared with respect to speed and accuracy. Simulating a large options portfolio ------------------------------------ We simulate a portfolio that models a real portfolio held by a market maker in vanilla options: it contains $10^4$ vanilla options written on 30 different underlyings. Each option is long or short with probability $\frac{1}{2}$, and a call or a put option with probability $\frac{1}{2}$. The maturity of each option is drawn from a uniform distribution on $[10/252,1]$ (10 days-1 year), and the moneyness for each option is drawn from a truncated normal distribution with mean 1 and standard deviation 0.1, bounded below by 0.5 and above by 1.5 — the options are between 50% out-of-the-money and 50% in-the-money. The returns from the underlyings are drawn (i) from a normal distribution or (ii) from a multivariate $t$-distribution with $\nu = 5$ degrees of freedom. In both cases, the covariance matrix is $\Delta t\Sigma$, where $\Sigma$ is a $30\times 30$ diagonal matrix with each diagonal element drawn from a uniform distribution on $[0.1^2,0.3^2]$ and $\Delta t := 10/252$ (so we are looking at the 10 day value-at-risk). The nominal value for each option is drawn from a uniform distribution on $[10^4,10^5]$. Having simulated the portfolio, we compute the deltas and gammas for each option. Finally, the deltas and gammas are summed up for each underlying, to give $\delta$ and $\Gamma$. Performance of the Fourier method --------------------------------- Given $\Sigma$, $\delta$ and $\Gamma$ from the simulation, we compute $\lambda_1,\ldots,\lambda_{30}$ and $b_1,\ldots,b_{30}$ in Theorems \[Cf\] and \[tCf\]. As seen in the proof of Proposition \[Cf\], this is done by computing the Cholesky factorization of $\Sigma$, and diagonalizing the matrix $\Sigma \Gamma$. This gives us the complete closed-form expression for the characteristic function and the moment generating function. Let $\varepsilon > 0$ be given, and compute the necessary parameters, $A,\alpha, B$ and $\beta$, as described in Remarks \[rem:Aopt\] and \[rem:Bopt\]. The level-$\gamma$ value-at-risk is then computed as described in Remark \[rem:computeVaR\]. The algorithm gives a number $x^*$, which is close to VaR$_\gamma = P^{-1}(\gamma)$ in the sense that $|P(x^*) - \gamma|\leq \varepsilon$. The computational effort is proportional to the integer $N$, so we report this together with the total computational time[^4] for various choices of $\varepsilon$ in Table 2 (normal risk factors) and Table 3 (multivariate $t$-distributed risk factors). Performance of the Monte Carlo method ------------------------------------- To compute an estimate $x^*$ of VaR$_\gamma = P^{-1}(\gamma)$ by the Monte Carlo method, simulate $M$ samples from the $\mathcal{N}(0,\Sigma)$-distribution (or the multivariate $t$-distribution), compute the corresponding values of $\Delta V$ and order these to get $\Delta V_ {(1)}\leq \cdots \leq \Delta V_{(M)}$. Then $x^* := \Delta V_{(\lceil M\gamma \rceil)}$, where $\lceil M\gamma \rceil$ is the smallest integer greater than or equal to $M\gamma$. The computed $x^*$ corresponds to some confidence level $\gamma^* := P(x^*)$, hopefully not too far from $\gamma$. To study how large sample size $M$ we need to reach a desired level of accuracy we look at the number $\varepsilon$ such that $\mathbb{P}(|\gamma - \gamma^*|\leq \varepsilon) = 1-\rho$ for some small positive number $\rho$. For a moderate sample size $M$, the corresponding $\varepsilon$ can be estimated experimentally in the following way: run the Monte Carlo $R$ times, order the resulting estimates $x^*_{(1)}\leq\cdots \leq x^*_{(R)}$ and compute the corresponding confidence levels $\gamma_{(1)}^*\leq\cdots\leq\gamma^*_{(R)}$ by evaluating $\gamma_{(k)}^*:= P(x^*_{(k)})$, for $k = 1,\ldots,R$, using the Fourier method with an extremely low error. Then take $$\varepsilon:= \frac{1}{2}\left(\gamma^*_{(\lceil(1-\rho/2)R\rceil)} - \gamma^*_{(\lfloor\rho R/2\rfloor)}\right),$$ where $\lfloor\rho R/2\rfloor$ denotes the largest integer smaller than or equal to $\rho R/2$. For a large sample size $M$, we can compute $\varepsilon$ from the approximate distribution of $\gamma^*$. Since $x^*$ is the $\lceil M\gamma \rceil$th order statistic, it is asymptotically (as $M\rightarrow \infty$) normally distributed[^5] with mean VaR$_\gamma$ and variance $\gamma(1-\gamma)/(MP'($VaR$_\gamma)^2)$. If $P$ is approximately linear in a neighborhood of VaR$_\gamma$, then $\gamma^* = P(x^*)$ is approximately normally distributed with mean $\gamma$ and variance $\gamma(1-\gamma)/M$ by Gauss’ approximation formulas. So, $\varepsilon \approx \Phi^{-1}(1-\rho/2)\sqrt{\gamma(1-\gamma)/M}$, where $\Phi(\cdot)$ is the cumulative distribution function of the standard normal distribution. Figure \[fig:MC\] show $\varepsilon$ estimated experimentally for $M = 10^3,10^4,10^5$, with $R = 500$ and $\rho = 0.01$. It also shows $\varepsilon$ computed theoretically from the approximate distribution of $\gamma^*$, for $M = 10^3,10^4,\ldots,10^9$ — the two methods for computing $\varepsilon$ agree nicely for $M \geq 10^3$. If $\varepsilon$ is small enough, we can thus use the theoretical approximate distribution of $\gamma^*$ to compute the sample size $M$ needed to make $\mathbb{P}(|\gamma-\gamma^*|\leq \varepsilon) \approx 1- \rho$ for a given $\varepsilon$ — see Table 3 for $\rho = 0.01$ and various choices of $\varepsilon$. The total computing time for $M = 6.5\cdot 10^4$ is 1.7 s for normally distributed risk factors, and 2.4 s for multivariate $t$-distributed risk factors. It is moderately more time consuming to simulate from the multivariate $t$-distribution than from the normal distribution, see [@GlassermanVaR]. ![The graph shows $\varepsilon$ as a function of the Monte Carlo sample size $M$, where $\varepsilon$ is computed experimentally (stars) and from the approximative theoretical distribution of $\gamma^*$ (circles).[]{data-label="fig:MC"}](Fig1.eps){width="10cm"} Comparison of the Fourier method and the Monte Carlo method ----------------------------------------------------------- Comparing the results from the Fourier method and the Monte Carlo method, we see that the Fourier method is superior both with respect to speed and accuracy. For $\varepsilon = 10^{-3}$ and normally distributed risk factors, the Fourier method takes 0.12 seconds to compute $x^*$ such that $|\gamma - P(x^*)| \leq \varepsilon$, while the Monte Carlo method takes 1.76 s to compute $x^*$ such that $\mathbb{P}(|\gamma - P(x^*)|\leq \varepsilon)\geq 0.99$. As $\varepsilon \rightarrow 0$, the Monte Carlo method becomes impractical: a 10 times smaller $\varepsilon$ gives 100 times longer computing time. The Fourier method however scales nicely: for $\varepsilon = 10^{-6}$ the whole computation still takes only about 0.3 s. The picture is similar for multivariate $t$-distributed risk factors: the Fourier method is significantly faster than the Monte Carlo method, especially for very small $\varepsilon$. Conclusion ========== We have given a complete description of how to compute the value-at-risk of a delta-gamma approximated portfolio by numerical integration of the characteristic function, in the case of normally or multivariate $t$-distributed risk factors. In particular, we showed how to calculate the necessary parameters in the numerical integration scheme as a function of the data (the distribution of the risk factors, and $\delta$ and $\Gamma$), in order to satisfy a given error tolerance. Thus we avoid ad hoc choices of parameters, and allow for using the method in a fully automated risk management system. Our numerical experiments illustrate that the method is significantly faster than the Monte Carlo method — we conclude that the Fourier method is a highly competitive alternative to the Monte Carlo method for computing the value-at-risk of delta-gamma approximated portfolios. Appendix {#appendix .unnumbered} ======== Proof of Proposition \[Cf\]. Let $L$ be the Cholesky factor of $\Sigma$, so $L L' = \Sigma $ and $L^{-1} \Delta S$ is a vector of independent, standard normals. Since $\Sigma$ is a symmetric matrix, $L'\Gamma L$ has real eigenvalues, and these eigenvalues are the same as those of $LL'\Gamma = \Sigma \Gamma$, namely $\lambda_1,\ldots,\lambda_p$. Moreover, $L'\Gamma L = O\Lambda O'$, where $O$ is an orthogonal matrix whose columns are eigenvectors of $L' \Gamma L$. Since $O'L'\Gamma L O = \Lambda$ and $(LO)(LO)' = L L' =\Sigma$, setting $C = LO$ produces the required matrix. Introduce the identity matrix $I = LOO'L^{-1} = (L^{-1})'OO'L'$ in the expression for $\Delta V$: $$\begin{aligned} \Delta V &=& \delta'\Delta S + \frac{1}{2}\Delta S'\Gamma \Delta S\\ &=&\delta'LOO'L^{-1}\Delta S + \frac{1}{2}\Delta S'(L^{-1})'OO'L'\Gamma LOO'L^{-1}\Delta S\\ &=&(O'L'\delta)'(O'L^{-1}\Delta S) + \frac{1}{2}(O'L^{-1}\Delta S)'(O'L'\Gamma LO)(O'L^{-1}\Delta S).\end{aligned}$$ Write $\tilde{\Delta S} =(\tilde{\Delta S}_1,\ldots,\tilde{\Delta S}_p)' : = O'L^{-1}\Delta S$ and recall that $b = C'\delta = O'L'\delta$. Then $$\begin{aligned} \Delta V &=& b'\tilde{\Delta S} + \frac{1}{2}\tilde{\Delta S}'\Lambda \tilde{\Delta S} = \sum_{j = 1}^pb_j\tilde{\Delta S}_j + \frac{1}{2}\sum_{j = 1}^p\lambda_j\tilde{\Delta S}_j^2,\end{aligned}$$ where $\tilde{\Delta S}_1,\ldots,\tilde{\Delta S}_p$ are independent, $\mathcal{N}(0,1)$-distributed random variables. Let $J := \{j\in \{1,\ldots,p\};\ \lambda_j\neq 0\}$ and write $$\begin{aligned} \Delta V &=& \sum_{j\not\in J}b_j\tilde{\Delta S}_j + \sum_{j\in J}\left( b_j\tilde{\Delta S}_j + \frac{1}{2}\lambda_{j}\tilde{\Delta S}_j^2\right)\\ &=& \sum_{j\not\in J}b_j\tilde{\Delta S}_j-\sum_{j\in J}\frac{b_j^2}{2\lambda_{j}} + \sum_{j\in J}\frac{1}{2}\lambda_{j}\left( \tilde{\Delta S}_j + \frac{b_j}{\lambda_{j}}\right)^2,\end{aligned}$$ where the second equality arises from completing the squares. Define $Q_0 := \sum_{j\not\in J}b_j\tilde{\Delta S}_j - 1/2\sum_{j\in J}b_j^2/\lambda_{j}$, and $Q_j := (\tilde{\Delta S}_j + b_j/\lambda_{j})^2$, for $j\in J$. Then $\Delta V = Q_0 + 1/2\sum_{j\in J}\lambda_j Q_j$ is a linear combination of independent random variables — $Q_0$ and $Q_j$, $j\in J$, are independent since $\tilde{\Delta S}_1,\ldots,\tilde{\Delta S}_p$ are independent, so the characteristic function of $\Delta V$ is given by $$\phi(u) = \mathbb{E}[e^{iu\Delta V}] = \mathbb{E}[e^{iuQ_0}]\prod_{j\in J}\mathbb{E}[e^{i(\lambda_j/2)uQ_j}].$$ The distribution of $Q_0$ is normal with mean $-1/2\sum_{j\in J}b_j^2/\lambda_{j}$ and variance $\sum_{j\not\in J}b_j^2$, and $Q_j$ has a non-central $\chi^2$-distribution[^6] with 1 degree of freedom and non-centrality parameter $b_j^2/\lambda_j^2$, for $j\in J$. If follows that $$\begin{aligned} \phi(u) &=& \exp\left(-i\frac{u}{2}\sum_{j\in J}\frac{b_j^2}{\lambda_{j}} - \frac{u^2}{2}\sum_{j \not \in J} b_j^2\right) \prod_{j\in J} \exp\left(\frac{b_j^2}{\lambda_{j}^2}\frac{i\frac{\lambda_j}{2}u}{1-i\lambda_ju}\right)\frac{1}{\sqrt{1-i\lambda_j u}}\\ &=& e^{-\frac{1}{2}\sum_{j = 1}^pb_j^2\frac{u^2}{1 - i\lambda_j u}} \prod_{j\in J}\frac{1}{\sqrt{1-i\lambda_j u}}.\end{aligned}$$ $\Box$ Proof of Proposition \[prop:Aopt\]. Assume that $\tilde{\psi}(u)<\infty$ and consider for a moment $\alpha > 1$ as given. Then the constraint will be satisfied if $A$ is taken large enough. For the smallest possible $A$, the graph of the function $f(y) = Ay^{-\alpha}$ will not intersect the graph of $h(y) = \tilde{\psi}(u) e^{-uy}$, but be tangent to it at some point $y^*$. This is expressed in the following system, $$\left\{ \begin{array}{rcl} f(y^*) &=& h(y^*),\\ f'(y^*) &=& h'(y^*),\\ f''(y^*) &\geq& h''(y^*), \end{array}\right.$$ which is solved by $y^* = \alpha/u$ and $A(\alpha,u) = \tilde{\psi}(u)e^{-\alpha}(\alpha/u)^{\alpha}$. Plugging the expression for $A(\alpha,u)$ into the minimization problem (\[eq:Asubopt\]) reduces it to $$\min_{\alpha > 1}\frac{\alpha}{u}\left(\frac{3\tilde{\psi}(u)}{\varepsilon}\right)^{1/\alpha}.$$ This target function has the unique minimum $\alpha(u) := \log(3\tilde{\psi}(u)/\varepsilon)$. The result follows, since $(3A(\alpha(u),u)/\varepsilon)^{1/\alpha(u)} = \frac{1}{u}\log (3 \tilde{\psi}(u)/ \varepsilon)$. $\Box$ Proof of Proposition \[CfBounds\]. If $\phi$ is given by Proposition \[Cf\], then $\phi(u) = \phi_1(u)\phi_2(u)$, with $\phi_1(u):=\exp\left(-\frac{1}{2}\sum_{j = 1}^pb_j^2\frac{u^2}{1 - i\lambda_j u}\right)$ and $\phi_2(u):=\prod_{j = 1}^p (1-i \lambda_j u)^{-1/2}$. If $\phi$ is given by Proposition \[tCf\], then $\phi(u) = \phi_3(u)\phi_2(u)$ with $\phi_3(u) := (1 - 2\xi(u))^{-\nu/2}$. Since $u^2/(1-i\lambda_j u) = \frac{u^2}{1+\lambda_j^2u^2} + i\frac{u^3\lambda_j}{1+\lambda_j^2u^2}$, it follows that $$|\phi_1(u)| =e^{-\frac{1}{2}\sum_{j=1}^p b_j^2\frac{u^2}{1+u^2\lambda_j^2}} \leq 1.$$ It also follows that $$|1 - 2\xi(u)|= \left|1 + \frac{1}{\nu}\sum_{j = 1}^pb_j^2\frac{u^2}{1 +\lambda_j^2 u^2} + i\textrm{Im}(-2\xi(u))\right|\geq 1,$$ so $|\phi_3(u)| = |1 - 2\xi(u)|^{-\nu / 2} \leq 1$. To bound $|\phi_2(u)| \geq \lambda_ju|$, first note that $|1-iu\lambda_j| = \sqrt{1 + \lambda_j^2u^2}\geq \max\{1,|\lambda_ju|\}$, so $|1-i\lambda_j u|^{-1/2}\leq \min\{1,|\lambda_ju|^{-1/2}\}$. This implies that $$|\phi_2(u)| = \prod_{j = 1}^p |1-i\lambda_j u|^{-1/2} \leq \prod_{j \in I}|\lambda_j|^{-1/2}|u|^{-1/2} = |u|^{-|I|/2}\prod_{j \in I}|\lambda_j|^{-1/2}$$ for any subset $I\subset \{1,\ldots,p\}$. It follows that $|\phi(u)|\leq B|u/2\pi|^{-\beta}$ with $\beta = |I|/2$ and $B = (2\pi)^{-\beta}\prod_{j\in I}|\lambda_j|^{-1/2}$ both for $\phi = \phi_1\phi_2$ and $\phi = \phi_3 \phi_2$. $\Box$ Proof of Proposition \[prop:Iopt\]. Assume the contrary to the Proposition: $I \neq I_k$ for $k = 1,\ldots,p$. Then there exists $m,m' \in \{1,\ldots,p\}$, $m< m'$, such that $j_m\not \in I$ and $j_{m'}\in I$. Let $I' := (I\setminus\{j_{m'}\})\cup\{j_m\}$. Then $\beta_I = \beta_{I'}$ and, unless $|\lambda_{j_m}| = |\lambda_{j_{m'}}|$, $B_{I'}<B_I$ — this contradicts the optimality of $I$. The degenerate case $|\lambda_{j_m}| =|\lambda_{j_{m'}}|$ only arises from the trivial ambiguity in ordering numbers of the same size. To rule it out, we adopt the following convention: if $s$ indices $j_{t+1},\ldots,j_{t+s}$ correspond to $|\lambda_{j_{t+1}}|=\cdots=|\lambda_{j_{t+s}}|$ and if $I$ contains $k<s$ of these indices, then it contains the $k$ first ones: $j_{t+1},\ldots,j_{t+k}$. $\Box$ [^1]: The distribution of quadratic forms of random variables is extensively studied by [@MathaiProvost]. [^2]: The Hurwitz zeta function is defined by $\zeta(z,a):= \sum_{k = 1}^\infty (k+a)^{-z}$. For computing it with desired accuracy, see [@HughettBounds Lemma 4]. [^3]: If $\psi$ is finite in a neighborhood of 0, then $\psi(u) = \phi(-iu)$, so this function is also known on closed form. [^4]: The computations were performed in the software [R]{} on a standard workstation. [^5]: This is true if $\Delta V$ has a continuous non-zero density at $P^{-1}(\gamma)$, see [@orderStat]. [^6]: The characteristic function of a $\chi^2$-distributed random variable $Z$ with $k$ degrees of freedom and non-centrality parameter $\alpha$ is given by $\mathbb{E}[e^{iuZ}]= e^{\alpha\frac{iu}{1-i2u}}(1-i2u)^{-k/2}$. | High | [
0.696148359486447,
30.5,
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Our View: Bet against Cruz in Republican primary at your own risk Midland Reporter-Telegram Published 4:22 am, Wednesday, March 25, 2015 Photo: Andrew Harnik Image 1of/1 Caption Close Image 1 of 1 Prior to his election to the Senate, Cruz's career was centered on practicing law at the highest level. A graduate of Harvard Law School and former clerk for Chief Justice William Rehnquist, Cruz led a Houston-based firm's Supreme Court practice, taught such litigation at the University of Texas and was charged with representing the state before the high court as its solicitor general. He also served in the George W. Bush administration, at both the Federal Trade Commission and as an associate deputy attorney general at the Justice Department. less Prior to his election to the Senate, Cruz's career was centered on practicing law at the highest level. A graduate of Harvard Law School and former clerk for Chief Justice William Rehnquist, Cruz led a ... more Photo: Andrew Harnik Our View: Bet against Cruz in Republican primary at your own risk 1 / 1 Back to Gallery So Ted Cruz is running for president. His speech at Liberty University in Virginia on Monday wasn’t an announcement as much as it served notice to other conservative candidates. In our view, the junior senator from Texas told it like it was, and if other Republicans were officially going to put their hats in the race they will be in for a fight for the party’s most conservative voters. We like Cruz and have since he was polling at 1 percent when he announced his run for senator just four years ago. We told our readers of this brash, candid, very articulate former solicitor general who challenged then Lt. Gov. David Dewhurst for the open Senate seat in 2012. He was armed with endorsements from conservative giants such as then Sen. Jim Demint, Sen. Rand Paul of Kentucky, Sen. Pat Toomey of Pennsylvania and Sen. Mike Lee of Utah. At the time, most people in Midland were like “Ted who?” That’s not the case any more. A significant number of Midlanders appreciate a Cruz candidacy. They appreciate that he went to Washington and backed up his strong talk with strong actions. They didn’t want someone to back down to the Washington machine and Obama administration, and Cruz cannot be accused of that. No way. Those voters will not mind that he’s not even halfway through his first term as a U.S. senator -- something they held against the current president during his candidacy in 2008. The nation is in a full-fledged fiscal and constitutional crisis, they will tell you. What Cruz’s announcement does politically is send a message to the competition, specifically former Arkansas Gov. Mike Huckabee, Dr. Ben Carson and former Sen. Rick Santorum, the other candidates likely to fight for the most conservative wing of the Republican Party. In our view, one of those will be in the real fight when Texas comes around in the primary process. There will be a conservative, a more “establishment” candidate, a current governor and Rand Paul representing the party’s growing libertarian voting bloc. If you like politics at its best, it will be the Super Bowl, March Madness, the Masters and Daytona 500 all wrapped up together with a 2016 bow on top. Is Cruz the man? We don’t know, and being consistent with Reporter-Telegram policy, we will not endorse now or later. But for those who believe Cruz can’t win the primary because his current poll numbers could be better, we say don’t doubt this man. Few politicians are better in person, better with the grassroots or better in the straw polls, and few on the Republican ticket can come close to match the enthusiasm of a voting bloc that he can. It doesn’t mean he can win one battleground state, do better with Hispanics or would be the best general election candidate in November 2016. But in primary politics, there are few better than Cruz. Texans know this well. | High | [
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There will be blast motions in the House today, Wednesday, March 13, on two pieces of legislation critical to the safety of Montana’s children and youth. A blast attempt is when a motion is made on the floor to take a bill that has been tabled in committee and put it on 2nd reading for the entire chamber to debate. The blasts today will be on the House floor. Two of the bills are carried by Rep. Ellie Boldman Hill. HB 527 generally revises cyber-bullying laws. It creates the offense of cyberbullying and is targeted at protecting minors. According to the bill, the offense of cyberbullying results when with the purpose to terrify, intimidate, threaten, harass, or torment a minor a person builds a fictitious profile or internet website; poses as a minor in an internet chat room, electronic mail message, instant message, or other electronic communication; posts or encourages others to post on the internet private, personal, or sexual information pertaining to a minor; signs a minor up for a pornographic internet website. Read the entire the bill here. The second bill seeks to eliminate license exemption for certain private adolescent treatment programs. The bill is in response to abuses at the Pinehaven Christian Children’s’ Ranch in western Montana. (See coverage on the abuses and the legislation on CNN, Anderson Cooper, here.) Pinehaven is unaccredited and unlicensed. Former staff and students have reported that students were choked and dragged. During the hearing on HB 236, the Montana Family Foundation, a conservative lobbying organization, testified against the bill and the committee Republicans fell into line. The bill died on a party line vote. Both of these bills are critical to the safety of children and youths. Both were tabled by Republican majorities. Blast motions are coming. Do you want to see these bills blasted out of committee today? You can find your legislator contact information here. | High | [
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<?xml version="1.0" encoding="UTF-8"?> <!-- * (C) Copyright Uwe Schindler (Generics Policeman) and others. * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. --> <project xmlns:au="antlib:org.apache.ant.antunit"> <fileset id="main.classes" dir="${antunit.main.classes}"/> <target name="testFailOnViolation"> <au:expectfailure expectedMessage="Check for forbidden API calls failed, see log"> <forbiddenapis classpathref="path.all"> <fileset refid="main.classes"/> java.awt.Color @ Color is disallowed, thats not bad, because ANT has no colors... java.lang.String @ You are crazy that you disallow strings </forbiddenapis> </au:expectfailure> <au:assertLogContains level="error" text="java.lang.String [You are crazy that you disallow strings]"/> </target> <target name="testDoNotFailOnViolation"> <forbiddenapis classpathref="path.all" failOnViolation="false"> <fileset refid="main.classes"/> java.awt.Color @ Color is disallowed, thats not bad, because ANT has no colors... java.lang.String @ You are crazy that you disallow strings </forbiddenapis> <au:assertLogContains level="error" text="java.lang.String [You are crazy that you disallow strings]"/> </target> </project> | Low | [
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The human acoustic tensor tympani reflex. A case report. In a patient with unilateral lower motoneuron facial paralysis secondary to Bell's palsy, we evaluated the characteristics of what we believe to be an acoustically-evoked reflex contraction of the tensor tympani muscle. Ipsilateral stimulation of the involved ear yielded a pattern of impedance change different from the pattern characterizing normal stapedius muscle contraction. Threshold of the reflex was elevated, amplitude was large and variable, onset latency was greater, onset rise was more gradual, and offset decay was more rapid. Contralateral stimulation, with probe in the involved ear, failed to elicit the reflex contraction. Upon return of facial nerve function, the normal stapedius reflex contraction reappeared in response to both ipsilateral and contralateral stimulation. | Mid | [
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Q: Why is STATUS_OUT_OF_ORDER_API_CALL thrown when trying to send a payload? I am trying to send a bytes payload from an advertiser to a discoverer after the connection has successfully been established (STATUS_OK in onConnectionResult()), but I am getting a STATUS_OUT_OF_ORDER_API_CALL error (error 8009). How do I fix this? From the documentation page on status codes, I know that there is a method that I should be calling first, but I don't what method that is. I have seen the "How to resolve STATUS_OUT_OF_ORDER_API_CALL error?" on this issue. The accepted answer says that you could get the error if trying to connect to someone after disconnecting. This issue is when I first open the app and try to send a payload, and I am not getting the API_CONNECTION_FAILED_ALREADY_IN_USE or STATUS_ALREADY_ADVERTISING status code in onConnectionResult(). Also, that post was to do with receiving the error when trying to request the connection, whereas in my situation, both advertiser and discoverer have connected fine. if (isAdvertising) { Log.d(TAG, "send: advertising fine"); } connectionsClient .sendPayload(endpointId, payload) .addOnFailureListener(e -> Log.w(TAG, "(send payload) onFailure: " + failureMsg, e) ) .addOnSuccessListener(aVoid -> Log.w(TAG, "(send payload) onSuccess: " + successMsg)); The strange part is that from the the first payload I try to send works, but subsequent payloads don't get sent. Error message: 2019-04-03 19:14:13.535 31128-31128/com.example.adhocdisplay W/ConnectionsActivity: (send payload) onFailure: Failed to send calibration direction payload com.google.android.gms.common.api.ApiException: 8009: STATUS_OUT_OF_ORDER_API_CALL at com.google.android.gms.internal.nearby.zzby.setFailedResult(Unknown Source:4) at com.google.android.gms.internal.nearby.zzba.zzc(Unknown Source:18) at com.google.android.gms.internal.nearby.zzea.dispatchTransaction(Unknown Source:7) at com.google.android.gms.internal.nearby.zzb.onTransact(Unknown Source:22) at android.os.Binder.execTransact(Binder.java:731) A: Disclaimer: I work on Nearby This error shouldn't occur in normal use... It means that we've lost track of the strategy you're using. This could be because you called stopAllEndpoints or somehow disconnected from our service (note: not the same as disconnecting from the remote device). Or it could be a consequence of trying to mix and match strategies (eg. CLUSTER, STAR, POINT_TO_POINT). The good news is that this particular error condition was removed in a recent submission and will be rolled out to devices somewhat soon. But I'm still a bit stumped as to how you ran into it. | Mid | [
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Jovovich headlining Survivor movie; Jeff Probst nowhere in sight James McTiegue (“V for Vendetta”) has rounded up a pretty nifty cast for his next venture behind the lens, a Millennium films thriller called “Survivor”. According to Deadline, former 007 Pierce Bronsnan, Milla Jovovich, Emma Thompson and Angela Bassett are onboard the film which tells of an American embassy employ, charged with the task of stopping terrorists, who finds herself a target. She is ultimately framed for crimes she didn’t commit, and is forced to go on the run. Meanwhile, terrorists plan an attack on New York’s Times Square on New Year’s Eve. The information and views set out in this website are of the author's and do not necessarily reflect the opinion of the editor or Moviehole as a whole. No personal information is stored in this website. | Low | [
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Tonight the first of many tests for Fairfield But, for a second, look deeper than this game. Consider that Cooley and company, despite what in many respects was an admirable loss against Memphis last Saturday evening, are clear-cut favorites in this game, a position Fairfield does not normally find itself in too frequently. A win is just a job well done; a loss could be catastrophic. Fairfield flies to Puerto Rico four hours after tonight's game ends, and there waiting for them will be three opponents from powerhouse conferences. Even the most optimistic fan will tell you that 1-2 is probably a best-case scenario. The Stags then come back to campus for two of their more challenging out-of-conference games: a Thanksgiving weekend game at Alumni Hall against American, last season's Patriot League champions, and then Holy Cross, a talented team that downed Sacred Heart in its season-opener and has beaten Cooley in each of his first two seasons. Translation: If the Stags lose tonight, they could be staring at 0-6 going into MAAC play. Another slow start. The same script all over again. Granted, in the Metro Atlantic conference, the only chance that Fairfield has to clinch a berth in the NCAA tournament is to run the table in Albany come March. Still, a second preseason ranking means higher expectations. The best way for Fairfield to match those expectations is to win the games the are supposed to win. No more St. Francis or Yale games, like a year ago. Tonight is one of those games. ___________________________________________________________ Siena looked every bit the team they are projected to be last night in their home-opener against Boise State. Still, we won't see what this team is really made of until those out-of-conference stunners: Pittsburgh, Kansas, and (in just nine days) Tennessee. Niagara's Tyrone Lewis stepped right in to the go-to scoring role in the team's 79-62 win over Towson. It will be interesting to see the Purple Eagles offense evolve sans Charron Fisher. Up next: No. 23 Villanova. St. Joseph's (Pa.) defeated Rider, 69-57, in the Broncs' season-opener. Not sure what to make of this one, but I can't say that it is a bad outing for a team that: 1) just lost its best player to the NBA, 2) was playing a great mid-major and a regional rival, and 3) had its best freshman (Jermaine Jackson) and point guard (Justin Robinson) hurt. All things considered, not bad at all. good morning dudes. I'm really into shoes and I have been searching for that singular brand. The prices seeking the boots were all over 330 dollars on every site. But definitively I set this location selling them for half price. I really love those [url=http://www.shoesempire.com]prada sneakers[/url]. I will probably buy these. what can you say about it? good evening ppl. I'm actually into shoes and I have been digging as far as something that exact brand. 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About Me Keith Connors is a Fairfield Mirror Sports Writer/Columinst and Online Editor. Tom Cleary and I covered the 2006-07 Fairfield Stags men's basketball team as beat writers. Also, I covered the 2007 Fairfield men's lacrosse team. New York Sports fan in my spare time, I'll do plenty of updates on the hometown crowd. Even those Rangers... | Low | [
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Q: React multipages, component data passing I'm doing a react app and id I'd like to know how to think multipages websites. Actually i'im I'm doing a course searcher,i searcher; I use routie to render the different components that renders render the page. The problem is that they arent aren't related by hierarchy, so the ajax data isn't accessible to the component that renders the result.I've I've tried vainly to use a js var data but doesnt var data but that doesn't work too either.Ive read https://facebook.github.io/react/tips/communicate-between-components.html but i don't see what to do with own event system. If someone could illustrate the last paragraph of this doc it is great for all the people that are in this case. var data = {}; var CourseSearcher = React.createClass({ getInitialState: function(){ return { return { places: '', branch: 0, dayOfMonth: '', timeStart: '', timeEnd: '', data: []}; },; }, handlePlacesChange: function(e){ this.setState({places: e.target.value}); }, handleBranchChange: function(e){ this.setState({branch: e.target.value}); }, handleDayOfMonthChange: function(e){ this.setState({dayOfMonth: e.target.value}); }, handleTimeStartChange: function(e){ this.setState({timeStart: e.target.value}); }, handleTimeEndChange: function(e){ this.setState({timeEnd: e.target.value}); }, handleSubmit: function(e){ // stop the default browser action e.preventDefault(); // Do an ajax post $.ajax({ url:'php/results.php', dataType: 'json', type: 'GET', data: { data: {places: this.state.places, branch:this.state.branch, dayOfMonth:this.state.dayOfMonth, timeStart:this.state.timeStart, timeEnd:this.state.timeEnd}, }, success: function(data){ this.setState({data: data}); data = this.state.data; routie('results'); }.bind(this), error: function (xhr,status,err){ console.error('php/results.php',status,err.toString()); }.bind(this) }); }, render: function(){ return( <div> <form method="get" onSubmit={this.handleSubmit}> <label>Où?</label> <input type="text" placeholder="Lieux" value={this.state.places} onChange={this.handlePlacesChange} /> <label>Quoi?</label> <select value={this.state.branch} onChange={this.handleBranchChange}> <option>Matière</option> <option>Français</option> <option>Anglais</option> </select> <label>Quand ?</label> <input type="date" value={this.state.dayOfMonth} onChange={this.handleDayOfMonthChange} /> <input type="time" value={this.state.timeStart} onChange={this.handleTimeStartChange} /> - <input type="time" value={this.state.timeEnd} onChange={this.handleTimeEndChange}/> <button type="submit">Go!</button> </form> </div> ); } }); console.log(data); var ResultList = React.createClass({ render: function() { console.log(data); return( <h1>Hello</h1>); } ); } }); var ResultBox = React.createClass({ render: function() { return ( <div> <h4>{}</h4> </div> ); } }); routie({ '':function() { React.render(<CourseSearcher />, document.getElementById('content')); }, 'results': function() { React.render( React.render(<ResultList results={data} />, document.getElementById('content')); } }); Done well with react router ;) A: I've done it with react router where components are related to some dedicated urls | Low | [
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This invention is directed to a door latch having an auxiliary bolt which activates the latch bolt, and the use of a latch to confine small children in the home. | Low | [
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1. Introduction {#sec1} =============== Neurodegeneration with brain iron accumulation (NBIA) is a collective term to indicate a group of neurodegenerative diseases characterized by abnormal accumulation of iron in the basal ganglia (most often in the*globus pallidus* and/or*substantia nigra*) and progressive extrapyramidal clinical manifestations \[[@B1]\]. The most common form of NBIA seems to be pantothenate-kinase-associated neurodegeneration (PKAN), accounting for 35--50% of NBIA cases \[[@B2]\]. The worldwide prevalence of PKAN has been estimated at a ratio of 1 : 1.000.000 \[[@B3]\], with no race or gender related variations \[[@B4]\]. PKAN can be classified either as classic (typical) PKAN or as late-onset (atypical) PKAN \[[@B3], [@B5]\]. The typical form of the disease, with onset in the first decade of life, is characterized by rapidly progressing gait impairment, focal dystonia, pyramidal dysfunction, pigmentary retinopathy, and cognitive impairment and with loss of ambulation occurring within 10--15 years from the onset. The atypical form, with onset in the second or third decade, is characterized by psychiatric symptoms and focal dystonia (with or without parkinsonism or chorea, cognitive impairment, and late gait dysfunction), as well as by a slower progression and eventually by loss of ambulation occurring from 15 to 40 years after the onset \[[@B5]\]. Both forms of PKAN share a sign in brain MRIs: the "eye-of-the-tiger" sign, a T2-weighted hypointense signal in the*globus pallidus* with a central region of hyperintensity \[[@B1]\]. Although 15% of cases are sporadic \[[@B4]\], PKAN is an autosomal recessive disorder caused by mutations in the PANK2 gene located in chromosome 20p13 \[[@B3]\]. As well as PKAN, other conditions are presently considered as part of the NBIA group of disorders: PLA2G6-associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, FAHN, MPAN, BPAN, Kufor-Rakeb, and other more rare disorders with an identified genetic background \[[@B1]\]. Instead, individuals with clinical, radiographic, and sometimes pathologic evidence of NBIA, but without a mutation of one of the nine known NBIA-associated genes, should be classified as idiopathic NBIA \[[@B1]\]. Idiopathic NBIA is of unknown origin, although it is suspected to be genetic. In many families, the person diagnosed with NBIA is the first and only affected individual. The symptoms are more varied because there are probably several different causes for the neurodegeneration in the individuals of this group. As with other forms of NBIA, the idiopathic form features early- and late-onset types. As previously said, there is a specific pattern in brain MRIs, called the "eye-of-the-tiger" sign which, in the past, was considered to be virtually pathognomonic for PKAN \[[@B6]\]. This sign used to be considered as having a one-to-one correlation with the presence of a positive PANK2 gene mutation; however, more recently, several PANK2 negative "eye-of-the-tiger" cases have also been reported \[[@B5], [@B7], [@B8]\]. Most of the PANK2 negative "eye-of-the-tiger" sign cases were in fact late-onset or atypical ones \[[@B5], [@B7]\]. Although psychiatric symptoms (e.g., cognitive deficit, personality changes with impulsivity and violent outbursts, depression, anxiety, emotional lability, and obsessive compulsive disorder) are common in the atypical form \[[@B2], [@B5]\], psychosis has rarely been reported as a major symptom of PKAN \[[@B4], [@B9]\]. Here, we present an interesting case of "undiagnosed" NBIA. This case was genetically PANK2 (and PLA2G6) negative, but it showed the "eye-of-the-tiger" sign in the MRI and the clinical features of an atypical form of PKAN. The patient also showed psychotic symptoms which improved after treatment with antipsychotic and anticonvulsant/mood stabilizer medications. 2. Case Presentation {#sec2} ==================== Our patient is a Caucasian 48-year-old woman, who was voluntarily admitted to the Psychiatric Diagnosis and Care Service (inpatients unit), in a condition of manic state and pathological behaviour. The patient had no family history of psychiatric disorders. Her psychophysical development was normal; after compulsory schooling, she carried on to obtain a high school diploma. By the age of 18, she had been diagnosed for a Schizoaffective disorder and treated in a community mental health outpatients service. In the following years, she was admitted several times in psychiatric inpatients unit. For many years, she was treated with first generation antipsychotics (in particular haloperidol and chlorpromazine). During her youth, the patient presented a periodic substance abuse (heroin, cannabis, and alcohol). She was indeed also treated with methadone antiaddictive therapy. Moreover, during her youth, the patient was reported for an oculogyration of uncertain origin (probably antipsychotics-related), as well as for cervical dystonia and dystonia in flexion of the left*hallucis*, which appeared at the age of 35 after therapy with high doses of first generation antipsychotics (haloperidol and chlorpromazine). These conditions were treated with botulinum toxin first and by a movement disorder unit for the followup. At the age of 42, she was diagnosed with a brain and cervical rachis MRI showing wide-spread white matter hyperintensity in both cerebral hemispheres. Two years later, a new brain and*sella turcica* MRI showed a focal area of hypointensity in the central area of the anterior pituitary and a bilateral signal distortion on the*globus pallidus*, which presented hyperintensity in the central area and high hypointensity on the edge, with the typical "eye-of-the-tiger" sign and concomitant bilateral hypointensity of the*substantia nigra*. Moreover, a widely extended mild cortico-subcortical atrophy was also detected. Because of the evidence shown by the brain MRI, NBIA was suspected, hence the suggestion for a genetic test. The latter (search for gene mutation in PANK2 and PLA2G6) resulted negative, also ruling out possible duplications and/or deletions of whole exon in heterozygosity. Before the admission to our acute inpatients unit, the patient was living with a friend who shared an apartment with her; she did not work and she received a disability subsidy. Earlier, the patient, who after her mother passed away lived for many years with her aunt, was living alone. As reported by her aunt, her cognitive level and ability in daily living activities were not significantly impaired before being admitted to our unit. In the week prior to the admission to our acute inpatients unit, the patient presented with insomnia, irritability, logorrhoea, increased energy, and mental confusion. In the months before hospitalization, the patient had irregularly taken the psychopharmacological therapy (risperidone 6 mg/qd and delorazepam 4 mg/qd). At the moment of admission, she was alert, oriented in time and space. Her mood was euphoric, with incoherent and pressured speech. She also showed auditory hallucinations and delusions, loosening of associations, tangential thinking, and derailment of thought. On presentation, the neurological examination revealed a moderate dystonia in flexion of the left*hallucis*, and a mild tremor was present on the upper extremities; reflexes were conserved and she was able to ambulate independently. Verbal and motor stereotypies were also detected as well as bizarre gestures and behaviours, short-term memory disturbances, and concentration deficiencies. Ophthalmologic examination showed no alterations. The ECG resulted normal. Haematobiochemical exams resulted within the norm (including complete blood count, liver enzymes, renal function, glycemia, electrolytes, fat levels, ferritin, ceruloplasmin, oestrogens, progesterone, thyroid hormones, EMA IgA, and anti-tTG IgA) with the exception of monocytes (10.1%), ammonium (16 *μ*g/dL), total proteins (6.0 *μ*g/dL), prolactin (118.0 ng/mL), and a high anti-HCV antibody titer. No traces of psychotropic drugs were found in the urine samples. A risperidone 6 mg/qd and diazepam 10 mg/qd therapy was prescribed, which was later integrated with chlorpromazine 150 mg/qd, valproic acid 1000 mg/qd, and orphenadrine 100 mg/qd. After ten days, the patient showed signs of visible improvement. Her mood resulted fairly stable and her speech was fluid, less accelerated, and verbose. There were no signs of oddities, misperceptions, and alterations in the form and content of her thought. There was an overall motor improvement with a visible progressive reduction of dystonia and motor stereotypies. After about three weeks of hospitalization, the patient was discharged and returned to the care of the mental health outpatients service. During her hospitalization, the patient underwent a new brain MRI, which confirmed the signal alteration in both*globi pallidi* showing in the T2 sequences hyperintensity in the central portion and net hypointensity in the periphery, with the typical "eye-of-the-tiger" aspect. Moreover, in the same sequences, hypointensity was detected bilaterally in the*substantia nigra*. The aforementioned reports were radiologically compatible with NBIA. After the discharge, the patient went back to live with a friend and, presently, she is going on with the prescribed therapy, without showing new psychotic symptoms or showing mood dyscontrol and without reported movement disturbances. No new hospitalizations were needed at present day. 3. Discussion {#sec3} ============= Our interpretation of the patient\'s condition is of a psychotic symptomatology within the context of an "undiagnosed" form of NBIA presenting the clinical characteristics of an atypical PKAN. The absence of currently identifiable genetic mutations in genes PANK2 and PLA2G6 allowed excluding PKAN and PLAN. The negative family case history ruled out the hypothesis of a neuroferritinopathy that is transmitted in an autosomal dominant manner. Clinical exams and neuroimaging techniques performed on the patient allowed excluding other forms of NBIA, such as FAHN and aceruloplasminemia (without, however, carrying out the genetic investigations for these conditions). The related manifestation, the presence of focal dystonias and of psychiatric disturbances, the slow progression of the pathology as deduced from the anamnesis, and the "eye-of-the-tiger" sign in the MRI---without balance-related problems, pyramidal dysfunction, pigmentary retinopathy, and severe cognitive deterioration---allowed us to determine a diagnosis of "undiagnosed" NBIA with atypical features. Certainly, a great limitation of our case report is that the patient has not been screened for all known NBIA genes. The main psychiatric symptoms found in the present case study are the typical ones of psychotic conditions such as disorganized speech, verbal and motor stereotypies and affectation, behavioural oddities, auditory hallucinations, and delusions with alterations in the cognitive sphere (disorientation and short-term memory delay) and in the emotional sphere (euphoria and logorrhoea). It has been widely proved that basal ganglia are involved in the outset of the psychiatric manifestations of schizophrenia. In consideration of the fact that from a pathogenetic standpoint NBIA is characterized by an abnormal accumulation of iron at cerebral level, with a greater prevalence in the*globus pallidus* and in the*substantia nigra*, it can be inferred that the psychotic symptoms, mood disorders, cognitive deficits, and motor alterations are probably caused by the lesions in this area \[[@B9]\]. However, another limitation of this report is that the diagnostic procedure did not include a MRI-spectroscopy, looking for the presence of iron in the hypointense pallidal regions. In this case study, a combination of typical and atypical antipsychotics allowed resolving the productive psychotic symptomatology with partial improvement in the cognitive sphere. By introducing an anticonvulsant/mood stabilizing agent, the alterations in the emotional sphere were also improved. Also neurological movement disorders, such as focal dystonia, upper extremities\' tremor, and motor stereotypies, improved but the introduction of an anticholinergic/spasmolytic drug was necessary. Consent ======= The patient agreed on the publication of the present information. Conflict of Interests ===================== The authors declare that there is no conflict of interests regarding the publication of this paper. [^1]: Academic Editor: Volker Arolt | Mid | [
0.617283950617283,
31.25,
19.375
] |
An in vitro model of persistent epileptiform activity in neocortex. An in vitro model of persistent epileptiform activity was developed to study the mechanisms involved in epileptogenesis. Extracellular recordings were obtained from rat neocortical slices exposed to magnesium-free solution for 2 h. During exposure to magnesium-free solution spontaneous epileptiform activity consisting of interictal bursting and ictal-like discharges were observed. Interestingly, this activity persisted for hours after the slices were returned to magnesium-containing control solution. The N-methyl-D-aspartate (NMDA) receptor antagonist CPP prevented the development of the epileptiform activity, while the non-NMDA receptor antagonist CNQX abolished the epileptiform discharge that persisted after slices were returned to control solution. These findings suggest there are two distinct phases in the development of epileptic activity in this model, namely, induction (mediated by NMDA receptor activity) and maintenance (supported largely by non-NMDA receptor activity). The similarities and possible parallels between the mechanisms underlying this epileptogenesis and other forms of use-dependent modification of synaptic excitation, such as long-term potentiation, are discussed. This in vitro model of neocortical epileptogenesis may provide insights into the events underlying the development of clinical partial epilepsy. | High | [
0.6810344827586201,
29.625,
13.875
] |
Effects of BCR-ABL inhibitors on anti-tumor immunity. In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple in vitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on different immune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as important cellular components of anti-tumor immunity. | High | [
0.688741721854304,
32.5,
14.6875
] |
Journal of Applied Economic Sciences Volume, Issue, 2016 Tangible and intangible rewards in service industries: problems and prospects Tetiana GRYNKO Dnipropetrovsk National University named after Oles Honchar, Ukraine [email protected] Oleksandr KRUPSKYI Dnipropetrovsk National University named after Oles Honchar, Ukraine [email protected] Mykola KOSHEVYI Dnipropetrovsk National University named after Oles Honchar, Ukraine [email protected] Olexandr MAXIMCHUK Dnipropetrovsk National University named after Oles Honchar, Ukraine [email protected] Abstract Willingness and readiness of people to do their jobs are among the key factors of a successful enterprise. In XXI century intellectual human labour is gaining unprecedented value and is being developed actively. The demand for intellectual labour calls forth an increasing number of jobs and professions that require an extensive preparation, a large number of working places, high level of integration of joint human efforts, growth of social welfare. These trends are becoming ever more pervasive and are spreading widely in service industries, and that explains the rapid development of the latter when compared to the traditional areas of human activity. In its turn, it heightens the need for staff in service companies, supported by significant personnel turnover and a certain shortage of skilled professionals. These circumstances determine the need for developing a new concept of fostering staff motivation at the enterprises in the sphere of services. In order to reach the stated purpose while conducting our research into tourism and hospitality industry, as well as retail chains, we have examined the problems that arise in the process of staff motivation, and studied the foreign practice of motivating staff in hotels. The obtained analysis results enabled us to work out practical recommendations on improvement of the mechanism of tangible and intangible rewards in service companies, which are based on external and internal motivational factors. Additional attention in the article is paid to the statement that financial incentives should be based on key performance indicators (KPI). We give a detailed consideration to the classification of internal motivation incentives of the staff according to the terms of their realization, and give a schematic representation of the performance dynamics of the internal motivation model in service businesses. Keywords: Staff turnover, staff motivation, service industries, internal incentives, management. JEL Classification: J 320, O 150, M 120. 1. Introduction In every country, service industries represents the level of civilization on the nation, so that the higher the level of services is, the more civilized the country is considered. And it is service industries that make the largest part of the national economy in more economically developed countries (over 60%). The rapid development of the service sphere, and its gaining of the status of one of the key sectors of the economy calls forth the need for an increasing number of personnel, which in its turn causes significant staff turnover. This trend is clearly observed in respect of the low-wage employees, and the demand for them is growing exponentially. Staff turnover negatively affects the work of service companies, it is an obstacle to team formation and, consequently, to fostering of the corporate spirit, and this invariably entails a lowering of the overall performance indicators. In addition, the turnover impedes the raising of the staff competence and professionalism level, as well as makes it difficult to get payback of investment in retraining. All this reduces the possibilities of high-quality workforce training: it is provided mainly in the workplace. Although the profession of service sector specialist is gaining popularity among the younger generation, recruiters note the obvious shortage of personnel that complies with the requirements laid down in service companies. Multiple reasons explain for staff turnover – starting from disruptive enterprise management style and Journal of Applied Economic Science no/2006 ending with selection of non-professional applicants to fill in the vacant positions. However, there is no doubt that the path to the effective management of employees lies through understanding of their motivation. Knowing of the factors that stimulate employees and motivate them to their activities should be of the principal consideration while building the effective labour motivation system. All this said, the investigation of the problems and prospects of use of tangible and non-tangible motivation tools in service companies is of particular relevance today and requires additional in-depth research. 2. Theoretical and conceptual aspects The questions of staff motivation are studied by scientists and practitioners from the point of view of theoretical justification of the need for various means of boosting the zeal of employees. An important contribution to the development of the research area was made by such well-known international and Ukrainian scientists as I. Ansoff (1989), J. Cole (2004), M. Meskon, M. Albert and F. Khedouri (2004), L. Balabanova and O. Stelmashenko (2010), M. Shulha (2008) et al. In numerous works, the Ukrainian researchers, for example N. Alekseeva and I. Prykhodko (2012), A. Dolzhanskyi (2010), Z. Zhyvko (2010), N. Izyumtseva and H. Myronchuk (2012), A. Nemchenko, H. Yurchenko and I. Zhyrova (2011) study the mechanisms of establishing interconnections between motivation and work performance through the use of motivational factors and formation of a motivational environment in companies, which stimulates employees to develop their abilities, improve the psychological climate in the team and raise their performance indicators. Such authors as M. Vedernikov (2013), O. Hryvkivska (2010), A. Hubenko (2010), T. Kovalenko (2010), O. Kovalchuk and O. Sytnik (2013), A. Mohsin, J. F. B. Lengler and R. L. Aguzzoli (2015), Branham Leigh (2005) are engaged in research of global experience in the development of motivational systems and their evaluation. However, in spite of a significant number of studies, as well as the currently existing achievements, problems associated with the formation of a practical mechanism of managing staff motivation in services companies have no definite solution. Just the same way, there is no accepted formula for motivation, which would explain the behaviour of an employee, regardless of the circumstances. The methods for managing motivational process call for understanding of the basics of control, with due regard paid to their stochastic ambiguous nature. 3. Purpose of the study Through the analysis of companies that represent tourism and hospitality industry, as well as retail chains, the author strives to explore the problems that came up in the process of motivation, to examine the motivational programmes for the personnel in service industries in the different countries, and then, by using the obtained results, to work out practical recommendations of how to overcome the difficulties and create a new concept of building motivation by personnel in the sphere of services. 4. Results of the study The problems that came up in the process of motivation in service industries First of all, it seems appropriate to mention the problems that exist at the macrolevel and hamper the introduction of any incentive schemes for employees of service industries. These problems seem to be inherent to the countries with national economies under transformation. So, these problems are: 1. Lack of clear standards for requirements to personnel in service companies, as well as lack of qualification standards. 2. Fragmentation and lack of a single standard list of professions related to the service sector. 3. Scarcity of differentiated methods of specialist training for work in the service sector. 4. Lack of standards of educational programmes and a common approach to assessment of service quality and service technologies. 5. Underdevelopment of the labour market. 6. Low level of professional culture of the staff. 7. High staff turnover. Of special note is one of the key problems in the sector of services of any type and orientation. It lies in the fact that the greatest difficulties are related to the motivation of staff employed in soJournal of Applied Economic Sciences Volume, Issue, 2016 called "non-prestigious" service sector jobs (cleaners of the premises, maids, nurses, technicians, repairmen, etc.). The problems are explained by unattractiveness, not prestigious of the professions that form the very basis of the infrastructure of the service-rending process; low wages; poor working conditions, and others. Ever more people in modern society are no longer satisfied with "any" work. People want the work process to give them an opportunity for self-development, self-affirmation and selfrealization, they want to feel the importance and necessity of the performed work (Dwivedula and Bredillet, 2010). More and more often employees try to evaluate the innovation potential of the job, its creative constituent, which plays a significant part in self-identification of a personality (Hrynko, 2010). At the level of a separate enterprise, there are other problems, which hinder the effective implementation of modern concepts of motivation: • lack of a clearly defined policy and specifically worded objectives in work with the staff; • fragmentation in personnel management and planning; • lack of integrated educational framework; • insufficient competence of HR personnel; • low degree of realization of the whole complex of staffing social goals. Of course, there are much more problems at each level; besides, in each individual case they are quite particular and depend on both objective and subjective factors. Low level of motivation, imperfect programmes and systems of stimulation of employees are one of the most crucial factors, which causes a significant personnel turnover in service companies. The annual research conducted by BenchmarkPro that analyses information about 30,000 organizations around the world testifies that the average personnel turnover in the services sector is more than twice as high as that in the industrial sector (see. Fig. 1, 2). Figure 1 Voluntary discharge (CompData Surveys) Figure 2 General personnel turnover (CompData Surveys) As is clearly shown in Fig. 1 and 2, the first place for turnover among service industries holds the industry of tourism and hospitality, and the second one – retail networks. High staff turnover in the tourism and hospitality industry has brought about the crisis of productivity, which costs to the sector $ 272 million per year. According to expert data, 1% increase in labour productivity can provide an additional $ 1.43 billion of revenue in the year. At the same time, labour productivity in the tourism and hospitality industry per employee makes $ 21,600 per year, in retail networks – $ 46,000, and in the industrial sector – $ 52,000 (Brien et al., 2015). Journal of Applied Economic Science no/2006 Antal International company experts in the course of their studies found out that employees of the tourism and hospitality industry leave their positions in search of more interesting work in 67% of cases, and in 65% of cases in search of a better work / life balance (Eisele et al., 2013). In this context, of considerable interest is the gradation of the reasons of dismissals from hotel positions, established by Kelly Services, Inc., the world leader in providing solutions for personnel, as a result of their study of more than 4000 hotels in the USA and Europe (see Fig. 3). So, in the first place lack of career development, on the second the difficulty with management and management of the hotel circuit and the third too many standards and requirements for operation. This material component is only in seventh place. Figure 3 Rating of the reasons of dismissals from hotel positions (% of the sample) (Kelly Services) The generalization of the results of various investigations and surveys has enabled the author to formalize the reasons that account for the hospitality industry employees being not loyal to their work, and that led to their leave (the reasons are enumerated in a free list without regard to priority). Accordingly, these very reasons are the prime guidelines of motivational mechanism, which will allow its adjusting according to the needs, wishes and aspirations of the staff. 1. A significant level of bureaucracy or inadmissible tolerance in the company. There are often quite an excessive number of formulated rules that employees do not understand and do not accept. Once an employee disagrees overtly with these rules and gets disappointed with them, it is the direct reason for his rejection of further cooperation. 2. Lack of transparency. Employees should have the possibility to share their thoughts, concerns and suggestions with the company management. 3. Lack of accountability / responsibility. Good employees want to be responsible for their projects, for the results of their activities and, what is more important, they do not mind being guilty and suffer due punishment, in case of mistakes. Also, they do not object to the control of the management, they are ready to discuss conclusions and comments and listen to advices. 4. The lack of vision and prospects of the enterprise development. Employees need to see and understand where the company is moving, what is their future. 5. Inattention to the talents of employees, lack of appropriate projects that can ignite a passion for work. The head which has a team of talented employees and does not make use of their potential will soon be deprived of this opportunity. It is well known that talented people are driven by not money, but the opportunity to become a part of something huge, and when having such an opportunity, they can increase the cost and competitiveness of the enterprise many times. 6. Lack of discussion on career development. It is very important to conduct a dialogue face to face with an employee about his career path. When management takes part in the debate and demonstrates that there is space for promotion, employees tend to be more loyal to their work. 7. Irregular analysis of performance or its total lack. It entails irregular evaluation of quality and effectiveness of personal efforts, which consequently has a negative impact on remuneration, both material and moral. Journal of Applied Economic Sciences Volume, Issue, 2016 In order to work out specific recommendations for overcoming the difficulties and forming a new concept of building motivation in this area, the next stage seems to be to explore the usual practice of motivating personnel in the tourism and hospitality industry. World experience of personnel motivation in service industries (evidence for hotels) Table 1 Provides an overview of motivational programmes for staff that are used in hotels around the world. Table 1 Motivational programmes for hotel staff Country The content of the motivational programme USA • discount card for hotel services; • payment of newly-employed workers and junior staff is at the level of the minimum wage, but there is an opportunity to earn an increase of 20 to 40 cents per hour due to the additional actions (Association International Hotels and Restaurants Associations); • high productivity entails a salary increase of up to 60% per year, depending on the personnel policy of each hotel; • hourly workers are entitled to receive quarterly bonuses if their performance exceeds the planned expectations; • middle and high managers are offered reduced-price medical care. China • employment contracts are concluded for a period of 3 to 5 years; • there is a possibility of promotion to senior manager in 6 years; • one extra payment of the salary every year; • two free medical examinations a year; • annual guided tour organized by the hotel for the best employees; • rewards such as extra credit programme for the outstanding employees; • regular training programmes aimed at improving skills and creating a sense of community in the team. India • a good salary; • promotion and growth; • an annual bonus; • employee discount cards; • partial payment for medical services; • on the results of the award; • discounts on medical care and life insurance; • competitions and team building exercises to bring together employees and encourage interaction. • at least 22 days of vacation. England • bonuses according to the performance; • discounts on medical care and life insurance; • competitions and team building exercise for bringing employees and encouraging interaction; • at least 22 days of vacation. As is shown in Table 1, about 80% of motivational programmes for hotel staff in all the countries employ financial incentives, which, in fact, are external motivational factors. When comparing the Journal of Applied Economic Science no/2006 information contained in Table 1 and shown in Figure 3, it is easy to see the non-conformity of motivational programmes and expectations of the employees. Practical recommendations for the formation of a new concept of building personnel motivation in service industries In general, one can observe that external stimuli (material component) are used to compensate for repetitive tasks or those tasks that require additional motivation. Various studies have shown that money as an incentive works effectively on the short distance, and when a person reaches a certain level of comfort, the quality of his work deteriorates gradually. People work better when they feel an emotional or personal connection with the work, and when their aspirations and target settings coincide with the aims and objectives of the enterprise. These factors increase their motivation much better than money (Tabassi et al., 2012). Of course, we do not suggest rejecting material incentives, but it seems that its role should be reconsidered, and compilation of monetary compensation programmes should take into account current market trends, aims of the personnel and the latest achievements of scientific thought. Besides, due attention must be paid to gender segregation of labour in service industries. Thus the author holds that the programme of material motivation should be based on proven key performance indicators (KPI) of the enterprise, the choice of which, in turn, should be carried out with compliance with SMART principles. KPI is an efficient tool that helps to coordinate harmonize the values of workers and the enterprise. KPI represent benchmarks for evaluating employees and, on the other hand, enables the employees to monitor the compliance with their own aims and achievement of goals (Mohsin et al., 2015). When developing a system of incentives based on the KPI, first of all it is necessary to identify the key performance indicators of the company and, on that basis, to formulate strategic goals and objectives with their subsequent transfer to the staff level. Though a list and immediate content of the tangible rewards for staff accompanies each goal statement, for certain tasks it is difficult to determine and establish an objective and adequate remuneration for a particular employee. Therefore, there is no doubt that such objectives as "involvement of employees" or "fostering of future leadership qualities" require an additional, internal motivation. On the evidence of retail networks, the correlation of KPI of a company and indicators of material staff stimulation is shown in Fig. 4. Considering the system of non-material incentives in the modern concept of motivation for enterprises of tourism and hospitality industry and retailers, we note that, according to the author, it must be based on self-determination theory, which features three variable predictors – autonomy, competence and cohesion with the company. These variables allow employees to form internal incentives to work, to increase efficiency and to develop a wish to remain in the company for a long time, as well as to participate in its development. According to this theory, instead of being a source of motivation, the manager must help employees to find their own internal motivation. Internal incentives suggest certain relieve of financial burden on the company, when compared with external incentives, which include bonuses, commissions, salary increase, etc. Expenses on these stimuli may exceed their feedback and lead to a yield decrease. Empirical observations and calculations show that job satisfaction in the service sector is but slightly correlated with material rewards. Thus, basing on these results we can offer the quadrant of motivation types for tourism and hospitality companies and retail networks (Fig. 5). If the employee likes what he is doing, then the combination of autonomy, competence (skills), or cohesion with the work and achievements of the company will encourage him to be active, and the efficiency and productivity of his work will be a result of his activity. According to a survey carried out among the employees of Park Inn hotel network in 2014, the first place among the internal motivators shared recognition and growth opportunities (see Fig. 6). The greatest effect is, of course, gives a combination of internal motivators, which excites the feelings that lead to effective customer service and efficient behaviour of employees. Journal of Applied Economic Sciences Volume, Issue, 2016 Figure 4 Correlation of KPI of a company and indicators of material staff stimulation (Retail) Figure 5 Quadrant of incentives and motivations for tourism and hospitality companies and retail networks Journal of Applied Economic Science no/2006 Figure 6 Popularity of internal incentives in Park Inn hotel network (% of the sample) (Sampaio et al., 2014). Basing on the concepts of self-determination theory, we suggest expanding variable predictors to service businesses, by adding self-efficacy, strength, emotions, mood, values, interest, utility, choice, persistence and effort to their number. In this case, the model of internal motivation for service companies, in particular for those who work in the tourism and hospitality industry and trade, will look and work as follows (see Fig. 7). Figure 7 Dynamics of performance of internal motivation model for service companies This model demonstrates that a certain type of behaviour has a very different effect on the efficiency of the enterprise, achieved in various ways, and employers should take these differences into account in order to reduce turnover. In addition, in order to effectively use internal incentives of employees as motivational factors, it would be reasonable for businesses to differentiate them, depending on the timing of implementation (see Table 2). Table 2 Classification of internal incentives as to terms of their implementation Short-term incentives – "quick victories" Long-term incentives – "long victories" Competitions: • competitions between teams of employees/shifts/crews for goal achievement, e. g., the largest number of clients fin a week, the least number of complaints, the quickest service etc.; • rewards, e.g., gift cards, cinema tickets, free lunch etc. Offers for proficiency enhancement and change of profile E. g., training courses. They help employees to feel that their part in the company is not just doing everyday routine work. With the aid of the studies they can build their careers and increase their value for the company. Social recognition: Development of talents Journal of Applied Economic Sciences Volume, Issue, 2016 E. g., most effective worker of the month. The reward can take the form of a poster with a photo on a corporate stand, congratulations of a team gathering – bestowing a certificate, expressing gratitude. • structured education, theoretical and practical training for coping with new tasks; • creation of a reserve for switching employees to other tasks, when needed; in its turn, it makes them feel incorporated into the functioning of the company and performing of new tasks; • the personnel is conscious of the meaning of the performed tasks and commissions; • employees that are qualified for various jobs are aware of their possibilities of career promotion, which inspires them and lets them understand the sense of their work and work of the whole enterprise. Internal notices on vacant positions on the informational stand Such notices gives employees a possibility to consider different roles in the company that they might play, to shape their own sensations and aspirations, which encourages them to work harder and perfect themselves. Flexibility that allows working in a series of company areas a possibility to work in various environments, with various clients and in the various areas; skills improving, which makes the employees quick to adapt to the various groups of clients and their requests; flexible work conditions, including proximity to home, university, school, if they are interested in studying new areas. Team building common monthly lunches; New Year and Christmas parties; monthly teambuilding events, such as picnics, film viewings, visits to clubs; participation in group meetings etc. Conclusions The most complicated situation with personnel and their motivation in service industries is observed in the tourism and hospitality industry, as well as in retail networks. Identification of the problems that arise in the process of motivation in service industries, helped to clarify the basic requirements for the modern concept of tangible and intangible rewards for work in service companies. A detailed analysis is given to the problems and factors causing the highest level of staff turnover, as a result of imperfect motivation programmes in the companies within tourism and hospitality industry, as well as in retail chains. A study of the positive experience of staff motivation in different hotels around the world was performed. Basing on the findings, the article provides practical recommendations that help to overcome the difficulties and create a new concept of building motivation in this area. Special attention is paid to the motivational programmes of material incentives; particular emphasis is placed on internal motivation factors, their classification and model of their implementation are offered. References [1] Ansoff, I. 1989. Strategic management. Ekonomika. Moskow. [2] Alekseeva, N., Prykhodko, I. 2012. Improving work motivation by machine building employees. Management, marketing and personnel administration: Mykhailo Ostrohradsky Kremenchuk National University Gerald, 3:174-178. [3] Association International Hotels and Restaurants Associations (IHRA). URL: http://ih-ra.com/ Journal of Applied Economic Science no/2006 [4] Balabanova, L. V., Stelmashenko, O. V., Tuhan-Baranovsky, M. 2010. Strategic personnel management in market economy. Donetsk National economy and trade university. Donetsk. 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[11] Eisele, L., Grohnert, T., Beausaert, S., Segers, M. 2013. Employee motivation for personal development plan effectiveness. European Journal of Training and Development, 37(6): 527-543. [12] Hrynko, T. 2010. On innovation potential as a constituent of innovation activities of businesses. The Economist, 2: 56-58. [13] Hryvkivska, O. V. 2010. Staff motivation in foreign companies. Topical problems of economy, 9: 86-91. [14] Hubenko, A. V. 2010. Importance of labour potential for economic development of a company. Economy and marketing in XXI century, 1:78 -80. [15] Izyumtseva, N. V., Myronchuk, H. V. 2012. Organization of system of motivation of bank personnel under conditions of post-crisis development of economy. Personnel management: Herald of University of Banking of National Bank of Ukraine, 1: 279-283. [16] Kelly Services. Inc. Business Services & Solutions. URL: http://www.kellyservices.us/US/Business-Services/ [17] Kovalchuk, O. A. 2013. Economical and mathematical modeling of managing the process of personnel motivation. Dnipropetrovsk university Gerald. Series Economy 21. 7(4): 268-273. [18] Kovalenko, T. L. 2010. Factors of social and economical motivation of personnel of communications service provider. Author's abstract of a thesis of PhD in economy: 08.00.04. O. S. Popov Odesa national academy of communications. [19] Meskon, M. Kh., Albert, M., Khedouri, F. 2004. Basic management. Delo. Moskow. [20] Mohsin, A.; Lengler, J. F. B.; Aguzzoli, R.L. 2015. Staff Turnover in Hotels: exploring the quadratic and linear relationships. Tourism Management, Forthcoming. Tourism Management, 51: 35-48. [21] Nemchenko, A. S., Yurchenko, H. M., Zhyrova, I. V. 2011. Analysis of motivational principles of personnel management. Mangement, economy and quality assurance in Pharmacy, 1:18-23. [22] Sampaio, S., Simoni, V., Isnart, C. 2014. Tourism and Transformation: Negotiating Metaphors, Experiencing Change. Journal of Tourism and Cultural Change, 12(2):93-101. [23] Shulha, M. A. 2008. Social and political management. Tsentr uchbovoi literatury. Kyiv. [24] Tabassi, A.A., Ramli, M., Bakar, H.A. 2010. Effects of training and motivation practices on teamwork improvement and task efficiency: the case of construction firms. International Journal of Project Management, 30(2): 213-224. [25] Vedernikov, M. D., Zelena, M. I. 2013. Is it reasonable to use foreign experience in Ukrainian companies. Khmelnytskyi national university Gerald, 5(1):18-21. [26] Zhyvko, Z. B. 2010. Mechanism and models of personnel motivation in call producing companies. Management and marketing. Science and economy, 1: 86-91. | Mid | [
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Last week I contributed an essay as part of the Patheos symposium "For Life and Family: Faith and the Future of Social Conservatism." The essay, in which I argued that fighting against gay marriage was a lost cause, generated a number of comments, and I am thankful to those who posted. I am returning to this topic to develop my argument further, in order to suggest that Catholics and other Christians are at a Gamaliel moment with regard to this important social question. The sound byte is this: law, no; persuasion, yes. Gamaliel was a first-century rabbi mentioned in the Acts of the Apostles. Speaking about Jesus' apostles, who were preaching about Jesus against the strict orders of the local judges, Gamaliel advised leaving them alone rather than prosecuting them: . . . if this endeavor or this activity is of human origin, it will destroy itself. But if it comes from God, you will not be able to destroy them; you may even find yourselves fighting against God (Acts 5:38-39). Gamaliel's insight was that new ideas that are not rooted in God eventually fade away, but new ideas that are rooted in God are here to stay. He further understood public sympathy for those who take courageous stands in the face of persecution: the public is likely to take the side of the underdog against the people in power, regardless of whether they are right or wrong. His exhortation to avoid legal proceedings was predicated on the belief that the movement would eventually fail to draw people's interest. Christians are at a Gamaliel moment with gay marriage, meaning that we must relinquish the legal battle in order to refocus on the moral one. I believe the main reason why people perceive it to be an issue of equal rights is because most Americans enter discussions about law through a door marked "freedom," and they perceive a failure among states to recognize the freedom of gay people to enter into marriage. My argument is that Christians need to leave behind the "freedom" door (and the legal argument that follows from it) and instead walk through a different door called "love and responsibility"—that is, to the discernment of relationships rooted in the New Testament and a spirituality of sexual love. Instead of arguing about law, we should be modeling the kind of love that the author of the letter to the Ephesians describes as most closely modeling the love of Christ for the church. And instead of targeting gays, we must turn the focus on ourselves and ask why our impoverished understanding of marriage has led to widespread non-marital sex, divorce, cohabitation, adultery, and general misery—especially for children, teens, and young adults. The Gamaliel moment means that we have to be realistic about how common that "freedom" door is. It's an inadequate door to enter the discussion about marriage, but it's the one most people use these days. My concern is that overemphasis on the legal question of gay marriage may, in fact, distract us from a more robust public witness, a more persuasive model of sexuality that is deeply rooted in a faithful discernment of God's project. American law is a square hole into which we are trying to force a round peg that is a biblical model of marriage. And in an increasingly pluralistic nation, it becomes easy to target the proponents of the biblical model of unfairly imposing their will on everyone else. My suggestion is let go of the power game, and instead preach the gospel. Our culture has sexuality deeply, deeply wrong. We have come to believe that it is a matter of self-expression, an act of freedom. That belief is radically impoverished, though. It is like the person whose craving for sugar has arisen because he has not nourished his body: he seeks what is most available, thinking it an act of freedom, when the reality is that he lacks what he unconsciously needs most. Our culture is spiritually starved for social practices of love, of generosity, of caring, of companionship: the kinds of rich interpersonal relationships that arise out of loving families and compassionate communities. Lacking these, so many people (especially the young) will take any kind of connection to another person that brings a temporary high. To make things worse, everyone with a product to sell uses that craving in a bait-and-switch game to sell products. Free sugar for starving bodies. In such a context, the faithful friendships of gay people represent one kind of healing, a kind that many Christians fail to recognize as rooted in love. For a faithful friendship is better than the kind of transient sexual experiences that so many experience today. | Mid | [
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Jules Henriet Jules Henriet (13 February 1918 – 27 November 1997), was a Belgian football player. He evolved from midfielder to defender in Sporting Charleroi and the Belgium national football team. He played 15 matches with the Red Devils between 1940 and 1949,during which he was 8 times captain in charge. He play 233 games and score 4 goals in the highest Level. He ended his career as trainer-player in RAEC Mons from 1956 to 1959. References Category:1918 births Category:1997 deaths Category:Belgian footballers Category:R. Charleroi S.C. players Category:R.A.E.C. Mons players Category:Belgium international footballers Category:Belgian First Division A players Category:Association football forwards | Mid | [
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Travel and explore South Africa! South African National Parks offers a variety of accommodation types and standards. Prices are dependent on location, size of unit and quality of experience. All of our South African National Parks offer park/camp-run accommodation. Each park/camp has its own unique selection of accommodation types. Conserving nature since 1926 National parks offer visitors an unparalleled diversity of adventure tourism opportunities including game viewing, bush walks, canoeing and exposure to cultural and historical experiences. Conferences can also be organised in many of the parks. Read more... History of the Park Mapungubwe: Becoming a National Park The Mapungubwe area became a focus of agricultural research in the 1920s through the efforts of a prominent botanist, Dr. I.B. Pole Evans. Pole Evans was instrumental in the creation of the Botanical Survey Advisory Committee which was tasked with coordinating botanical research throughout the Union of South Africa. One of the network of botanical and research stations set up by the Botanical Survey was situated in the Mapungubwe area. In 1918 the government, at the request of General Smuts, set aside a block of nine farms in this area as a preserve for wildlife and natural vegetation. A few years later this became known as the Dongola Botanical Reserve. Pole Evans set about expanding the Dongola Botanical Reserve. By the early 1940s the reserve had grown to include 27 farms, including Greefswald, the property on which the Mapungubwe Hill is situated. Pole Evans lobbied to have the reserve proclaimed as a national park, with the support of Prime Minister Jan Smuts. In 1944 Minister of Lands, Andrew Conroy proposed the formation of the Dongola Wild Life Sanctuary which would include 124 farms, 86 of which were privately owned. This proposal was strongly opposed by the National Party, then the official opposition in parliament and the National Parks Board of Trustees. In one of the longest running debates in the history of the South African parliament, supporters argued that it was necessary to conserve the country's natural assets, that the land set aside for the proposed reserve was unsuitable for agricultural purposes and that the area had a rich archaeology which should be protected. Those opposed to the establishment of the reserve argued that it was unacceptable to alienate agricultural land for wildlife conservation, to expropriate private land or to evict people from land they had occupied for generations. The debate, which has become known as the "Battle of Dongola", resulted in the declaration of a much reduced area as the Dongola Wildlife Sanctuary, after members of the ruling United Party voted in favour of the proposal. The National Party won the elections in 1948, and the sanctuary was abolished in 1949. Expropriated farms were returned to their original farmers, farms owned by the state were allocated for resettlement and funds returned to donors. In 1993 De Beers Consolidated Mines, which had established the Venetia Limpopo Nature Reserve on land that adjoins Greefswald, called for the area to be declared a national park. In 1995 the South African National Parks Board and the Limpopo provincial government signed an agreement committing themselves to the establishment of the new national park. The Vhembe Dongola National Park was proclaimed on 9 April 1998. In the 21st century Mapungubwe has been embraced as a site of significance by South Africans and the international community. The Mapungubwe National Park was declared in 1998. The Mapungubwe Cultural Landscape (MCL) was declared as a National Heritage Site in 2001 and it was inscribed on the World Heritage List in 2003. The MCL was inscribed on the World Heritage List in 2003 because it is believed to be of outstanding universal value for the following reasons: The MCL contains evidence for an important interchange of human values that led to far-reaching cultural and social changes in southern Africa between AD 900 and 1300. The remains in the MCL are a remarkably complete testimony to the growth and subsequent decline of the Mapungubwe State which at its height was the largest kingdom on the African subcontinent. The establishment of Mapungubwe as a powerful state trading through the East African ports with Arabia and India was a significant stage in the history of the African sub-continent. The remains in the MCL graphically illustrate the impact of climate change and record the growth, and then decline, of the Kingdom of Mapungubwe as a clear record of a culture that became vulnerable to irreversible change. The remains of this famous kingdom,when viewed against the present day fauna and flora, and the geo-morphological formations of the Limpopo/Shashe confluence, create an impressive cultural landscape of universal significance. Mapungubwe: An Archaeological Site In December 1932, Ernst van Graan, his son Jerry and three other men searched the farm Greefswald, where both Mapungubwe and K2 are located, for a sacred hill rumoured to hold the treasure of kings. Arriving eventually at the steep-sided and seemingly unscaleable hill, a local man, known only as Mowena, reluctantly pointed the way to a narrow path well concealed in a cleft in the rock. Reaching the top of the hill, the men found remnants of stone walls and large quantities of potsherds, some iron tools and copper and glass beads scattered on the ground. They returned the next day with spades and soon unearthed ancient graves, three which were different and probably belonged to royalty. The first, probably a woman, was buried in sitting position facing west. She wore gold bangles around her ankles and there were gold and glass beads in the grave. The second grave was a tall middle-aged man, also sitting up and facing west. He wore a necklace of gold beads and cowrie shells and some objects covered in gold foil, one resembling a crocodile. In the third grave, probably also from a man, a golden bowl, scepter and a golden rhino were found. This rhino has become a ymbol for Mapungubwe. The men split the gold between them but one, Jerry van Graan, realising the possible significance of the find, sent a few small pieces of gold together with a letter to his former professor, Leo Fouche at the University of Pretoria. Professor Fouche immediately mounted an expedition to recover and secure the newly found treasures and the surrounding environment for archaeological research. Excavations in the 1930s unearthed 23 graves on top of Mapungubwe Hill. Three were different and probably belong to high royalty. In June 1933 the government purchased the farm Greefswald, gave the University of Pretoria the right to excavate for a period of five years and constituted an Archaeological Committee at the university to take charge of the excavations. Exploratory excavations in 1933 were followed by large-scale excavations between 1934 and 1940. Unfortunately the lack of proper recording procedures during this time means that valuable evidence may have been lost. Work on the site was halted during World War II and limited, but more systematic excavations were undertaken in the 1950s and 1960s. After 1970 widespread excavations were undertaken at K2 and Mapungubwe. These were aimed at establishing a firm database by testing, correcting and supplementing the earlier research, coming to an understanding of the Iron Age settlement sequence and reconstructing the way of life of the sites' inhabitants. This information is available in a range of specialist reports, academic publications and guide-books. In the late 1990s, after the area was designated as a National Park, extensive rehabilitation and stabilisation work was undertaken to secure the archaeological sites. Research over the past decade has focused on the material held in the University of Pretoria's Mapungubwe Collection, gathered over the 60-year period of excavations. The Mapungubwe Museum, established by the University of Pretoria in 2000, serves as a centre for the conservation and display of the collection, disseminating information about Mapungubwe in all its diversity. Between 1933 and 1998 the remains of about 147 individuals were excavated from the Mapungubwe Cultural Landscape. These included individuals buried on Mapungubwe Hill and in the K2 area. These human remains were excavated from their graves and placed in the collections of the University of Pretoria, the University of the Witwatersrand and Ditsong Museum where they were used for research purposes. Individuals and organisations representing the descendants of the people of Mapungubwe, including the Vhangona Cultural Movement, the Lemba Cultural Association, the San Council, the Tshivula Royal Family, the Ga-Machete Royal Family and the Leshiba Royal Family came together after 1994 to request government to facilitate the process of repatriation and reburial of these human remains. The National Department of Environmental Affairs and Tourism was tasked with facilitating this process. After extensive consultation, the human remains were symbolically released to representatives of the descendants on 29 October 2007. The remains were reburied on 20 November, following a cleansing ceremony. Mapungubwe: A Cultural Landscape Two of the earliest plant-eating dinosaurs, Plateosauravus (Euskelosaurus) and Massospondylus, are known to have lived in the area now known as the Mapungubwe Cultural Landscape (MCL). Plateosauravus, the oldest South African dinosaur, lived about 210 million years ago and is believed to have grown to be about 10 metres long. Massospondylus, the most common South African dinosaur, lived about 195 million years ago and is believed to have grown to between three and six metres long. These two species are similar in many ways. They both had long tapered necks and tails and elongated cylindrical bodies and they both walked on all fours, standing upright on their hind legs in order to reach the succulent young fronds of cycads and seed ferns. Like many other dinosaurs, these used their hands to manipulate objects like branches or to prop or pull themselves up against objects. The first inhabitants of the Mapungubwe Cultural Landscape (MCL) who arrived about 300,000 years ago were people of the Earlier Stone Age (ESA). They walked upright but their brains were not as well developed as ours. Many ESA stone tools have been found at open-air sites such as Hackthorne and Keratic Koppie. The tools include handaxes, picks, cleavers and scrapers that were made from local rocks such as quartz, chert, chalcedony and occasionally dolerite. Between 250,000 and 130,000 years ago the heavy tools of the ESA were replaced by lighter and more technologically advanced Middle Stone Age (MSA) tools. At Kudu Koppie and Parma Farm these tools, made by physically modern people, include parallel-sided blades and triangular points which were hafted to make hunting spears. There is evidence from a rock shelter at Balerno that by 11,000 years ago, small groups of people of the Later Stone Age (LSA), ancestors of the San (Bushmen), had begun to live in the Mapungubwe Cultural Landscape. Tools associated with this and other LSA sites such as Thudwa Shelter at Little Muck, include carefully prepared blades and scrapers made from fine grained rocks, such as quartz or chalcedony. The tools are generally smaller than those of the MSA. Towards the end of the LSA, about 3,000 years ago, people in the MCL began painting images of animals and people on the walls of rock shelters to record their beliefs and rituals. MSA and LSA tools accumulated on the floor of rock shelters, together with bones of animals they ate and decayed plant matter that built up in layers when people returned to these places repeatedly. Analysis of the remains shows that the LSA inhabitants lived mainly off small animals such as small antelope, tortoises, hares and fish caught by hunting and snaring. Hunter-gatherers living in the Mapungubwe Cultural Landscape were probably surprised around the first century AD when LSA herders and early framers entered the area By AD 450, an even more dramatic change had taken place, as Early Iron-Age farmers moved into the area, bringing with them farmers with them domesticated cattle, sheep and goats, crops such as sorghum and millet, and skills such as iron- and copper-working and pottery-making. How did these three groups interact with each other? What effect did the influx of newcomers have on the people already living there? And what effect did the newcomers have on the landscape? Excavations in rock shelters in the MCL show that hunter-gatherers did not move away during the first millennium AD, and were in fact more active. This is reflected in larger numbers of stone tools, bone tools, ostrich eggshell and Achatina shell beads and ochre, as well as new items such as glass beads and pottery. The increased activity is believed to be the result of interaction with farmers who took over land and resources previously available to hunter-gatherers in the region. The hunter-gatherers therefore stayed for longer periods in rock shelters and other places less favoured by the farmers and created new economic networks, taking agricultural produce, pottery, metal and glass beads in exchange for hides and wild meat. Hunter-gatherers continued to make rock paintings during this period to emphasise their ownership of rock shelters and their powers of rain-making. By about AD 900, Zhizo people had moved into the area, establishing settlements in the MCL, eastern Botswana and south-west Zimbabwe. At least 25 Zhizo settlements have been identified in the MCL. In most cases these settlements are set back from the Limpopo and other rivers, in areas where crops could be cultivated without threat of destruction by floods or marauding elephants. Schroda is the largest of the Zhizo settlements in the MCL and is generally referred to as the Zhizo capital. Located on a rocky plateau close to the Limpopo River, Schroda was home to between 300 and 500 people. Zhizo presence in the MCL diminished after about a hundred years, and while some settlements remained, the chiefdom moved westwards into Botswana. The area was soon dominated by a new group, the Leopard's Kopje people. Hunter-gatherers were no longer able to move freely around the landscape to gather wild plant foods and to hunt easy prey. The differences in the belief systems and social organisation of farmers and hunter-gatherers made it difficult for them to inter-marry, and the perceived benefits of the goods and services that each group had to offer probably also changed over time. Zhizo farmers may have valued the services of the 'first people' who were considered to have power over nature and the supernatural in terms of rain-control, as well as local knowledge of plants and herbal remedies. Hunter-gatherers would have valued the metal tools, cultivated grains and glass beads that they received from the Iron Age farmers. People making Leopard's Kopje pottery began to live in the Mapungubwe Cultural Landscape about a thousand years ago. The largest settlement was at the site now known as K2, but there were many smaller villages in and around the Limpopo floodplain. The name 'K2' was given to the site by archaeologist Guy Gardner who was trained in Egypt where the word 'Kom' means a mound or midden, a heap of discarded food remains, artefacts, etc disc, built up by people living in the same place over many generations. K1 is a smaller mound to the east of K2. The Leopard's Kopje farmers cultivated crops on the flat lands between the hills where they could take full advantage of the seasonal flooding of the Limpopo River and its tributaries. They made a substantial impact on the natural landscape, clearing land for the cultivation of crops, dumping refuse and burning old houses and kraals. Even today, a thousand years later, middens and kraals are still easily identifiable because very little vegetation grows on them. Animal bones excavated from these settlements show that the people ate meat from sheep, goats and cattle, supplemented with game and fish from the river. Seeds preserved from cultivated crops include sorghum, millet, beans and cowpeas. . Metal artefacts included arrowheads, spearheads, hoe blades, beads, bangles and wire. Small quantities of iron and copper ore and slag show that metal working took place in and around the settlement. Almost a hundred graves were found at K2. Information about them can be found in Cairn Three. Between AD 1220 and AD 1300, Leopard's Kopje people settled on and around Mapungubwe Hill. This site is renowned as the centre of southern Africa's first indigenous kingdom. The kingdom flourished as the result of trade with the Indian Ocean network. The emergence of a class-based society is reflected in the separation of an elite class with a sacred leader who lived on top of the hill, and commoners who lived on the plains below. At the height of its importance, between AD 1220 and AD 1300, the Mapungubwe Cultural Landscape sustained a population of at least 9,000 people. Mapungubwe is arguably best known for the gold artefacts found in graves on the hill in the 1930s. Three of these graves contained gold beads and other items confirming the high status of the individuals who lived and were buried on the hilltop. | Mid | [
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/*---------------------------------------------------------------------------*\ ========= | \\ / F ield | OpenFOAM: The Open Source CFD Toolbox \\ / O peration | Website: https://openfoam.org \\ / A nd | Copyright (C) 2011-2020 OpenFOAM Foundation \\/ M anipulation | ------------------------------------------------------------------------------- License This file is part of OpenFOAM. OpenFOAM is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. OpenFOAM is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with OpenFOAM. If not, see <http://www.gnu.org/licenses/>. \*---------------------------------------------------------------------------*/ #include "cyclicPolyPatch.H" #include "addToRunTimeSelectionTable.H" #include "polyBoundaryMesh.H" #include "polyMesh.H" #include "demandDrivenData.H" #include "OFstream.H" #include "matchPoints.H" #include "EdgeMap.H" #include "Time.H" #include "transformField.H" #include "SubField.H" #include "unitConversion.H" // * * * * * * * * * * * * * * Static Data Members * * * * * * * * * * * * * // namespace Foam { defineTypeNameAndDebug(cyclicPolyPatch, 0); addToRunTimeSelectionTable(polyPatch, cyclicPolyPatch, word); addToRunTimeSelectionTable(polyPatch, cyclicPolyPatch, dictionary); } // * * * * * * * * * * * * Protected Member Functions * * * * * * * * * * * // void Foam::cyclicPolyPatch::initCalcGeometry(PstreamBuffers& pBufs) { polyPatch::initCalcGeometry(pBufs); } void Foam::cyclicPolyPatch::initCalcGeometry ( const primitivePatch& referPatch, pointField& nbrCtrs, vectorField& nbrAreas, pointField& nbrCc ) {} void Foam::cyclicPolyPatch::calcGeometry(PstreamBuffers& pBufs) { static_cast<cyclicTransform&>(*this) = cyclicTransform ( name(), faceCentres(), faceAreas(), *this, nbrPatchName(), nbrPatch().faceCentres(), nbrPatch().faceAreas(), nbrPatch(), matchTolerance() ); } void Foam::cyclicPolyPatch::initMovePoints ( PstreamBuffers& pBufs, const pointField& p ) { polyPatch::initMovePoints(pBufs, p); } void Foam::cyclicPolyPatch::movePoints ( PstreamBuffers& pBufs, const pointField& p ) { polyPatch::movePoints(pBufs, p); } void Foam::cyclicPolyPatch::initUpdateMesh(PstreamBuffers& pBufs) { polyPatch::initUpdateMesh(pBufs); } void Foam::cyclicPolyPatch::updateMesh(PstreamBuffers& pBufs) { polyPatch::updateMesh(pBufs); deleteDemandDrivenData(coupledPointsPtr_); deleteDemandDrivenData(coupledEdgesPtr_); } // * * * * * * * * * * * * * * * Constructors * * * * * * * * * * * * * * * // Foam::cyclicPolyPatch::cyclicPolyPatch ( const word& name, const label size, const label start, const label index, const polyBoundaryMesh& bm, const word& patchType ) : coupledPolyPatch(name, size, start, index, bm, patchType), cyclicTransform(false), nbrPatchName_(word::null), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) { // Neighbour patch might not be valid yet so no transformation // calculation possible. } Foam::cyclicPolyPatch::cyclicPolyPatch ( const word& name, const label size, const label start, const label index, const polyBoundaryMesh& bm, const word& patchType, const word& nbrPatchName ) : coupledPolyPatch(name, size, start, index, bm, patchType), cyclicTransform(false), nbrPatchName_(nbrPatchName), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) { // Neighbour patch might not be valid yet so no transformation // calculation possible. } Foam::cyclicPolyPatch::cyclicPolyPatch ( const word& name, const dictionary& dict, const label index, const polyBoundaryMesh& bm, const word& patchType ) : coupledPolyPatch(name, dict, index, bm, patchType), cyclicTransform(dict, false), nbrPatchName_(dict.lookupOrDefault("neighbourPatch", word::null)), coupleGroup_(dict), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) { if (nbrPatchName_ == word::null && !coupleGroup_.valid()) { FatalIOErrorInFunction ( dict ) << "No \"neighbourPatch\" provided." << endl << exit(FatalIOError); } if (nbrPatchName_ == name) { FatalIOErrorInFunction(dict) << "Neighbour patch name " << nbrPatchName_ << " cannot be the same as this patch " << name << exit(FatalIOError); } // Neighbour patch might not be valid yet so no transformation // calculation possible. } Foam::cyclicPolyPatch::cyclicPolyPatch ( const cyclicPolyPatch& pp, const polyBoundaryMesh& bm ) : coupledPolyPatch(pp, bm), cyclicTransform(pp), nbrPatchName_(pp.nbrPatchName_), coupleGroup_(pp.coupleGroup_), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) { // Neighbour patch might not be valid yet so no transformation // calculation possible. } Foam::cyclicPolyPatch::cyclicPolyPatch ( const cyclicPolyPatch& pp, const polyBoundaryMesh& bm, const label index, const label newSize, const label newStart, const word& neiName ) : coupledPolyPatch(pp, bm, index, newSize, newStart), cyclicTransform(pp), nbrPatchName_(neiName), coupleGroup_(pp.coupleGroup_), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) { if (neiName == name()) { FatalErrorInFunction << "Neighbour patch name " << neiName << " cannot be the same as this patch " << name() << exit(FatalError); } // Neighbour patch might not be valid yet so no transformation // calculation possible. } Foam::cyclicPolyPatch::cyclicPolyPatch ( const cyclicPolyPatch& pp, const polyBoundaryMesh& bm, const label index, const labelUList& mapAddressing, const label newStart ) : coupledPolyPatch(pp, bm, index, mapAddressing, newStart), cyclicTransform(pp), nbrPatchName_(pp.nbrPatchName_), coupleGroup_(pp.coupleGroup_), nbrPatchID_(-1), coupledPointsPtr_(nullptr), coupledEdgesPtr_(nullptr), ownToNbrOrderDataPtr_(nullptr), ownToNbrCyclicOrderDataPtr_(nullptr), ownToNbrDebugOrderDataPtr_(nullptr) {} // * * * * * * * * * * * * * * * * Destructor * * * * * * * * * * * * * * * // Foam::cyclicPolyPatch::~cyclicPolyPatch() { deleteDemandDrivenData(coupledPointsPtr_); deleteDemandDrivenData(coupledEdgesPtr_); } // * * * * * * * * * * * * * * * Member Functions * * * * * * * * * * * * * // const Foam::word& Foam::cyclicPolyPatch::nbrPatchName() const { if (nbrPatchName_.empty()) { // Try and use patchGroup to find samplePatch and sampleRegion label patchID = coupleGroup_.findOtherPatchID(*this); nbrPatchName_ = boundaryMesh()[patchID].name(); } return nbrPatchName_; } Foam::label Foam::cyclicPolyPatch::nbrPatchID() const { if (nbrPatchID_ == -1) { nbrPatchID_ = this->boundaryMesh().findPatchID(nbrPatchName()); if (nbrPatchID_ == -1) { FatalErrorInFunction << "Illegal neighbourPatch name " << nbrPatchName() << endl << "Valid patch names are " << this->boundaryMesh().names() << exit(FatalError); } // Check that it is a cyclic const cyclicPolyPatch& nbrPatch = refCast<const cyclicPolyPatch> ( this->boundaryMesh()[nbrPatchID_] ); if (nbrPatch.nbrPatchName() != name()) { WarningInFunction << "Patch " << name() << " specifies neighbour patch " << nbrPatchName() << endl << " but that in return specifies " << nbrPatch.nbrPatchName() << endl; } } return nbrPatchID_; } const Foam::edgeList& Foam::cyclicPolyPatch::coupledPoints() const { if (!coupledPointsPtr_) { const faceList& nbrLocalFaces = nbrPatch().localFaces(); const labelList& nbrMeshPoints = nbrPatch().meshPoints(); // Now all we know is that relative face index in *this is same // as coupled face in nbrPatch and also that the 0th vertex // corresponds. // From local point to nbrPatch or -1. labelList coupledPoint(nPoints(), -1); forAll(*this, patchFacei) { const face& fA = localFaces()[patchFacei]; const face& fB = nbrLocalFaces[patchFacei]; forAll(fA, indexA) { label patchPointA = fA[indexA]; if (coupledPoint[patchPointA] == -1) { label indexB = (fB.size() - indexA) % fB.size(); // Filter out points on wedge axis if (meshPoints()[patchPointA] != nbrMeshPoints[fB[indexB]]) { coupledPoint[patchPointA] = fB[indexB]; } } } } coupledPointsPtr_ = new edgeList(nPoints()); edgeList& connected = *coupledPointsPtr_; // Extract coupled points. label connectedI = 0; forAll(coupledPoint, i) { if (coupledPoint[i] != -1) { connected[connectedI++] = edge(i, coupledPoint[i]); } } connected.setSize(connectedI); if (debug) { OFstream str ( boundaryMesh().mesh().time().path() /name() + "_coupledPoints.obj" ); label vertI = 0; Pout<< "Writing file " << str.name() << " with coordinates of " << "coupled points" << endl; forAll(connected, i) { const point& a = points()[meshPoints()[connected[i][0]]]; const point& b = points()[nbrMeshPoints[connected[i][1]]]; str<< "v " << a.x() << ' ' << a.y() << ' ' << a.z() << nl; str<< "v " << b.x() << ' ' << b.y() << ' ' << b.z() << nl; vertI += 2; str<< "l " << vertI-1 << ' ' << vertI << nl; } } } return *coupledPointsPtr_; } const Foam::edgeList& Foam::cyclicPolyPatch::coupledEdges() const { if (!coupledEdgesPtr_) { const edgeList& pointCouples = coupledPoints(); // Build map from points on *this (A) to points on neighbourpatch (B) Map<label> aToB(2*pointCouples.size()); forAll(pointCouples, i) { const edge& e = pointCouples[i]; aToB.insert(e[0], e[1]); } // Map from edge on A to points (in B indices) EdgeMap<label> edgeMap(nEdges()); forAll(*this, patchFacei) { const labelList& fEdges = faceEdges()[patchFacei]; forAll(fEdges, i) { label edgeI = fEdges[i]; const edge& e = edges()[edgeI]; // Convert edge end points to corresponding points on B side. Map<label>::const_iterator fnd0 = aToB.find(e[0]); if (fnd0 != aToB.end()) { Map<label>::const_iterator fnd1 = aToB.find(e[1]); if (fnd1 != aToB.end()) { edgeMap.insert(edge(fnd0(), fnd1()), edgeI); } } } } // Use the edgeMap to get the edges on the B side. const cyclicPolyPatch& nbrPatch = this->nbrPatch(); const labelList& nbrMp = nbrPatch.meshPoints(); const labelList& mp = meshPoints(); coupledEdgesPtr_ = new edgeList(edgeMap.size()); edgeList& coupledEdges = *coupledEdgesPtr_; label coupleI = 0; forAll(nbrPatch, patchFacei) { const labelList& fEdges = nbrPatch.faceEdges()[patchFacei]; forAll(fEdges, i) { label edgeI = fEdges[i]; const edge& e = nbrPatch.edges()[edgeI]; // Look up A edge from HashTable. EdgeMap<label>::iterator iter = edgeMap.find(e); if (iter != edgeMap.end()) { label edgeA = iter(); const edge& eA = edges()[edgeA]; // Store correspondence. Filter out edges on wedge axis. if ( edge(mp[eA[0]], mp[eA[1]]) != edge(nbrMp[e[0]], nbrMp[e[1]]) ) { coupledEdges[coupleI++] = edge(edgeA, edgeI); } // Remove so we build unique list edgeMap.erase(iter); } } } coupledEdges.setSize(coupleI); // Some checks forAll(coupledEdges, i) { const edge& e = coupledEdges[i]; if (e[0] < 0 || e[1] < 0) { FatalErrorInFunction << "Problem : at position " << i << " illegal couple:" << e << abort(FatalError); } } if (debug) { OFstream str ( boundaryMesh().mesh().time().path() /name() + "_coupledEdges.obj" ); label vertI = 0; Pout<< "Writing file " << str.name() << " with centres of " << "coupled edges" << endl; forAll(coupledEdges, i) { const edge& e = coupledEdges[i]; const point& a = edges()[e[0]].centre(localPoints()); const point& b = nbrPatch.edges()[e[1]].centre ( nbrPatch.localPoints() ); str<< "v " << a.x() << ' ' << a.y() << ' ' << a.z() << nl; str<< "v " << b.x() << ' ' << b.y() << ' ' << b.z() << nl; vertI += 2; str<< "l " << vertI-1 << ' ' << vertI << nl; } } } return *coupledEdgesPtr_; } void Foam::cyclicPolyPatch::initOrder ( PstreamBuffers&, const primitivePatch& pp ) const { if (pp.empty()) { return; } if (owner()) { ownToNbrOrderDataPtr_ = new ownToNbrOrderData(); if (coupledPolyPatch::debug) { ownToNbrDebugOrderDataPtr_ = new ownToNbrDebugOrderData(); } coupledPolyPatch::initOrder ( ownToNbrOrderDataPtr_(), ownToNbrDebugOrderDataPtr_, pp ); const scalarField magAreas(mag(pp.faceAreas())); ownToNbrCyclicOrderDataPtr_ = new ownToNbrCyclicOrderData(); ownToNbrCyclicOrderDataPtr_->ctr = sum(pp.faceCentres()*magAreas)/sum(magAreas); ownToNbrCyclicOrderDataPtr_->area = sum(pp.faceAreas()); } } bool Foam::cyclicPolyPatch::order ( PstreamBuffers& pBufs, const primitivePatch& pp, labelList& faceMap, labelList& rotation ) const { if (pp.empty()) { return false; } ownToNbrOrderData ownToNbr; autoPtr<ownToNbrDebugOrderData> ownToNbrDebugPtr(nullptr); if (!owner()) { ownToNbr = nbrPatch().ownToNbrOrderDataPtr_(); ownToNbrDebugPtr = nbrPatch().ownToNbrDebugOrderDataPtr_; cyclicTransform ct ( name(), pp.faceCentres(), pp.faceAreas(), *this, nbrPatchName(), pointField(1, nbrPatch().ownToNbrCyclicOrderDataPtr_->ctr), vectorField(1, nbrPatch().ownToNbrCyclicOrderDataPtr_->area), nbrPatch(), matchTolerance() ); ownToNbr.transform(ct.transform()); if (ownToNbrDebugPtr.valid()) { ownToNbrDebugPtr->transform(ct.transform()); } } return coupledPolyPatch::order ( ownToNbr, ownToNbrDebugPtr, pp, faceMap, rotation ); } void Foam::cyclicPolyPatch::write(Ostream& os) const { coupledPolyPatch::write(os); if (!nbrPatchName_.empty()) { writeEntry(os, "neighbourPatch", nbrPatchName_); } coupleGroup_.write(os); cyclicTransform::write(os); } // ************************************************************************* // | Mid | [
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Ghosts A while ago I posted this image of the Shambles in York. It turns a simple street in the city of York into a twisted form with an unsettling atmosphere, only accentuated by the not-quite-human shape in the bottom-right of the frame. Yesterday I found myself in town with my camera and tripod, and I wanted to try and repeat this theme with other streets in York. York is supposedly the most haunted city in England, and so I think it’s fitting to name this series ‘Ghosts’. The subjects of these images are not human. They once were, but the half-second exposures have turned them into nothing but shapes. Minster YardStonegate Anyone who has been following me for a while will know that I’ve dabbled in street photography, but to be perfectly honest I’m not sure it’s my thing. To me photography is about projecting my thoughts, feelings, and experiences into the frame – whether intentionally or not – and I find that having concrete subjects in my images makes that harder. Here the people are not subjects. They are just shapes, like the buildings towering over them and the pavements on which they are walking, and what fascinates me about reducing this scene to mere shapes is that different people will see different things when they look at it. In Stonegate, I notice the man with the walking-stick, slightly less blurred than everyone else, but still with an unnerving haze surrounding him. To you he may just have been part of the background, and that, I think, says something about you as a person, just as my interest in this elderly man says something about me. | Low | [
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The IMF said the pandemic will cut world output by three per cent this year. China's economy contracted for the first time in around three decades in the first quarter as the coronavirus crisis brought the country to a standstill, according to an AFP poll of economists. The world's second-largest economy tanked in the first three months of the year as factories closed, consumers were compelled to stay home and the virus spread to other countries. Analysts from 14 institutions expect China's economy to have shrunk 8.2 percent from a year ago in the first quarter -- the first contraction since quarterly data started to be reported in the early 1990s. They also forecast that full-year gross domestic product (GDP) growth will come in at 1.7 percent, a dramatic drop from the 6.1 percent expansion logged last year and well below the pre-coronavirus prediction. If the forecast is accurate, it would represent the worst annual growth since 1976, the year Communist Party Chairman Mao Zedong died. The International Monetary Fund on Tuesday gave an even more dire estimate of 1.2 per cent growth in 2020. While many businesses in China have resumed work, the coronavirus pandemic has brought other economies to their knees around the world with many key trading partners under lockdown. The IMF said the pandemic will cut world output by three per cent this year. Economists differed on the impact of the coronavirus on China's economy, with first-quarter contraction estimates ranging from 4.6 per cent to 15 per cent. Larger Fall Than Expected China's downturn is "more disappointing than anyone expected", said Moody's Analytics economist Xu Xiaochun. He also noted that China's workforce returned to work slower than anticipated, pointing to a significant contraction in the first quarter. While labour supply will not be an issue in April and greater fiscal and monetary support for the economy is expected, "it will not be enough to overcome the heavy drag from suppressed world demand for the remainder of the year", he added. The slow return to work also bodes badly for jobs, and the unemployment rate has already risen from last December. Economists at ANZ Research noted in a recent report that double-digit contractions in economic indicators for the first two months had not been followed by a strong bounce-back in March. Labour flows were also not back to pre-virus levels, especially in major production bases, they said. "This is despite the central government's efforts in encouraging workers to return to the cities where they work, such as the relaxation of travel restrictions," they added. Difficult Recovery Although the virus situation in China has largely improved, JP Morgan chief China economist Zhu Haibin said: "External risks will likely restrain the expected second-quarter recovery in China's export-related manufacturing activity." Lockdowns in other countries could disrupt global supply chains, while fears over imported cases will probably cause a slower return to normal life, delaying the recovery of China's service consumption and domestic demand, Zhu added. Raphie Hayat, senior economist at Rabobank, added that the short-term impact of COVID-19 is expected to be "greater than the Great Financial Crisis of 2008/2009", with the fallout hurting China's growth. HSBC chief China economist Qu Hongbin warned that the shock to external demand should not be seen as a mere trade contraction. "US-China trade tensions last year showed us that an external demand shock can rapidly lead to a material deterioration in domestic demand growth," he said. The hit to supply chains is "deeper and more sprawling" this time, he added. "As we are now forecasting a contraction or very weak growth in almost all Asian countries this year, the impact of the headwinds this year for China could be much deeper and more broad-based compared with last year." | Mid | [
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/* * This program is free software; you can redistribute it and/or modify * it under the terms of the GNU General Public License as published by * the Free Software Foundation; either version 2 of the License, or * (at your option) any later version. * * This program is distributed in the hope that it will be useful, * but WITHOUT ANY WARRANTY; without even the implied warranty of * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the * GNU General Public License for more details. * * You should have received a copy of the GNU General Public License * along with this program; if not, write to the Free Software * Foundation, Inc., 59 Temple Place - Suite 330, Boston, MA 02111-1307, USA. */ package freenet.support; import java.util.Arrays; import java.util.Random; import junit.framework.TestCase; /** * Test case for {@link freenet.support.Base64} class. * * @author Alberto Bacchelli <[email protected]> */ public class Base64Test extends TestCase { // data from http://www.alanwood.net/unicode/unicode_samples.html static final String testSample = "!5Aa¥¼ÑñĄąIJijƏƐƕƺɖɞɫɷʱʬ˕˨o̕o̚ơo͡oΎΔδϠЉЩщӃԀԆԈԎԱԲաբסֶאבױ؟بحٍ۳܀ܐܠܘ݉ހސޤހި߄ߐ߰ߋ߹ࠀࠎࠏࠪ࠽ठःअठी३তঃঅ৩৵ਠਂਅਉਠੱઠઃઅઠૌ૩ଆଐଠୗ୩பஂஅபூ௩అఃఓఅౌ౩ಲಃಅಲೋ೩ഠഃഅഠൃ൩ෆංඑඣෆූกญกั๓ກຜໄ໓༣ཁངཱུངྵကဂု၄၍აზჵ჻ᄀᅙᇧᇸሀቻ፧፬ᎠᎫᏎᏴᐁᑦᕵᙧᚁᚈᚕ᚜ᚠᚳᛦᛰᜀᜄᜌᜊᜒᜠᜫᜪᜭᜯᝁᝊᝐᝊᝒᝠᝦᝮᝪᝲកឣខា៤᠀᠔ᡎᢥᢰᣇᣠᣴᤁᤥ᥅᥉ᥐᥞᥨᥲ᧠᧪᧴᧾ᨀᨁᨖᨔᨗᨠᨣᩯ᪁᪭ᬧᬀᬊᬧᭀ᭪ᮗᮀᮋᮗᮦ᮵ᰁᰘᰓᰯ᱅᱕ᱝᱰ᱿o᳐o᳢ᳩᳱᴂᴥᴽᵫḀẀẶỳἀὂᾑῼ—“‰※⁴⁾₃₌₢₣₪€o⃐o⃕o⃚o⃠℀℃№™⅛Ⅳⅸↂ←↯↻⇈∀∰⊇⋩⌂⌆⌣⌽␂␊␢␣⑀⑃⑆⑊③⑷⒌ⓦ┍┝╤╳▀▃▏░□▨◎◮☂☺♀♪✃✈❄➓⟐⟟⟥⟫⟰⟶⟺⟿⠀⠲⢖⣿⤄⤽⥈⥻⦀⦝⧰⧻⨇⨋⫚⫸⬀⬄⬉⬍ⰀⰉⰍⱙⱠⱥⱶⱺⲀⲑⲶⳂⴀⴆⴝⴢⴲⴶⵟⵥⶀⶆⶐⷖоⷠоⷩоⷶоⷿ⸁⸎⸨⸭⺀⺘⻂⻱⼀⼽⽺⿔⿰⿳⿷⿻々〒〣〰あぐるゞアヅヨヾㄆㄓㄝㄩㄱㄸㅪㆍ㆐㆕㆚㆟ㆠㆧㆯㆷㇰㇵㇺㇿ㈔㈲㊧㋮㌃㍻㎡㏵㐅㒅㝬㿜䷂䷫䷴䷾一憨田龥ꀀꅴꊩꒌ꒐꒡꒰꓆ꓐꓫꓻ꓿ꔁꔂꕝꕢꙂꙉꙮꚖꚠꛠꛕ꛰꛷꜁꜉ꜜꜟꜢꜮꝿꟿꠀꠇꠠꠤ꠪꠰꠶꠸꠹ꡁꡧꡳ꡷ꢝꢁꢍꢳ꣕ठ꣠ठ꣮ꣳꣻ꤅ꤎꤍꤪ꤮ꤰꤸꤷꥐ꥟ꥠꥪꥴꥼꦮꦀꦣꦮꦺ꧙ꨅꨍꨂꨬ꩖ꩠꩮꩴဂꩻꪀꪙꪒꪷ꫟ꯀꯌꯁꯧ꯹가뮀윸힣ힰퟎퟡퟻ豈朗歷館fffiﬗﭏﭐﰡﲼﷻo︠o︡o︢o︣︴︵﹃﹌﹖﹠﹩﹫ﹰﺗﺺﻼ３Ｆｶﾺ�𐀀𐀢𐁀𐁝𐂀𐂚𐃃𐃺𐄀𐄎𐄱𐄸𐅃𐅉𐅓𐆉𐆐𐆔𐆘𐆚𐇐𐇛𐇯𐇹𐊀𐊉𐊕𐊚𐊡𐊨𐊾𐋋𐌀𐌊𐌜𐌢𐌰𐌸𐍂𐍊𐎀𐎇𐎖𐎟𐐂𐐉𐐯𐑉𐑐𐑝𐑫𐑿𐒀𐒎𐒝𐒨𐠀𐠓𐠦𐠿𐡀𐡋𐡓𐡟𐤀𐤈𐤔𐤕𐤠𐤩𐤰𐤿𐨀𐨨𐨍𐨲𐩅𐩠𐩯𐩽𐩿𐬀𐬟𐬩𐬿𐭀𐭉𐭚𐭟𐭠𐭬𐭹𐭿𐰀𐰕𐰯𐱈𐹠𐹮𐹵𐹻𑂞𑂀𑂚𑂞𑂴𑃁𒀀𒀞𒅑𒍦𒐁𒐌𒐥𒑳𓀀𓅸𓉀𓐮𝁆𝂋𝃩𝃰𝄁𝄫𝅘𝅥𝅮𝇇𝌀𝌃𝌑𝍊𝍠𝍨𝍬𝍱𝓐𝕬𝝃𝟽🀀🀍🀒🀝🀴🁓🁮🂈🄀🄖🄭🆐🈐🈖🈪🉈𠀧𠤩𡨺𡽫𪜀𪮘𪾀𫜴勺卉善爨"; static final String testSampleStandardEncoding = "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"; static final String toEncode = "Man is distinguished, not only by his reason, but by this singular " + "passion from other animals, which is a lust of the mind, that by a perseverance " + "of delight in the continued and indefatigable generation of knowledge, exceeds " + "the short vehemence of any carnal pleasure."; static final String toDecode = "TWFuIGlzIGRpc3Rpbmd1aXNoZWQsIG5vdCBvbmx5IGJ5IGhpcyByZWFzb24sIGJ" + "1dCBieSB0aGlzIHNpbmd1bGFyIHBhc3Npb24gZnJvbSBvdGhlciBhbmltYWxzLCB3aGljaCBpcyBhIG" + "x1c3Qgb2YgdGhlIG1pbmQsIHRoYXQgYnkgYSBwZXJzZXZlcmFuY2Ugb2YgZGVsaWdodCBpbiB0aGUgY" + "29udGludWVkIGFuZCBpbmRlZmF0aWdhYmxlIGdlbmVyYXRpb24gb2Yga25vd2xlZGdlLCBleGNlZWRz" + "IHRoZSBzaG9ydCB2ZWhlbWVuY2Ugb2YgYW55IGNhcm5hbCBwbGVhc3VyZS4"; /** * Test the encode(byte[]) method * against a well-known example * (see http://en.wikipedia.org/wiki/Base_64 as reference) * to verify if it encode works correctly. */ public void testEncode() throws Exception { byte[] aByteArrayToEncode = toEncode.getBytes("UTF-8"); assertEquals(Base64.encode(aByteArrayToEncode), toDecode); } /** * Test the decode(String) method * against a well-known example * (see http://en.wikipedia.org/wiki/Base_64 as reference) * to verify if it decode an already encoded string correctly. */ public void testDecode() throws Exception { String decodedString = new String(Base64.decode(toDecode)); assertEquals(decodedString, toEncode); } /** * Test the encodeStandard(byte[]) method * This is the same as encode() from generator/js/src/freenet/client/tools/Base64.java */ public void testEncodeStandard() throws Exception { byte[] aByteArrayToEncode = testSample.getBytes("UTF-8"); assertEquals(Base64.encodeStandard(aByteArrayToEncode), testSampleStandardEncoding); } /** * Test the decodeStandard(byte[]) method. * This is the same as decode() from generator/js/src/freenet/client/tools/Base64.java */ public void testDecodeStandard() throws Exception { String decodedString = new String(Base64.decodeStandard(testSampleStandardEncoding), "UTF-8"); assertEquals(decodedString, testSample); } /** * Test encode(byte[] in) * and decode(String inStr) methods, * to verify if they work correctly together. * It compares the string before encoding * and with the one after decoding. */ public void testEncodeDecode() { byte[] bytesDecoded; byte[] bytesToEncode = new byte[5]; //byte upper bound bytesToEncode[0] = 127; bytesToEncode[1] = 64; bytesToEncode[2] = 0; bytesToEncode[3] = -64; //byte lower bound bytesToEncode[4] = -128; String aBase64EncodedString = Base64.encode(bytesToEncode); try { bytesDecoded = Base64.decode(aBase64EncodedString); assertTrue(Arrays.equals(bytesToEncode,bytesDecoded)); } catch (IllegalBase64Exception aException) { fail("Not expected exception thrown : " + aException.getMessage()); } } /** * Test the encode(String,boolean) * method to verify if the padding * character '=' is correctly placed. */ public void testEncodePadding() { byte[][] methodBytesArray = { //three byte Array -> no padding char expected {4,4,4}, //two byte Array -> one padding char expected {4,4}, //one byte Array -> two padding-chars expected {4}}; String encoded; for (int i = 0; i<methodBytesArray.length; i++) { encoded = Base64.encode(methodBytesArray[i],true); if (i == 0) //no occurrences expected assertEquals(encoded.indexOf('='),-1); else assertEquals(encoded.indexOf('='),encoded.length()-i); } } /** * Test if the decode(String) method * raise correctly an exception when * providing a string with non-Base64 * characters. */ public void testIllegalBaseCharacter() { // TODO: check many other possibile cases! String illegalCharString = "abcd=fghilmn"; try { Base64.decode(illegalCharString); fail("Expected IllegalBase64Exception not thrown"); } catch (IllegalBase64Exception exception) { assertSame("illegal Base64 character",exception.getMessage()); } } /** * Test if the decode(String) method * raise correctly an exception when * providing a string with a * wrong Base64 length. * (as we can consider not-padded strings too, * the only wrong lengths are the ones * where -> number MOD 4 = 1). */ public void testIllegalBaseLength() { //most interesting case String illegalLengthString = "a"; try { Base64.decode(illegalLengthString); fail("Expected IllegalBase64Exception not thrown"); } catch (IllegalBase64Exception exception) { assertSame("illegal Base64 length",exception.getMessage()); } } /** * Random test * * @throws IllegalBase64Exception */ public void testRandom() throws IllegalBase64Exception { int iter; Random r = new Random(1234); for (iter = 0; iter < 1000; iter++) { byte[] b = new byte[r.nextInt(64)]; for (int i = 0; i < b.length; i++) b[i] = (byte) (r.nextInt(256)); String encoded = Base64.encode(b); byte[] decoded = Base64.decode(encoded); assertEquals("length mismatch", decoded.length, b.length); for (int i = 0; i < b.length; i++) assertEquals("data mismatch: index " + i + " of " + b.length + " should be 0x" + Integer.toHexString(b[i] & 0xFF) + " was 0x" + Integer.toHexString(decoded[i] & 0xFF), b[i], decoded[i]); } } } | Mid | [
0.6341463414634141,
27.625,
15.9375
] |
Café Incognito Sometimes an idea sounds so good that you just have to look past its gratuitous extravagance, technical obstacles, logistical complexities, and uncertain outcomes and just fucking do it. So it went when I started talking to Jay Cunningham at Intelligentsia. Jay is a fifteen-year coffee pro who loves beer but thinks putting the two together has not generally been a very inspired process and that the results are not generally all that good. The tilt of coffee beer is unfortunately towards that generic burnt-caramel roast character that flows by the thousands of gallons from donut shop Bunns every morning, everywhere. It smells like what people think of as coffee, but to someone like Jay who’s been around the world buying beans and selling the end product, that’s what stale coffee smells like.We found common ground in our shared yawn at coffee beer in general, and in our shared hope for the idea that coffee beer can be great when it’s surprising and different, like when the coffee adds something of the delicate floral, fruity, nutty medley that is locked up in different character and degree in every variety. We learned this about each other when we teamed up for Good Beer Hunting’s Uppers & Downers event in Los Angeles last October, and we’re excited to bring you some new beers as a result of that initial encounter. Jay’s hope-giving coffee beer was Hell’s Black Intelligencer, the oatmeal coffee stout he created with Three Floyds. Jay told me that the coffee character was so strong that it almost didn’t take like beer–it was like something else entirely. It marked the first time Jay ever thought “Did we add too much coffee?” and that, for him, was a sign that it was challenging his expectations and worth the nonstop three days of brewing he had done. For me, it happened twice. First, it was To Øl Sleep Over Coffee IIPA, a really bizarre and intense beer that I was lucky to have really fresh and in great condition (thanks Bangers & Lace, you guys always fucking rock). It was eye-opening and had less roast character than fruitiness and acidity. I know brewers try all they can to keep coffee acidity and bitterness out of their beer, but I can’t really get on board with that. The second beer was a Bavarian-style wheat beer with Brazilian coffee by Urban Chestnut. Earthy, bready, slightly chocolatey, and as banana-laden and straw-colored as your favorite German standard. It was a really round, pleasant beer that tasted like nothing else I had ever tried–except our own Khlörost, which was something like the Belgian cousin of Urban Chestnut’s beer. We aspired to select some really interesting coffee and bring some of those flavors together with the nuances of hops and fermentation in ways that go beyond “roast-plus-stout-equals-roastier-stout!!!” and ended up with two beers that we hope will bring your tastebuds into terra incognita. It’s kind of an awkward time to mention this, but, um, one of them happens to be a stout. Stick with me; you’ll see why. Muerte Inmaculada Death By Viking, our imperial IPA, meets Laurina, an extremely rare coffee from the cutting-edge Café Inmaculada project in Colombia, where it is grown at 1780 meters alongside other experimental cultivars that were obtained from a research center in the country. Laurina was brought to the United States and expertly roasted by Intelligentsia Coffee for their Café Inmaculada collection, which sold out before its release. Laurina, also known as Bourbon Pointu, originally comes from Réunion Island off the coast of Madagascar and is considered the original Bourbon. It is responsible for seeding most of Latin America, though it was forgotten for almost the entire last century because of its low caffeine content and yield–that is, until Camilo Marizalde and his team decided to revive it alongside pilot plots of other ancient and special coffee with the most advanced technology available today. Irresponsible to put such a rare and distinguished coffee in a beer? Maybe. Surprising, delicious, and one-of-a-kind? Absodamnlutely. Jay cold-brewed one gallon of coffee concentrate and together we blended it carefully with fourteen gallons of finished beer so that both hop, fermentation, coffee character share your palate peacefully, in the kind of harmony and complexity you would expect to feel at two kilometers above sea level overlooking the coffee fields stretching across Colombia’s mountainous tropics. Allow it to warm and try it alongside Death to really smell and taste the coffee’s contribution. Very, very limited quantities. In the taproom until it’s gone, then maybe one more time for a special something or other, like when Uppers & Downers comes to Chicago. 90ish IBUs, 9.3% ABV. Most Important Beverage of the Day I know I said that adding coffee to already roasty beer isn’t usually all that interesting. Sure, there are lots of great examples, but they tend to emphasize the same character in coffee when there’s so much more to work with. That doesn’t mean there’s no point making a good one, or no hope of doing something different. We opted for the latter. The vision was for a breakfast stout of sorts, one that combined the creaminess of milk, cocoa fluffiness of chocolate milk, tangy acidity of coffee, and bright fruitiness of orange juice. We built the base beer as an eight-percent-ABV, extra-full-bodied milk stout with all British malt, including two varieties of chocolate malt and a hearty helping of roasted barley. We hopped with Centennial for its orange-citrus character and added sweet orange peel to the whirlpool. After the beer was finished fermenting, we blended a sample from the fermenter with several different coffees and arrived at Ljulu Lipati from Zambia as the right match. It had the brightness of grapefruit zest and tart cherry and enough acidity to cut through an already full-flavored beer. This time, though, we had about twenty-five barrels (fifty kegs) of beer to work with after we filled two Heaven Hill bourbon barrels (watch for Beverage of Champions later this year or next), not half a barrel like we did with Muerte. Our blending session showed us that we needed about sixty-five gallons of coffee concentrate to hit the right concentration, requiring eighty-five pounds of coffee and eighty-five gallons of water to start with. That’s a lot of coffee, and there’s really no perfect method for brewing and adding such a huge amount to beer. Jay can make five gallons at a time at Intelligentsia, at twelve hours per brew. No good. We decided instead to brew it all at once in a seven-barrel brite tank we keep around the brewery for crazy projects like this. The tank doesn’t have its own method of straining grounds from brewed coffee, so we had to bag all of the grounds in mesh bags and tie them up off the bottom of the vessel to avoid blocking the port we would later use to transfer, but low enough that they would be saturated with the tank less than half-full. We weren’t sure we would get the right amount of saturation and extraction, so we roiled the tank repeatedly with carbon dioxide to move the bags around, which also served to deaerate the coffee and protect the finished beer from staling. We also thought the orange character was a bit weak, so made a strong tea of sweet orange peel and pushed it into the tank along with the coffee. The result? I really, really like it, but you’ll have to try it for yourself. Available now in the taproom for at least few weeks and out in the Chicagoland area on draft as early as next week. 35 IBUs, 7.2% ABV after blending. Photo credit to Michael Kiser, www.GoodBeerHunting.com on the header and photo of John Barley and Jay Cunningham. Intelligentsia on the shots of Colombian coffee cherries, Camilo showing off the goods, and the Laurina drying bed. Jay and Paul on the rest. SOBs tend to keep to themselves, until we don’t. Sometimes the need to connect with others and share in the work of making beer calls for collaboration with other artisans who share our dedication to experimentation and quality, but whose expertise in a given field far surpasses anything we could learn on The Google. These are those stories. Most Important Beverage of the Day—HELL YES. Only wish I had some to start the day too. Paul said it would be ready on Tuesday, and we were so happy it was when we stopped in last night. What a superb stout.!!!! The orange at the end is a real kicker. Great beer—hope to see more stouts and porters | Mid | [
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Main menu Breadcrumb Inclusive Early Childhood Education Final Conference The Inclusive Early Childhood Education (IECE) conference took place on 1–2 November 2017 in Lisbon, Portugal. The Agency organised this event in co-operation with the General-Directorate of Education, Ministry of Education and Science, Portugal. The conference aimed to highlight and present the project’s main outcomes: the Self-Reflection Tool to improve the inclusiveness of the early childhood education environment. Some 180 participants attended the conference. These included project experts, Agency country representatives and Portuguese experts, as well as speakers from international organisations and European institutions. The conference programme consisted of panel presentations in plenary and parallel workshop sessions where participants discussed key project themes and explored in depth how to use the Ecosystem Model of IECE and the Self-Reflection Tool. The conference was closed by the Agency’s Chair, Ana Magraner, together with Ana Sofia Antunes, Secretary of State for Inclusion of People with Disabilities, Portugal, and João Costa, Secretary of State of Education, Portugal. The conference presentations and materials will be available on the project web area. Closing session with (from left to right): João Costa, Secretary of State of Education, Portugal; Ana Magraner, Agency Chair; Ana Sofia Antunes, Secretary of State for Inclusion of People with Disabilities, Portugal | High | [
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South Australian researchers claim they have made a significant breakthrough in tackling HIV and hepatitis C, using a new type of DNA vaccine which protects against the viruses and could possibly provide a cure in five years. A new study produced by Alzheimer’s Australia suggests up to 80 per cent of dementia patients in aged care facilities are being treated with psychotropic drugs. The Fair Work Commission has dismissed an appeal by the sacked Geelong Hospital anaesthetist, Mark Colson, to try to get his job back. Adelaide researchers claim breakthrough in tackling HIV and hepatitis C with DNA vaccine – Caroline Winter South Australian researchers claim they have made a significant breakthrough in tackling HIV and hepatitis C, using a new type of DNA vaccine which protects against the viruses and could possibly provide a cure in five years. The DNA vaccine stimulates the body’s immune response and combines with the white blood cells to kill HIV or hepatitis C cells. Adelaide University’s Professor Eric Gowans says the vaccine has already had positive results in animals, with human trials to start next year. Professor Gowans says he has found a way to stimulate the body’s immune system response which helps deliver the vaccine. “DNA vaccines in general have enormous potential, but haven’t worked very well in large animals and in patients, They work very nicely in mice and we’ve developed a protocol and a technique that simplifies the whole process and makes a DNA vaccine very much more effective in large animals.” He says DNA vaccines usually target muscles, but his technique injects DNA into the skin. “Because we want to improve the efficacy of the DNA vaccination, we target the skin because the skin has a much greater proportion of white blood cells, which are important for the kind of immunity that we’re trying to impart. What we need to do is to target that small population of white blood cells, which circulate generally in the body, and unless the vaccine targets those cells, the vaccine isn’t effective and isn’t efficient in any way. So we’ve developed a strategy that targets these white blood cells in an indirect manner; we generate a little inflammation and that attracts all these white blood cells to that site of vaccination.” Professor Gowans says other researchers have used skin to deliver the vaccine, but not to target white blood cells in this way. “We kill the cells that the vaccine is targeted to, and then those dead cells are highly inflammatory and they attract more of these white blood cells, so that is the difference,” he said. The vaccine is currently designed to treat patients who already have hepatitis C, Those human trials will involve about 40 people infected with hepatitis C. But Professor Gowans says it is likely it could be used as a preventative vaccine for hepatitis C and HIV in the next five years. “It’s a significant advance; the strategy is novel, because we have the patent and it’s been examined. I don’t want to be too optimistic, but I think when we do the clinical trial next year, I think we can then begin to work out how best to take it forward from there.” Up to 80 per cent of dementia patients in aged care facilities restrained with psychotropic drugs: report – by Steve Cannane A new study produced by Alzheimer’s Australia suggests up to 80 per cent of dementia patients in aged care facilities are being treated with psychotropic drugs. The report suggests only one in five dementia patients receive any benefit from taking such medication. Anti-depressants, anti-anxiety medications and ADHA drugs are some examples. Alzheimer’s Australia says the use of drugs in nursing homes is excessive and it has called for reform of the sector. Psychotropic drugs are psychiatric medicines that alter chemical levels in the brain, affecting mood and behaviour. Alzheimer’s Australia chief executive Glenn Rees says about 140,000 nursing home residents are being sedated and restrained with psychotropic drugs. “For people with dementia in residential care – and remember that people with dementia account for 50 per cent of residents – about 80 per cent will be on restraint at some time or other,” he said. “Restraint can be necessary and as an organisation we accept that physical restraint in some circumstances and medical restraint are necessary, but we think it should be the last resort, not the first resort.” But the aged care industry argues it has been following the advice of medical professionals. “It’s not the aged care facility that does the diagnosis nor prescribes the medication,” said Patrick Reid, the chief executive of Leading Age Services Australia. “They’re acting on the … information from the clinical pathway, from a doctor.” But Mr Rees says there are alternatives to medication. “There are a number of things that can be done to reduce restraint,” he said. “One is to adapt the physical environment so it’s less confusing and less noisy. Another is to give a person activities and a sense of purpose in life, whether it’s rehabilitation, social activities, physical recreation. “Another is to adopt person-centred care approaches so that the care staff can relate better to the individual and know their personal histories.” Mr Reid says the industry is open to change. “Any changes to environment, whether it be the built environment, the culture and other things, are important,” he said. “Certainly many of the refurbishments we are seeing in aged care, about 60 per cent of new buildings are around improving that environment. So I think it is a positive. “My members do embrace those approaches and are trying very hard to make sure everyone is treated as well as they can be, and with their dignity and respect.” A Senate committee has been hearing evidence about the overuse of psychotropic drugs in aged care facilities. The committee will hand down its recommendations today. Geelong Hospital doctor’s appeal against sacking dismissed – Margaret Paul The Fair Work Commission has dismissed an appeal by the sacked Geelong Hospital anaesthetist, Mark Colson, to try to get his job back. Dr Colson was dismissed in May 2012 as a result of allegations of serious misconduct. Last year, the Fair Work Commission decided his dismissal was conducted unfairly and ordered Barwon Health to pay him $59,050 in compensation, which was the maximum penalty available at the time. Dr Colson’s former colleagues estimate his loss of earnings would be more than $400,000. The Fair Work Commission’s Deputy President, Val Gostencnik, found that although it would be challenging for Dr Colson to find similar work as an anaesthetist in Geelong, reinstatement was not the answer. “Although this matter is finely-balanced and the significant consequences for Dr Colson in not being reinstated has weighed heavily on me, I am satisfied, based on the totality of the evidence, that reinstatement in this case is inappropriate,” he said. “The relationship of trust and confidence between Barwon Health’s managers responsible for Dr Colson, along with the management of the department and Dr Colson, has broken down and the evidence strongly points to a conclusion that the relationship cannot be repaired, making ongoing employment unworkable.” Yesterday, the full bench of the Fair Work Commission refused Dr Colson’s application to appeal against that decision. A spokeswoman for Barwon Health says the hospital accepts the decision. | High | [
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Sources of variation in the interaction between three cereal aphids (Hemiptera: Aphididae) and wheat (Poaceae). The relative contributions of host plant, herbivore species and clone to variation in the interaction between cereal aphids and wheat were investigated using five clones each of three species, Rhopalosiphum padi (Linnaeus), Sitobion avenae (Fabricius) and Schizaphis graminum (Rondani), on seedlings of two cultivars of Triticum aestivum L. and one cultivar of Triticum durum Desf. More individuals and biomass of R. padi than of the other two species were produced on seedlings. The three wheat cultivars lost similar amounts of biomass as a result of infestation by aphids, with the amount lost depending on aphid species: S. avenae caused the lowest loss in biomass. Variation in aphid biomass production was due mostly to differences among aphid species (70%), less to the interaction between wheat type and aphid species (7%), and least to aphid clone (1%). The specific impact of the aphids on the plants ranged from 1.7 to 3.7 mg of plant biomass lost per mg of aphid biomass gained, being lowest for R. padi and highest for S. graminum. Variation in plant biomass lost to herbivory was due mostly to unknown sources of error (95%), probably phenotypic differences among individual seedlings, with 3% due to aphid species and none attributable to aphid clone. For these aphid-plant interactions, differences among aphid clones within species contributed little to variation in aphid and plant productivity; therefore, a small sample of clones was adequate for quantifying the interactions. Furthermore, one clone of each species maintained in the laboratory for about 200 parthenogenetic generations was indistinguishable from clones collected recently from the field. | Mid | [
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Q: How do I initialize a Counter from a list of key/initial counts pairs? If I have a sequence of (key, value) pairs, I can quickly initialize a dictionary like this: >>> data = [ ('a', 1), ('b', 2) ] >>> dict(data) {'a': 1, 'b': 2} I would like to do the same with a Counter dictionary; but how? Both the constructor and the update() method treat the ordered pairs as keys, not key-value pairs: >>> from collections import Counter >>> Counter(data) Counter({('a', 1): 1, ('b', 2): 1}) The best I could manage was to use a temporary dictionary, which is ugly and needlessly circuitous: >>> Counter(dict(data)) Counter({'b': 2, 'a': 1}) Is there a proper way to directly initialize a Counter from a list of (key, count) pairs? My use case involves reading lots of saved counts from files (with unique keys). A: I would just do a loop: for obj, cnt in [ ('a', 1), ('b', 2) ]: counter[obj] = cnt You could also just call the parent dict.update method: >>> from collections import Counter >>> data = [ ('a', 1), ('b', 2) ] >>> c = Counter() >>> dict.update(c, data) >>> c Counter({'b': 2, 'a': 1}) Lastly, there isn't anything wrong with your original solution: Counter(dict(list_of_pairs)) The expensive part of creating dictionaries or counters is hashing all of the keys and doing periodic resizes. Once the dictionary is made, converting it to a Counter is very cheap about as fast as a dict.copy(). The hash values are reused and the final Counter hash table is pre-sized (no need for resizing). | Mid | [
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1. Introduction {#sec1-ijms-21-00307} =============== Hypoxia is characterized by a decrease in the partial pressure of oxygen in the blood and a consequent decreased supply of oxygen to the tissues. This condition can occur both in para-physiological conditions (subjects exposed to low atmospheric pressures, at high altitudes) and as a consequence of respiratory pathologies such as Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF). In such pathologies, as long as in the maladaptation to high altitude which results in High Altitude Pulmonary Edema (HAPE), both the hypoxia-induced and inflammatory pathways play a key role in determining the disease progression. Inflammation is one of the main mechanisms influencing the maladaptation to hypoxia, especially when causing a chronic decrease in hemoglobin (Hb) production, a phenomenon known as anemia of inflammation. Alveolar hypoxia itself is a strong inducer of pulmonary inflammation. It is well recognized that it generates reactive oxygen species (ROS) and that it promotes nuclear factor kappa B (NFĸB) activation, which in turn upregulates numerous pro-inflammatory cytokines such as IL-1, IL-6, and TNFα \[[@B1-ijms-21-00307]\]. Excess ROS production, enhanced by the presence of unbound iron through the Fenton reaction \[[@B2-ijms-21-00307]\], results in lipid peroxidation \[[@B3-ijms-21-00307]\] and in the decrease in vasodilator NO pool \[[@B2-ijms-21-00307]\]. Chen and colleagues observed that alveolar hypoxia triggers pulmonary vasoconstriction and systemic inflammation by activating alveolar macrophages that in turn promote the ET-1, iNOS, and NO/cGMP pathways \[[@B4-ijms-21-00307]\]. In a model of inflammation following aspiration-induced lung injury, HIF-1α robust increase upregulates the release of pro-inflammatory cytokines depending on NF-κB signaling in type 2 alveolar epithelial cells \[[@B5-ijms-21-00307]\]. In this narrative review, we mention respiratory pathologies as examples of either acute (HAPE and ARDS) or chronic (CF and COPD) hypoxia, and highlight some of the potential mechanisms influencing the prognosis of patients. We will focus on the roles of iron and sphingolipid (SPL) metabolism in determining the adaptation or maladaptation to hypoxia, either physiological or pathological. Upon an overview of the role of iron and SPL in hypoxia, we started by reviewing studies investigating the effects of hypoxia on healthy subjects at high altitude. Then, we looked for studies assessing the most relevant markers that could correlate with prognosis and therapy in hypoxic patients. Our aim is to identify pathways and/or markers involved in the para-physiological adaptation to low atmospheric pressures (high altitudes) that could play a key role in pathological adaptation to hypoxia conditions such as HAPE, or respiratory pathologies such as ARDS, COPD, and CF. 2. Maladaptation to Hypoxia: The Case of HAPE and Respiratory Pathologies {#sec2-ijms-21-00307} ========================================================================= 2.1. High-Altitude Pulmonary Edema {#sec2dot1-ijms-21-00307} ---------------------------------- HAPE is a potentially fatal condition, occurring at altitudes greater than 3,000 m. It affects rapidly ascending, non-acclimatized healthy individuals and it is the leading cause of death due to high-altitude illnesses \[[@B6-ijms-21-00307]\]. At 3000 m, the reduction in mitochondrial PO2 due to the hypobaric hypoxia induces dysfunctions into the electron transport chain that fails in providing cellular energy. As recently reviewed by Montgomery and colleagues \[[@B7-ijms-21-00307]\], the hypoxic pulmonary vasoconstriction (HPV) that redistributes the pulmonary perfusion and the activation of HIF-1α-mediated pathways that ameliorate the oxygen availability can override the regional hypoxia in healthy subjects. In the case of HAPE, hypoxia is not regional, and this leads to exaggerated HPV which may end up in overperfusion of the non-constricted pulmonary vessels \[[@B8-ijms-21-00307]\] and eventually in pulmonary hypertension and edema. Currently, misdiagnosis is quite frequent due to the broad heterogeneity of clinical symptoms and the characterization of metabolites involved in the pathophysiology of HAPE would be of great value. 2.2. Acute Respiratory Distress Syndrome {#sec2dot2-ijms-21-00307} ---------------------------------------- ARDS is an acute condition characterized by sudden onset of severe hypoxemia without evidence of heart failure or volume overload \[[@B9-ijms-21-00307]\]. As it is a severe condition with multiple and complex etiology, it requires hospitalization in the Intensive Care Unit (ICU), and has a high mortality (35--46%) \[[@B10-ijms-21-00307]\]. The main feature of ARDS is an increase in pulmonary capillary permeability. Protein-rich fluids accumulate inside the alveoli, as a result of the damage to the capillary endothelium and alveolar epithelium \[[@B11-ijms-21-00307]\]. In several patients, ARDS is associated with low Hb despite persisting hypoxia, down to severe anemia (\<8 g/dl Hb), which correlates with worse prognosis \[[@B12-ijms-21-00307],[@B13-ijms-21-00307]\]. Frequent among ICU patients \[[@B14-ijms-21-00307]\], this anemia may be due to inflammation. 2.3. Chronic Obstructive Pulmonary Disease {#sec2dot3-ijms-21-00307} ------------------------------------------ COPD is a prevalent airway disease functionally characterized by non or partly reversible proximal bronchial obstruction that is a major cause of respiratory disability \[[@B15-ijms-21-00307]\]. Exposure to inhaled pollutants and most often to cigarette smoke \[[@B16-ijms-21-00307]\] leads to chronic airway and lung inflammation that is regarded to promote structural changes, obstructions, and respiratory symptoms \[[@B17-ijms-21-00307]\]. Small airways (inner diameter less than 2 mm) give the major contribution to airflow limitation in COPD since intraluminal obstruction could occur for mucus or substances deposition or for increased wall thickness \[[@B18-ijms-21-00307]\]. Moreover, loss of alveolar attachment could alter the luminal diameter by means of small airway distortion \[[@B19-ijms-21-00307]\]. Pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension precede development of alveolar destruction, as seen in the lungs of a mouse model of emphysema and in lung tissue from humans with end-stage COPD \[[@B20-ijms-21-00307]\]. Beyond small airway obstruction, pulmonary vascular abnormalities triggered by the inflammatory process may participate in COPD disability. Hypoxia-induced vascular changes may characterize the early onset as well as the disease evolution of COPD, contributing to pulmonary hypertension and heart dysfunction \[[@B21-ijms-21-00307]\]. Due to hypoxia-mediated lung vessel remodeling, COPD patients exhibit structural alterations of the intimal layer in small pulmonary arteries \[[@B22-ijms-21-00307]\], vessel wall thickening, proliferation of vascular smooth muscle, and infiltration of inflammatory cells \[[@B23-ijms-21-00307]\]. Low levels of oxygen activate HIF-1α that controls the transcription of genes regulating angiogenesis, vascular remodeling, and glucose metabolism \[[@B24-ijms-21-00307]\]. In response to HIF-1α, platelet derived growth factor β (PDGF β) is released in the endothelium, thus favoring the vasodilation of pulmonary arterial smooth muscle \[[@B25-ijms-21-00307]\] together with vascular endothelial growth factor (VEGF), involved in tissue remodeling and angiogenesis in COPD \[[@B26-ijms-21-00307]\]. 2.4. Cystic Fibrosis {#sec2dot4-ijms-21-00307} -------------------- CF is a fatal genetic disorder caused by dysfunction of the anion transporter cystic fibrosis transmembrane conductance regulator (CFTR), which is expressed on the apical membrane of epithelial secretory cells. It involves several organs, but mortality is mainly due to lung disease. The reduced epithelial chloride transport and the excessive sodium reabsorption lead to dehydrated surface airway liquid, increased viscosity of the mucus layer, and plugging of the airway lumen \[[@B27-ijms-21-00307],[@B28-ijms-21-00307]\]. Lumen obstruction caused by mucus plaques together with increased epithelial oxygen consumption probably due to enhanced ENaC-mediated sodium transport \[[@B27-ijms-21-00307],[@B29-ijms-21-00307]\], create regional hypoxic niches within airway epithelial cells \[[@B30-ijms-21-00307]\]. CF patients are characterized by perfusion deficit and the dysfunctional CFTR impairs the HIF-1α stabilization and activity thus affecting the adaptive response to hypoxia. The unresolved regional hypoxia exacerbates neutrophilic sterile inflammation that is triggered by the release of IL-1α. In fact, the hypoxic stimulus promotes the necrosis of airway cells and the consequent passive release of IL-1α together with the activation of NLRP3 inflammasome that in turn results in the active release of IL-1α \[[@B7-ijms-21-00307]\]. 3. The Variegate Pathways Involved in Hypoxia Adaptation {#sec3-ijms-21-00307} ======================================================== Hypoxia activates rho kinase, inducing vasoconstriction \[[@B31-ijms-21-00307]\]. Hypoxic pulmonary vasoconstriction (HPV) is known as an adaptive mechanism that optimizes pulmonary ventilation-perfusion matching in regional hypoxia. Such phenomenon can be both protective and harmful, depending on the hypoxia condition to which the subject is exposed. In case of global hypoxia, as it happens at high altitude, or if the respiratory impairment involves most of the lung area, HPV can be harmful, as a potential cause of pulmonary hypertension \[[@B8-ijms-21-00307],[@B32-ijms-21-00307]\]. On the other hand, when hypoxia is restricted to a confined area of the lung, HPV allows the blood flow to be deviated to the better ventilated compartments, in order to compensate the local lack of O~2~. The mechanism triggering HPV involves an impairment in the redox equilibrium that triggers the smooth cells' contraction \[[@B8-ijms-21-00307]\]. The main mechanism of adaptation involves the inducible transcription factors HIF-1α and HIF-2α, which enhance the transcription of several proteins with the aim of increasing oxygen availability \[[@B33-ijms-21-00307]\]. One of these proteins, upregulated through HIF-2 is erythropoietin \[[@B34-ijms-21-00307]\], which causes an increase in hematopoiesis and circulating Hb, as an attempt to optimize the transport of the available oxygen \[[@B35-ijms-21-00307]\], Hb levels increase with altitude in acclimatized newcomers, but vary among high-altitude populations \[[@B36-ijms-21-00307]\]. Higher Hb values are common among the Oromo population of East Africa, which lives at 4000 m above sea level, as compared to the values of a population living at lower altitude \[[@B37-ijms-21-00307]\]. An excessive increase in hemoglobin can promote cardiovascular disease and pulmonary hypertension in those populations \[[@B38-ijms-21-00307]\]. Recently, iron and SPL metabolisms have been considered as potentially involved in hypoxia adaptation response. The relationship between hypoxia and iron metabolism has been widely explored as therapeutic targets for anemic patients \[[@B39-ijms-21-00307]\]. Indeed, the PubMed hits for the terms "hypoxia" AND "iron" total more than 2500. A less explored field is the role of SPL in hypoxia (224 PubMed hits). This heterogeneous class of lipids plays, on the other hand, a key role in the inflammation enhancing hypoxia in respiratory diseases, and in hypoxia itself \[[@B40-ijms-21-00307],[@B41-ijms-21-00307]\]. 3.1. Hypoxia and Iron Metabolism: Role of Hepcidin {#sec3dot1-ijms-21-00307} -------------------------------------------------- Since iron is an essential component of Hb, the response to hypoxia also increases the need for iron. In fact, HPV and the potential consequent hypoxic pulmonary hypertension may be reduced by iron supplementation and exacerbated in case of iron deficiency \[[@B42-ijms-21-00307],[@B43-ijms-21-00307]\]. In order to optimize iron use for hematopoiesis, the degradation of ferroportin (Fpn) must be reduced. Fpn is the transmembrane protein that allows the release of iron from the cells, mediating its intestinal absorption, and subsequent release into the circulation, bound to its transporter, the transferrin. Fpn degradation is mediated by the regulating peptide hepcidin, whose decrease, in healthy subjects, contributes to a good compensatory response to hypoxia and to iron deficiency \[[@B44-ijms-21-00307]\]. A decrease in hepcidin has indeed been observed in healthy subjects exposed to high altitude hypoxia, both after acute (hours) and chronic (weeks) exposure \[[@B45-ijms-21-00307],[@B46-ijms-21-00307]\]. However, in the clinical setting, hepcidin is not yet considered among the routine parameters for the assessment of iron metabolism, although some studies are considering its decrease as a factor suggestive of the need for iron-based intravenous therapy \[[@B47-ijms-21-00307]\]. The values described in literature are very variable and denote a marked difference between healthy subjects \[[@B48-ijms-21-00307]\] or anemic subjects hospitalized in Intensive Care Unit, in which high values are observed \[[@B49-ijms-21-00307]\]. As circulating hepcidin is mainly produced by the liver, most of the in vitro studies about hepcidin expression are performed on hepatic cell lines, such as HepG2. Hepcidin expression is enhanced by a treatment with the iron chelant deferoxamine \[[@B50-ijms-21-00307]\], despite the main effect of such compound being a reduced iron availability. Interestingly, deferoxamine is also used in several in vitro studies as a hypoxia mimetic as it activates the HIF-1 α pathway \[[@B51-ijms-21-00307]\]. This suggests that, other than an increased iron request, there are several mechanisms that play active roles in regulating hepcidin production and action on iron storage and use. HIF-2α expression in intestinal cells is influenced by a decrease in hepcidin expression other than by hypoxia. Inducible deletion of hepatic hepcidin in a mouse model has indeed been found to activate intestinal HIF-2α and rapid iron accumulation \[[@B52-ijms-21-00307]\]. HIF2 inhibitors have been proposed to treat iron accumulation diseases characterized by dysfunction of the hepcidin/FPN axis \[[@B53-ijms-21-00307]\]. ### 3.1.1. Iron Metabolism and HAPE {#sec3dot1dot1-ijms-21-00307} Hepcidin can be proposed as one of the potential markers of HAPE, as higher hepcidin values have been found in subjects developing HAPE, when compared to a group of subjects reaching the same altitude with the same timings, but without any sign of misadaptation \[[@B54-ijms-21-00307]\]. ### 3.1.2. Iron Metabolism and ARDS {#sec3dot1dot2-ijms-21-00307} Anemic ICU patients, among which patients with ARDS, have higher values of hepcidin than healthy subjects \[[@B49-ijms-21-00307]\]. In addition, ferritin, the protein involved in intracellular iron storage and now known as an acute phase protein, is increased in the plasma of ARDS patients \[[@B55-ijms-21-00307]\]. Inflammation, particularly through the pro-inflammatory cytokine IL-6, is a cause of increased hepcidin production \[[@B50-ijms-21-00307]\], which may therefore interfere with the previously described hematopoietic compensation mechanism. ### 3.1.3. Iron Metabolism and COPD {#sec3dot1dot3-ijms-21-00307} In contrast to the physiological adaptation to hypoxia that should increase iron absorption and utilization with consequent compensatory Hb elevation \[[@B44-ijms-21-00307]\], this pattern is observed only in a limited fraction of COPD patients: 40--50% of COPD patients instead develop iron deficiency, with anemia representing a predictive risk factor of worse outcome in 5--30% of cases \[[@B56-ijms-21-00307],[@B57-ijms-21-00307]\]. Several studies demonstrated that COPD patients with chronic hypoxia have a reduced production of erythropoietin at either the level of the kidney or bone marrow. This response may correlate with an increase in systemic inflammatory markers though the interplay between iron, hypoxia, inflammation, and erythropoietin is complex and needs to be elucidated \[[@B58-ijms-21-00307],[@B59-ijms-21-00307],[@B60-ijms-21-00307]\]. ### 3.1.4. Iron Metabolism and CF {#sec3dot1dot4-ijms-21-00307} Hypoxia maladaptation in CF has been correlated to altered iron homeostasis that comprises systemic iron deficiency as well as increased iron accumulation and defective iron sequestration in the airway cells. Furthermore, there is preliminary evidence that iron deficiency in CF patients prevents secondary erythrocytosis \[[@B61-ijms-21-00307]\]. In in vitro CF airway epithelial cells, the deficiency of heme-oxygenase-1 (HO-1), which plays a pivotal role in regulating cellular iron, correlates with increased iron concentration \[[@B62-ijms-21-00307]\]. This in turn impairs HIF-1α stability by promoting its prolyl hydroxylase-mediated polyubiquitination and proteasomal degradation leading to an altered cellular response to hypoxia \[[@B62-ijms-21-00307]\]. In a study performed on a small cohort of CF patients with mild to moderate pulmonary dysfunction and borderline hypoxia \[[@B63-ijms-21-00307]\], hemoglobin and hematocrit values did not significantly differ from normal control subjects while serum iron and iron-binding capacity were lower, leading to a tendency to anemia. A prospective observational study by Fischer et al. showed that a hypoxia driven increase in red cells mass is absent in CF patients who often exhibit normal or even decreased hemoglobin levels. The occurrence of subclinical anemia may involve the absolute iron deficiency due to gastrointestinal malabsorption, loss via sputum, a lack of vitamin E, and inflammation \[[@B61-ijms-21-00307]\]. 3.2. Hypoxia and Sphingolipid Metabolism {#sec3dot2-ijms-21-00307} ---------------------------------------- SPLs are a minor class of lipids of all mammal cells composed by a hydrophilic head group protruding into the extracellular environment and a hydrophobic moiety, the ceramide (Cer), located into the membrane bilayer \[[@B64-ijms-21-00307]\]. As the main components of plasma and intercellular organelle membranes, they have structural roles, but they also act as signaling molecules regulating cellular processes such as cell growth and death, senescence, inflammatory response \[[@B65-ijms-21-00307],[@B66-ijms-21-00307]\]. Cer, the central hub of the SPL metabolism, is synthesized in the de novo pathway, from palmitoyl-CoA and serine, in the sphingomyelin (SM) hydrolysis pathway, which generates Cer from SMs and in the salvage pathway, from the catabolism of complex glycosphingolipids \[[@B67-ijms-21-00307],[@B68-ijms-21-00307]\]. Cer can be cleaved by a ceramidase (CDase) to produce sphingosine (Sph) that, in turn, can be phosphorylated by two enzymes, sphingosine kinases 1 (SK1) and 2 (SK2) for the synthesis of sphingosine 1 phosphate (S1P) that is a crucial bioactive SPL. Similar to iron, Cer, and S1P must be finely tuned to preserve cellular homeostasis. Several lines of evidence outlined the opposite cellular effects of Cer and S1P in response and adaptation to hypoxia. ### 3.2.1. Role of Ceramide {#sec3dot2dot1-ijms-21-00307} Cer levels increase in hypoxia and other forms of cell stress. Cer accumulated via activation of both de novo synthesis or SM hydrolysis pathway mediates hypoxia-derived cytotoxicity in different cellular models \[[@B69-ijms-21-00307],[@B70-ijms-21-00307],[@B71-ijms-21-00307],[@B72-ijms-21-00307]\]. In neonatal mice exposed to 10% of oxygen (close to oxygen level at 5,260 m), cardiac Cer content was dependent on the acute (1 day) or chronic (1; 4; 8 weeks) hypoxia condition, suggesting a role for Cer decrease \[[@B73-ijms-21-00307]\] together with its upstream precursor dihydroceramide increase \[[@B74-ijms-21-00307]\] in the right ventricle adaptive response to chronic hypoxia. Such studies not only support a key role for Cer de novo synthetic pathway, but also propose the enzyme dihydroceramide desaturase which converts dihydroceramide to Cer as an important regulator in the adaptation to hypoxia \[[@B73-ijms-21-00307],[@B74-ijms-21-00307]\]. Interestingly, this enzyme is oxygen-dependent \[[@B75-ijms-21-00307]\]. Other evidence indicates that the augmented sphingomyelinase activity critically contributes to the hypoxia-induced increases in Cer content \[[@B76-ijms-21-00307]\]. Klevstig and colleagues found that cardiac Cer accumulation was reduced in sphingomyelinase deficient mice under ischemic conditions \[[@B76-ijms-21-00307]\]. In addition, Cer has been described as a promoter of hypoxic pulmonary vasoconstriction, although its vascular effects deserve further investigations \[[@B77-ijms-21-00307]\]. These results would suggest that enhanced Cer synthesis and accumulation contribute in mediating the downstream toxic signals in response to hypoxia. Although S1P has intracellular targets, it acts commonly as an autocrine or paracrine mediator by binding to five cell surface S1P receptors \[[@B78-ijms-21-00307]\]. In lung disease, S1P receptors 1 (S1PR1) are of particular interest since they enhance vascular barrier functions and they counteract apoptosis \[[@B79-ijms-21-00307]\]. In a mouse model of emphysema induced by VEGF receptor blockade, Diab and colleagues reported that activation of S1P-S1PR1 signaling axis reduced the deleterious effects of ceramide on airspace enlargement \[[@B4-ijms-21-00307]\]. Intracellular S1P accumulation, derived from exogenous S1P-activated SK1, prevents lung cell apoptosis by promoting the expression of HIF-1α and VEGF. This effect contributes to prevent the airspace enlargement together with the S1P-S1PR1 axis that maintains the alveolar septal integrity and mediate S1P effects on endothelial cell differentiation and integrity (together with S1PR3) via the Akt pathway \[[@B80-ijms-21-00307]\]. In a model of fenretinide-induced emphysema, the protective effect of S1P injection was mediated by preservation of the transcription factor HIF-1α expression and its target gene VEGF and by the increase of Nrf2 expression \[[@B81-ijms-21-00307]\]. ### 3.2.2. Role of Sphingosine 1 Phosphate {#sec3dot2dot2-ijms-21-00307} S1P is mainly considered a pro-survival and pro-proliferative factor. Since mature blood cells contain the biosynthetic machinery but not the degrading enzyme, they represent a large source of S1P for the plasma \[[@B82-ijms-21-00307]\]. Intra erythrocyte S1P enhances the glycolytic metabolic fluxes leading to the generation of more 2,3-biphosphoglicerate that in turn promotes O~2~ release to protect against tissue hypoxia \[[@B82-ijms-21-00307]\]. Human healthy volunteers brought to high altitude at 5260 m for up to 16 days, showed a time-dependent increase in plasma levels of S1P concurrently with elevated hemoglobin capacity to release oxygen \[[@B83-ijms-21-00307]\]. Exogenous S1P has been proved effective as a potential preconditioning agent favoring adaptation to hypobaric hypoxia in in vivo models of different pathologies, such as respiratory, cardiovascular, and cerebral \[[@B84-ijms-21-00307]\]. A pioneering study by Chawla et al. shows that S1P pre-treatment facilitates hypoxia adaptation in rats remained at 7620 m of altitude for 6 h. They propose that the beneficial effects of S1P rely on the enhanced blood oxygen carrying potential, mediated by HIF-1α stabilization and consequent dependent transcription of adaptive gene expression \[[@B85-ijms-21-00307]\]. A recent work by Barbacini and colleagues investigated the potential role of SPL in metabolic adaptation of Andean children, born and living at 3775 m of altitude. They exhibit a prevalence of dyslipidemia and hypertension as compared to children at lower altitudes, suggesting that they undergo different metabolic adaptations. They observed that high density lipoprotein-cholesterol (HDL-C), Cer and S1P are involved in hypoxia adaptation though they propose S1P as the main actor in this process \[[@B86-ijms-21-00307]\]. Further studies are needed to deepen in the complex mechanisms of SPL involvement in hypoxia adaptation though, up to now, several pieces of evidence would indicate S1P, instead of Cer, as a good candidate to counteract hypoxia-induced tissue damage. ### 3.2.3. SPL Metabolism and HAPE {#sec3dot2dot3-ijms-21-00307} To the best of our knowledge, only one study reports the correlation between Cer and S1P alterations and HAPE. The metabolomics analysis of plasma metabolites from HAPE subjects and healthy controls by Guo and colleagues revealed that, among others, C-8 Cer and sphingosine were significantly higher in HAPE subjects \[[@B87-ijms-21-00307]\]. The accumulation of these SPL metabolites could play a role in hypoxia maladaptation occurring in HAPE since it has been proven that Cer may contribute to pulmonary endothelial decreased barrier function, lung inflammation and edema \[[@B88-ijms-21-00307]\]. Therefore, reestablishing the SPL homeostasis could represent a novel therapeutic target to improve acclimatization. ### 3.2.4. SPL Metabolism and ARDS {#sec3dot2dot4-ijms-21-00307} Sphingolipids contribute to the modulation of endothelial barrier integrity \[[@B89-ijms-21-00307],[@B90-ijms-21-00307]\]. In ARDS, endothelial barrier is disrupted and functionally altered. In a neonatal piglet ARDS model \[[@B91-ijms-21-00307]\], aSMase hyper-activity and the consequent ceramide-C16/C18 accumulation in lung tissues correlate with inflammasome NLRP3 oligomerization, NF-κB and pro-fibrotic pathway activation. By inhibiting aSMase function with inositol 1,2,6-trisphosphate (IP3), Cer generation and NLRP3 oligomerization was completely blocked, resulting in improved oxygenation. Pandolfi and colleagues described a new aSMase-IL-6 pathway as pathogenic mediator of pulmonary vascular dysfunction in rat or human pulmonary artery smooth muscle cells (PASMCs) model of ARDS \[[@B92-ijms-21-00307]\]. In a mouse model of ARDS, S1P analogue FTY720 reduces inflammatory lung injury induced by lipopolysaccharide (LPS) treatment \[[@B93-ijms-21-00307]\]. Camp and coworkers synthesized novel FTY720 analogs and demonstrated that their effect in reversing the pulmonary vascular leak that characterizes ARDS in human pulmonary artery endothelial cells (HPAEC) is mediated by S1PR1-dependent receptor ligation \[[@B94-ijms-21-00307]\]. Combination therapy of human umbilical cord (hUC-MSCs) and FTY720 in ALI/ARDS mice model induced by LPS resulted in higher survival rates and attenuated lung injuries \[[@B95-ijms-21-00307]\]. ### 3.2.5. SPL Metabolism and COPD {#sec3dot2dot5-ijms-21-00307} Omics data on sphingolipid, arachidonic acid, hypoxia and energy signaling network in sputum of COPD patients, showed that upregulation of Cer, together with a dysfunctional response to hypoxia, strongly influence cellular energy metabolism. This is probably achieved by inhibiting mediators in energy metabolism and lipid trafficking such as fatty acid binding protein 4 and uncoupling protein 2 \[[@B96-ijms-21-00307]\]. In COPD patients, oxygen limitation and airway inflammation correlate with sphingolipid imbalance whose main feature is the alveolar Cer accumulation \[[@B41-ijms-21-00307],[@B97-ijms-21-00307]\]. Several pieces of evidence demonstrate that increased Cer further aggravates the compromised airway homeostasis \[[@B88-ijms-21-00307]\]. Very recently, Bodas et al. showed that Cer/Sph ratio was elevated in COPD subjects as well as in mice exposed to cigarette smoke, worsening COPD-emphysema severity \[[@B98-ijms-21-00307]\]. Excessive Cer content triggers damages of structural airway epithelial cells \[[@B99-ijms-21-00307],[@B100-ijms-21-00307],[@B101-ijms-21-00307]\], which is involved in pulmonary tissue destruction \[[@B102-ijms-21-00307]\] and contributes to maintain pulmonary inflammation \[[@B103-ijms-21-00307]\]. A critical role for S1PR mediated signaling pathway has been demonstrated in the control of airway function in COPD though the precise mechanisms underlying the effects of S1PR modulation in COPD have to be further clarified. Cigarette smoke induced pulmonary S1P pathway upregulation in a mouse model of mild COPD, with an evident increase in S1PR2 and S1PR3 expressions \[[@B104-ijms-21-00307]\]. Defective ability to phagocytose apoptotic cells in alveolar COPD macrophages has been related to the increased expression of the S1PR5 gene that correlates with its reduced methylation status \[[@B105-ijms-21-00307]\]. On the contrary, the analysis of lung tissue samples from 25 patients with COPD showed that the relative mRNA expression of S1PR5 was reduced in COPD. Moreover, a positive correlation was found between the mRNA expression of S1PR5, S1PR1, and S1PR3, and between S1PR3 and S1PR2. In conclusion, the authors suggest S1PR5 as a possible novel target for pharmacotherapy \[[@B106-ijms-21-00307]\]. S1PR1 has been found to be downregulated in human pulmonary diseases such as COPD \[[@B79-ijms-21-00307]\] and induction of the S1PR1 receptor activity increases survival and vascular permeability \[[@B107-ijms-21-00307]\]. ### 3.2.6. SPL Metabolism and CF {#sec3dot2dot6-ijms-21-00307} Though several in vitro and in vivo CF studies describe the involvement of Cer and S1P metabolism dysregulation in worsening the pulmonary conditions (for a comprehensive review, please refer to Aureli et al. \[[@B108-ijms-21-00307]\]), the role of SPLs in mediating the adaptation to hypoxia is still a poorly investigated field. There is only one paper, by Tabelling et al. \[[@B40-ijms-21-00307]\] that focused on the interplay between SPLs, hypoxia adaptation, and CF. The authors proposed a dual role for SPL signaling in CFTR-mediated HPV, suggesting an nSMase-derived Cer and SphK1-dependent conversion to S1P as the mediators of this hypoxia adaptation response. They demonstrated that, in CF, CFTR dysfunction impairs HPV by inhibiting the Cer-mediated translocation and the S1P-mediated activation of TRPC6 (transient receptor potential canonical 6) that plays a crucial role in the contraction of pulmonary artery smooth muscle cells \[[@B40-ijms-21-00307]\]. 4. Perspectives: Sphingolipid and Iron Metabolism in the Prognosis and Treatment of Chronic Respiratory Diseases {#sec4-ijms-21-00307} ================================================================================================================ 4.1. Sphingolipids and Iron Interplay {#sec4dot1-ijms-21-00307} ------------------------------------- Recently, SPL alterations in response to dysregulated iron pathways have been observed in different animal models and patients. As reviewed by Rockfield and colleagues \[[@B109-ijms-21-00307]\], iron toxicity correlates with increased synthesis of SPLs in different eukaryotic organisms as well as in mammalian cell lines. In *D. melanogaster* and *M. musculus*, iron-induced toxicity that recapitulates neurodegenerative damages seems to be mediated by SPLs and downstream signaling pathways \[[@B110-ijms-21-00307]\]. In Neurodegeneration with Brain Iron Accumulation (NBIA) disease, a gene network analysis found an SPL enrichment as well as high iron levels in basal ganglia \[[@B111-ijms-21-00307]\]. Iron accumulation triggers Cer production (via activation of SM hydrolysis) that in turn promotes hepcidin expression by transcriptional upregulation of HAMP gene (Hepcidin Antimicrobial Peptide) in HepG2 cells \[[@B112-ijms-21-00307]\]. Thus, hepcidin entangles iron and Cer in a vicious loop that sustains the high levels of both mediators. Iron deficiency was found to reduce SPLs synthesis in *S. cerevisiae* strains, probably due to the inactivation of SPL biosynthetic enzymes that require iron as an essential cofactor \[[@B113-ijms-21-00307]\]. Such interplay between iron and SPL, under hypoxia and inflammation conditions, is shown in [Figure 1](#ijms-21-00307-f001){ref-type="fig"}. The inflammatory cascade, particularly through the pro-inflammatory cytokine IL-6, can increase hepcidin production \[[@B50-ijms-21-00307]\], which may therefore interfere with the previously described hematopoietic compensation mechanism. Failure to regulate the mechanism of hepcidin decrease in response to hypoxia may limit the effectiveness of iron-based therapies or transfusions \[[@B49-ijms-21-00307]\]. In fact, even a red blood cell transfusion has an inducing effect on hepcidin blood concentrations, in addition to increasing the concentration of free iron (non-transferrin-bound iron, NTBI), without however having effects on transferrin (Tf) saturation \[[@B114-ijms-21-00307]\]. Tf, by binding iron, allows a reduction of toxicity and a more effective use by cells. Furthermore, its receptor (TfR) that allows the transport from the extracellular to the intracellular compartment increases in physiological response to iron deficiency. Tf saturation is often used for a more precise evaluation of the presence of iron in the blood, together with the total serum iron, which measures both the iron bound to transferrin, and therefore recruited for the hematopoiesis, and the NTBI. The increase in NTBI is one of the harmful effects of irregular iron metabolism as it can cause oxidative stress, catalyzing the formation of reactive oxygen species \[[@B2-ijms-21-00307]\]. The link between iron/hepcidin content and SPL metabolism in inflammation is further strengthened since inflammatory hypoxia has been proved to modulate the synthesis of Cer and S1P and, in turn, to be modulated by these lipid molecules. Cer and S1P are both described as important signaling mediators in inflammation \[[@B115-ijms-21-00307]\]. Cer accumulation induces inflammation \[[@B116-ijms-21-00307]\] and hepcidin expression \[[@B112-ijms-21-00307]\], while S1P acts as an oxygen-independent regulator of HIFs \[[@B117-ijms-21-00307],[@B118-ijms-21-00307]\]. These data suggest that there is a unique relationship between SPL levels and iron-mediated cellular toxicity, since downregulating SPL metabolism is sufficient to allow survival in high iron conditions. Whether alterations in other elements of iron signaling pathway are induced in response to Cer and other SPLs is actually an open field. 4.2. The Potential Prognostic Factors {#sec4dot2-ijms-21-00307} ------------------------------------- [Table 1](#ijms-21-00307-t001){ref-type="table"} summarizes the main iron and sphingolipids metabolism markers and their role in influencing the adaptation to hypoxia. Further investigation on their role in determining the respiratory diseases prognosis are still required, especially for ceramide and intra-erythrocyte S1P. Here, we propose to compare the adaptation to high altitude in healthy subjects to the one to respiratory disease, in order to propose new biomarkers. Ceramide, measurable in plasma samples through mass spectrometry, has already been proposed as a biomarker of pulmonary and hepatic metastasis response to specific radiochemotherapy \[[@B119-ijms-21-00307]\]. A metabolomic study of plasma shows that ceramides, sphingomyelin, and gangliosides levels are altered in specific COPD phenotypes such as emphysema and in COPD exacerbations \[[@B120-ijms-21-00307]\]. Cystic Fibrosis is the first disease in which excessive airway epithelial cell ceramide was found to play a role in airway pathophysiology \[[@B116-ijms-21-00307],[@B121-ijms-21-00307],[@B122-ijms-21-00307]\]. In the lung parenchyma, the accumulation of ceramide but also the ceramide to S1P balance influences cell fate and lung remodeling responses. High ceramide-to-S1P ratio due to either ceramide increase \[[@B4-ijms-21-00307]\] or S1P decrease \[[@B123-ijms-21-00307]\] correlates with emphysema-like pathology and cell death. 4.3. Enhancing Hypoxia Adaptive Mechanism for the Treatment of Inflammatory Anemia {#sec4dot3-ijms-21-00307} ---------------------------------------------------------------------------------- HIF and hepcidin are both already considered as therapeutic targets for inflammatory anemia, also in subjects without any respiratory disease \[[@B39-ijms-21-00307]\]. The clinical utility of enhancing the HIF pathway to increase and optimize hemopoiesis is already under assessment through phase II clinical studies. Roxadustat, a small molecule which inhibit HIF prolyl-4-hydroxylases, therefore increasing HIF action, has been showing its effectiveness in patients with chronic kidney disease, and, as a secondary effect, was found to decrease circulating cholesterol \[[@B131-ijms-21-00307]\]. Lexaptepid, an L-oligoribonucleotide with a strong affinity to hepcidin mRNA, has been assessed in healthy subjects for its ability of decreasing hepcidin levels \[[@B132-ijms-21-00307]\], and might be useful in treating anemic COPD patients too. On the other hand, a decrease in hepcidin has been suggested as a potential criteria to discriminate the patients who may need iron-based intravenous therapy \[[@B47-ijms-21-00307]\]. Iron infusion has an acute increasing effect on hepcidin concentration, but has been shown to reduce the hypoxia-induced increase in Pulmonary Artery Systolic Pressure \[[@B43-ijms-21-00307]\]. Although the ubiquitous SPL expression could be a limitation, there are ongoing preclinical and clinical studies targeting both Cer and S1P in CF \[[@B133-ijms-21-00307],[@B134-ijms-21-00307]\]. S1PR1 agonists may represent a new therapeutic strategy in the treatment COPD \[[@B4-ijms-21-00307]\]. As reviewed by Becker and colleagues \[[@B133-ijms-21-00307],[@B134-ijms-21-00307]\], systemic treatment with amitriptyline, an inhibitor of acid sphingomyelinase, is used in clinical trials to improve lung function in CF patients. Moreover, the application of recombinant acid ceramidase, a Cer degrading enzyme, is currently under development for clinical use in children with Farber disease, and it could be evaluated in CF patients since it has been proven to prevent infection in CF mice. 5. Conclusions {#sec5-ijms-21-00307} ============== Among the various mechanisms involved in the patho-physiological adaptation to hypoxia, iron and SPL pathways play a key role, as described in pathological conditions such as HAPE, ARDS, COPD, and CF. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets. S.O. was supported by the PhD program in "Translational Medicine" of the University of Milan, Italy. A.Z.'s post doc position was funded by Fondazione Umberto Veronesi. This research received no external funding. The authors declare no conflict of interest. CDase ceramidase Cer ceramide CF Cystic Fibrosis CFTR Cystic Fibrosis Transmembrane conductance Regulator COPD Chronic Obstructive Pulmonary Disease Fpn ferroportin HAPE High altitude pulmonary edema Hb hemoglobin HIF Hypoxia-inducible factor HPV Hypoxic Pulmonary Vasocostriction nSMase neutral sphingomyelinase O2 oxygen S1P sphingosine 1 phosphate Sph sphingosine SPL sphingolipids {#ijms-21-00307-f001} ijms-21-00307-t001_Table 1 ###### Iron and SPL metabolism markers and their trend in comparison to the normal values, in response to different hypoxic conditions. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Parameter High Altitude Good Adaptation High Altitude\ ARDS COPD Cystic Fibrosis Bad Adaptation\ (HAPE) ---------------------- ------------------------------------------------------------------------ ------------------------------------------------------------- ------------------------------------------------------------------------------------------------- --------------------------------------------------------------- ---------------------------------------------- hepcidin Low \[[@B44-ijms-21-00307],[@B45-ijms-21-00307],[@B46-ijms-21-00307]\] High \[[@B54-ijms-21-00307]\] High (anemic ICU patients \[[@B49-ijms-21-00307]\]) Low in stable \[[@B57-ijms-21-00307],[@B124-ijms-21-00307]\]\ Low in stable kids \[[@B126-ijms-21-00307]\] high in exacerbations \[[@B125-ijms-21-00307]\] ferritin Low \[[@B44-ijms-21-00307],[@B45-ijms-21-00307]\] Normal/high \[[@B54-ijms-21-00307]\] High \[[@B55-ijms-21-00307]\] Normal/high \[[@B56-ijms-21-00307]\] Normal/high \[[@B61-ijms-21-00307]\] Erythropoietin (EPO) High \[[@B44-ijms-21-00307],[@B45-ijms-21-00307]\] High \[[@B127-ijms-21-00307]\] ? high \[[@B56-ijms-21-00307]\]\ Normal/high \[[@B61-ijms-21-00307]\] low in exacerbations \[[@B128-ijms-21-00307]\] hemoglobin High \[[@B35-ijms-21-00307]\] Very high/low \[[@B44-ijms-21-00307],[@B45-ijms-21-00307]\] Low (ICU patients) \[[@B14-ijms-21-00307]\] high \[[@B128-ijms-21-00307]\]\ Normal/Low \[[@B61-ijms-21-00307]\] Low in worse prognosis \[[@B128-ijms-21-00307]\] SPL Metabolites S1P high \[[@B86-ijms-21-00307]\] Cer High \[[@B87-ijms-21-00307]\] S1PR3 high \[[@B129-ijms-21-00307]\] and SMase high \[[@B92-ijms-21-00307]\] in worse prognosis Cer High \[[@B98-ijms-21-00307],[@B130-ijms-21-00307]\] Cer high \[[@B121-ijms-21-00307]\] ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | Mid | [
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The invention relates to the treatment of inflammatory disorders. Inflammation occurs when tissues are injured by viruses, bacteria, trauma, chemicals, heat, cold or any other harmful stimulus. Chemicals including bradykinin, histamine, serotonin and others are released, attracting tissue macrophages and white blood cells to localize in an area to engulf and destroy foreign substances. During this process, chemical mediators such as TNFα are released, giving rise to inflammation. Inflammatory disorders are those in which the inflammation is sustained or chronic. One example of an inflammatory disorder is osteoarthritis. Immunoinflammatory disorders (e.g., rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, stroke-induced brain cell death, ankylosing spondylitis, fibromyalgia, and autoimmune diseases such as asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, and Sjögren's syndrome) are inflammatory disorders characterized by dysregulation of the immune system and inappropriate mobilization of body's defenses against its own healthy tissue. One percent of humans world-wide are afflicted with rheumatoid arthritis, a relentless, progressive disease causing severe swelling, pain, and eventual deformity and destruction of joints. According to the Arthritis Foundation, rheumatoid arthritis currently affects over two million Americans, of which women are three times more likely to be afflicted. Rheumatoid arthritis is characterized by inflammation of the lining of the joints and/or other internal organs, and the presence of elevated numbers of lymphocytes and high levels of proinflammatory cytokines. Treatment of rheumatoid arthritis generally includes administration of (i) non-steroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, aspirin, choline salicylate, salsalte, and sodium and magnesium salicylate); (ii) steroids (e.g., cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone); (iii) DMARDs, i.e., disease modifying antirheumatic drugs (e.g., cyclosporine, azathioprine, methotrexate, leflunomide, cyclophosphamide, hydroxychloroquine, sulfasalazine, D-penicillamine, minocycline, and gold); or (iv) recombinant proteins (e.g., ENBREL® (etanercept, a soluble TNF receptor) and REMICADE® (infliximab) a chimeric monoclonal anti-TNF antibody). There is a need to develop new regimens for the treatment of rheumatoid arthritis, and other inflammatory disorders. | Mid | [
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Q: Is there a way to make atom move faster without heating them? The more heat you add the faster the atom will move. This is something that is common knowledge. My question is it possible to make the atoms in let's say a gas move faster without adding heat of a large volume of heat? A: If you take a bottle of gas and carry it with you on a supersonic plane, then the molecules will go much faster without the temperature changing. If you let pressurized gas flow through a well-designed nozzle (De Laval nozzle), the gas will accelerate to supersonic velocity (i.e., faster than the original thermal speed of the molecules) while the temperature of the gas decreases. Note that the temperature of high-speed gases is a tricky subject; a thermomemeter moving along with the gas stream will sense a lower temperature than a stationary thermometer. The former measures the static temperature, while the latter measures the recovery temperature (depends on the shape of the thermometer probe). There is also the stagnation temperature, which represents the energy of the molecules regardless of whether it is due to thermal (random) motion or due to the kinetic energy of a gas jet. So, with the gas bottle on a plane, the static temperature doesn't change, but the stagnation temperature increases for an observer who stays on the ground. Gas flowing through a nozzle (assuming that the nozzle is thermally insulated) does not change in stagnation temperature, but its static temperature drops. | Mid | [
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Nikiana Beach club is ideally situated for exploring the beautiful islands of the Ionian. Breakfast and unlimited use of the dinghies, kayaks, SUPs and windsurf watersport equipment is included. The location is ideal for beginners to advance and improve on their sailing skills during their stay. Ideal for windsurfers with high performance kit. Located on Kos island in Greece, the beach club has a sandy beach and strong winds. The accommodation is offered on a bed and breakfast basis and includes unlimited use of the high performance watersports equipment. Nikiana Beach club is ideally situated for exploring the beautiful islands of the Ionian. Breakfast and unlimited use of the dinghies, kayaks, SUPs and windsurf watersport equipment is included. The location is ideal for beginners to advance and improve on their sailing skills during their stay. Ideal for windsurfers with high performance kit. Located on Kos island in Greece, the beach club has a sandy beach and strong winds. The accommodation is offered on a bed and breakfast basis and includes unlimited use of the high performance watersports equipment. Sailing Holiday Summary Lefkas flotilla, sailing from our base at Lefkas we plot a course for the pristine waters of Meganisi and onwards to the sophistication of Fiskardo and the picture Sailing Holiday Summary Lefkas flotilla, sailing from our base at Lefkas we plot a course for the pristine waters of Meganisi and onwards to the sophistication of Fiskardo and the picture postcard beauty of Kioni on Ithaca. Week two explores the south coast of Lefkas, with Sivota and Vassiliki within reach before heading to the unspoilt islands of Kastos and Kalamos. | Mid | [
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Q: WCF Json GET Service: Check that the sender and receiver's EndpointAddresses agree I've been working in .NET for a while now, but I'm new to WCF. I'm trying to create my very first WCF service using JSON. I thought I would start really, really simple and then build from there. But I have somehow managed to screw up even the most simple of services. Here's what I've got so far. Web.Config: <?xml version="1.0"?> <configuration> <system.web> <compilation debug="true" targetFramework="4.0" /> </system.web> <system.serviceModel> <services> <service name="MarathonInfo.MarathonInfoService"> <endpoint address="http://localhost:10298/MarathonInfoService.svc" binding="webHttpBinding" contract="MarathonInfo.IMarathonInfo" /> </service> </services> <behaviors> <serviceBehaviors> <behavior> <!-- To avoid disclosing metadata information, set the value below to false and remove the metadata endpoint above before deployment --> <serviceMetadata httpGetEnabled="true"/> <!-- To receive exception details in faults for debugging purposes, set the value below to true. Set to false before deployment to avoid disclosing exception information --> <serviceDebug includeExceptionDetailInFaults="false"/> </behavior> </serviceBehaviors> </behaviors> <serviceHostingEnvironment multipleSiteBindingsEnabled="false" /> </system.serviceModel> <system.webServer> <modules runAllManagedModulesForAllRequests="true"/> </system.webServer> </configuration> Then, in the service file: namespace MarathonInfo { public class MarathonInfoService : IMarathonInfo { public String GetData() { return "Hello World"; } } } And in the interface: namespace MarathonInfo { [ServiceContract] public interface IMarathonInfo { [OperationContract] [WebInvoke(Method = "GET", UriTemplate = "/GetData", RequestFormat = WebMessageFormat.Json, ResponseFormat = WebMessageFormat.Json)] String GetData(); } } So, when I go to this url: http://localhost:10298/MarathonInfoService.svc/GetData I get this error: The message with To 'http://localhost:10298/MarathonInfoService.svc/GetData' cannot be processed at the receiver, due to an AddressFilter mismatch at the EndpointDispatcher. Check that the sender and receiver's EndpointAddresses agree. I am able to execute the service just fine through Visual Studio in debug mode. But in the browser, I only get that error. What am I doing wrong? Thanks! Casey A: If you want to create a WCF WebHTTP Endpoint (i.e., one which returns JSON, and uses the [WebGet] / [WebInvoke] attributes), the endpoint needs to have the <webHttp/> behavior associated with it. <system.serviceModel> <services> <service name="MarathonInfo.MarathonInfoService"> <endpoint address="http://localhost:10298/MarathonInfoService.svc" binding="webHttpBinding" contract="MarathonInfo.IMarathonInfo" behaviorConfiguration="Web"/> </service> </services> <behaviors> <serviceBehaviors> <behavior> <serviceMetadata httpGetEnabled="true"/> <serviceDebug includeExceptionDetailInFaults="false"/> </behavior> </serviceBehaviors> <endpointBehaviors> <behavior name="Web"> <webHttp/> </behavior> </endpointBehaviors> </behaviors> <serviceHostingEnvironment multipleSiteBindingsEnabled="false" /> </system.serviceModel> | High | [
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Graham Rice's New Plants Blog Editor-in-Chief of the RHS Encyclopedia of Perennials; writer for a wide range of newspapers and magazines including The Garden and The Plantsman; member of the RHS Herbaceous Plant Committee and Floral Trials Committee; author of many books on plants and gardens. Follow me on Twitter Graham Rice's other blogs As a cut flower, ageratum is does not always come to mind. We tend to think of it more as an edging plant. But it’s actually one of the best of all blue flowers for cutting, especially as it’s not difficult to grow. And this year sees the arrival of two new varieties, one available as seed and one as plugs. ‘Everest Blue’ (above left, click to enlarge), new from Holland, is perhaps a fraction taller, reaching 20-26in/50-65cm in height and continues to produce new colour all through the summer. ‘High Tide Blue’ (above right, click to enlarge), new from across the Atlantic, is a very productive variety reaching 20-24in/50-60cm in height and is very well branched. Frankly they both look good, and your choice may well depend on whether you’d rather grow plants from seed, in which case choose ‘High Tide Blue’, or if you’d prefer to start with mini-plugs, in which case choose ‘Everest Blue’. Both are happy in any reasonably fertile soil, but prefer at least six hours of sunshine each day. Expect up to twenty cut stems from each plant, cut the stems when the central floret in the head is completely open and there is colour in the florets to the side. Always use flower preservative and that should give you a ten day vase life. Cut Ageratum stems do not store well or travel well – so Ageratum ideal as a home grown cut flower Most of us are familiar with the shrubby hibiscus, attractive summer flowering shrubs with single or double, mallow-like flowers. But there’s also a wide range of hardy perennial types that we hardly ever see – and they have HUGE flowers. Now’s your chance to try the latest varieties (above, click to enlarge). Let’s start with the flowers. They’re like lavatera or single hollyhock flowers, in red, pinks, bicolours and white but they reach from 8-12in/20-30cm across. They’re probably about the size of your head! They develop on upright stems from large thongy roots and flower from mid summer into autumn on plants about 3ft/90cm high. Can you imagine? So why do we see them so rarely? It’s not that they’re tender. A few years ago, when I was in Michigan, I visited a nursery where one of the top breeders was trialing new varieties. They were planted in a windswept field in an area where the winter temperature reaches as low as -29C/-20F. So they’re tough. But they do like a hot summer, so they’re more likely to thrive in the warmer parts of the country and they appreciate a cosy sunny area in cooler regions. They’re also good in large containers. Six varieties are available this year, from three of America’s top breeders, so you can choose the colours you prefer. The recent trial of Alstroemeria at the RHS garden at Wisley not only highlighted the best of the familiar flowering types, but there were also some fine variegated forms that caught the eye, two of which received awards. Too new to be in the trial was this startling new variety from Australia, Alstroemeria Rock ‘n’ Roll (‘AlsDuno1’). (It’s sometimes written as Rock & Roll.) Making a bushy plant eventually reaching about 30-40in/80-10cm height and 20-28in/50-70cm, the centre of each leaf is brightly splashed, the colour starts off yellow in the young leaves and then matures through cream to white. And because the pale variegation is at the centre of the leaf, where it’s at its thickest, rather than at the thin and vulnerable edge of the leaf it doesn’t scorch. Topping this bright foliage display are clusters of six to twelve, 2-3in/4-7.5cm flowers in a contrasting vivid orange-scarlet. They start to open in late spring and continue into the autumn, especially if the faded flower stems are pulled right out at the root. Happy in large containers, or in any fertile soil that is not parched or waterlogged, Alstroemeria Rock ‘n’ Roll is happy in sun or a little shade. To ensure that plants in beds and borders overwinter happily in chilly conditions, cover with a deep mulch of bark chips in autumn after the stems are cut down. Cannas are very fashionable these days. With the recent enthusiasm for plantings with a tropical air, the bold foliage and colourful flowers of cannas create an exciting impact that’s seen far more often than a few years ago. But there are two problems. One is that cannas are big plants; 5-6ft/1.5-1.8m is perfectly normal and with that hefty foliage they take up a lot of space. Also many of the familiar varieties are infected with virus and don’t always thrive the way we hope. Dwarf cannas from seed solve both problems. Their scale is more suitable for small borders and small containers, and virus diseases are not transmitted by seed so they start off perfectly healthy. Dwarf seed-raised varieties have been around for a while and, to be honest, they’ve not been a great success. But they’ve all had green leaves and it’s the purple- and bronze-leaved types which are the most popular. Step forward Canna ‘Tropical Bronze Scarlet’. Reaching only 24-30in/60-75cm in height, with a spread of about 16-18in/41-46cm its foliage is deep coppery bronze and the flowers bright red with a slight carmine haze. At half the size of most other cannas it’s both small and dramatic. And you can keep the rhizomes till next year. Sow this month, grow warm and harden off before planting out after the last frost. Creating new magnolias is a long term project. New Zealand magnolia breeder Mark Jury made the cross that has now led to the appearance of this impressive new variety way back in 1996. And it looks as if the wait has been worthwhile. Unlike most spring flowering magnolias, Fairy Magnolia® Blush (‘MicJur01’) is an evergreen variety, in the group that until recently was classified in a separate genus, Michelia. Plants eventually reach about 9ft/2.7m high and about 8ft/2.4m across, with neat, dark green, lustrous foliage. It makes an attractive plant even when not flowering. From March to May, rich, honey-colored buds open to reveal blush pink fragrant flowers with attractive veining. And they open all along the branches, not just at the tips – that was one of the features that distinguished Michelia from the tip-flowering Magnolia. Fairy Magnolia® Blush is happy in full sun or partial shade and in any moist but well-drained soil. It makes a fine small garden or container-grown specimen, or an attractive fragrant hedge. It can be trained to a trellis and would be happy on a west wall near a door where the prettily patterned flowers and their attractive fragrance can be appreciated. It even makes a colourful flowering standard. Fairy Magnolia® Blush is the result of a cross between the white flowered Chinese Magnolia laevifolia (formerly Michelia yunnanensis) and the pink flowered Magnolia ‘Mixed Up Miss’, a hybrid between M. figo and M. doltsopa. Both parents are very fragrant, as is Fairy Magnolia® Blush. Plants that combine good looks with good flavour at the table are especially valuable in small gardens and in containers so the arrival of this new chilli pepper, ‘Basket of Fire’, is very welcome. So many chillies are either very upright or very dwarf and compact but although ‘Basket of Fire’ starts off as a rounded plant when young (as in the picture), it soon spreads out and develops a semi-trailing habit. Reaching about 12in/30cm in height it spreads out to twice that so ideal is in a container. And this new British-bred variety has two other important features. The small fruits can be used at any stage from early in their maturity, when they’re deep purple, through yellow to orange to full red ripeness. And this blend of colours makes a very attractive plant. You get the best of both worlds. Are they hot? Well, its Scoville heat rating is about 80000shu which puts it in the middle range between Cayenne and Habanero chillies. Plants are fairly quick to mature, there should be some useable fruits about five weeks after transplanting and fully ripe fruits after about three months. And ‘Basket of Fire’ is very prolific. Three plants can produce several hundred chillies and with useful tolerance to cool conditions the fruits continue ripening until well into the autumn. They can then be dried and stored for the winter. | Mid | [
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Qinling Pandas Giant pandas are black and white– most of the time. A subspecies of giant panda that lives in China’s Qinling Mountains has tan and brown fur. The different color is due to a genetic mutation. Scientists think that this mutation might be prominent in this group because the pandas are isolated up in the mountains, and the smaller gene pool leads to uncommon traits being concentrated. In addition to having brown fur, Qinling pandas differ from their black and white cousins in a couple ways. Qinling pandas are usually smaller than regular giant pandas, and their eye spots are located just below their eyes, rather than all around their eyes. | High | [
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/* * Copyright 2014 Toxic Bakery * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. */ package com.youth.banner.transformer; import android.view.View; public class ZoomOutTranformer extends ABaseTransformer { @Override protected void onTransform(View view, float position) { final float scale = 1f + Math.abs(position); view.setScaleX(scale); view.setScaleY(scale); view.setPivotX(view.getWidth() * 0.5f); view.setPivotY(view.getHeight() * 0.5f); view.setAlpha(position < -1f || position > 1f ? 0f : 1f - (scale - 1f)); if(position == -1){ view.setTranslationX(view.getWidth() * -1); } } } | Mid | [
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Q: Convert UTC to local time in Rails 3 I'm having trouble converting a UTC Time or TimeWithZone to local time in Rails 3. Say moment is some Time variable in UTC (e.g. moment = Time.now.utc). How do I convert moment to my time zone, taking care of DST (i.e. using EST/EDT)? More precisely, I'd like to printout "Monday March 14, 9 AM" if the time correspond to this morning 9 AM EDT and "Monday March 7, 9 AM" if the time was 9 AM EST last monday. Hopefully there's another way? Edit: I first thought that "EDT" should be a recognized timezone, but "EDT" is not an actual timezone, more like the state of a timezone. For instance it would not make any sense to ask for Time.utc(2011,1,1).in_time_zone("EDT"). It is a bit confusing, as "EST" is an actual timezone, used in a few places that do not use Daylight savings time and are (UTC-5) yearlong. A: Time#localtime will give you the time in the current time zone of the machine running the code: > moment = Time.now.utc => 2011-03-14 15:15:58 UTC > moment.localtime => 2011-03-14 08:15:58 -0700 Update: If you want to conver to specific time zones rather than your own timezone, you're on the right track. However, instead of worrying about EST vs EDT, just pass in the general Eastern Time zone -- it will know based on the day whether it is EDT or EST: > Time.now.utc.in_time_zone("Eastern Time (US & Canada)") => Mon, 14 Mar 2011 11:21:05 EDT -04:00 > (Time.now.utc + 10.months).in_time_zone("Eastern Time (US & Canada)") => Sat, 14 Jan 2012 10:21:18 EST -05:00 A: Rails has its own names. See them with: rake time:zones:us You can also run rake time:zones:all for all time zones. To see more zone-related rake tasks: rake -D time So, to convert to EST, catering for DST automatically: Time.now.in_time_zone("Eastern Time (US & Canada)") A: There is actually a nice Gem called local_time by basecamp to do all of that on client side only, I believe: https://github.com/basecamp/local_time | Mid | [
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Interferon-gamma suppresses Na+ -H+ exchanger in cultured human endolymphatic sac epithelial cells. Adequate regulation of endolymphatic pH is essential for maintaining inner ear function. The Na(+)-H(+) exchanger (NHE) is a major determinant of intracellular pH (pH(i)), and facilitates Na(+) and fluid absorption in various epithelia. We determined the functional and molecular expression of NHEs in cultured human endolymphatic sac (ES) epithelial cells and examined the effect of IFN-gamma on NHE function. Serial cultures of human ES epithelial cells were generated from tissue samples. The molecular expression of NHE1, -2, and -3 isoforms was determined by real-time RT-PCR. The functional activity of NHE isoforms was measured microfluorometrically using a pH-sensitive fluorescent dye, 2',7'-bis(carbonylethyl)-5(6)-carboxyfluorescein (BCECF), and a NHE-inhibitor, 3-methylsulfonyl-4-piperidinobenzoyl guanidine methanesulfonate (HOE694). NHE1, -2, and -3 mRNAs were expressed in human ES epithelial cells. Functional activity of NHE1 and -2 was confirmed in the luminal membrane of ES epithelial cells by sequentially suppressing Na(+)-dependent pH(i) recovery from intracellular acidification using different concentrations of HOE694. Treatment with IFN-gamma (50 nM for 24 h) suppressed mRNA expression of NHE1 and -2. IFN-gamma also suppressed functional activity of both NHE1 and -2 in the luminal membrane of ES epithelial cells. This study shows that NHEs are expressed in cultured human ES epithelial cells and that treatment with IFN-gamma suppresses the expression and functional activity of NHE1 and -2. | High | [
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Fairfield Energy of Colorado Springs regularly gave to The American Heart Association, who has a long and rich history of being one of the biggest advocates for research, awareness and cures towards cardiac ailments and conditions. Below is an excerpt from the group’s website that describes how they got off to such a successful start: “Before the American Heart Association existed, people with heart disease were considered to be doomed to complete bed rest – or worse. But a handful of pioneering physicians and social workers believed it didn’t have to be that way. They conducted studies to learn more about heart disease, eventually leading to the founding of the American Heart Association in 1924. ““We were living in a time of almost unbelievable ignorance about heart disease,”” said Paul Dudley White, one of six cardiologists who founded the organization. The early American Heart Association enlisted help from hundreds, then thousands, of physicians and scientists. The association reorganized in 1948, transforming from a scientific society to a voluntary health organization composed of both science and lay volunteers and supported by professional staff. Since then, the American Heart Association has grown rapidly in size and influence – nationally and internationally. In 1975, the headquarters moved from New York City to Dallas to be more centrally located. Volunteer-led affiliates formed a national network of local organizations providing research funding, education, community programs and fundraising.” | High | [
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namespace SteveCadwallader.CodeMaid.IntegrationTests.Cleaning.Insert.Data { namespace NestedNamespace1 { } namespace NestedNamespace2 { } namespace NestedNamespace3 { } public class PublicClass { } } namespace SteveCadwallader.CodeMaid.IntegrationTests.Cleaning.Insert.Data2 { } namespace SteveCadwallader.CodeMaid.IntegrationTests.Cleaning.Insert.Data3 { } | Low | [
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I specialize in Kentucky USDA Rural Housing mortgage loans in KY. Apply for free today for a Rural Housing loan Pre-Approval Letter. Same day approvals. I offer the USDA Rural Development Guaranteed Housing Loans for all counties in Kentucky that are eligible. Put my expert advice to use. Call or text 502-905-3708 or email [email protected] This website is not affiliated with USDA or any other government agency. NMLS# 57916 Equal Housing Lender Sunday, August 21, 2016 Kentucky USDA Rural Development Housing Guideline Changes for 2016 Kentucky Rural Housing Loans has made changes to the program guidelines for guaranteed loans, which will include the changes described below. The 1980-D and all associated publications are replaced by the 7 CFR Part 3555. All effective Administrative Notices must reflect "3555". The new handbook is the HB-1-3555 and can be accessed by clicking the link here. FLOOD ZONES: Existing properties located in a flood zone are now eligible as long as flood insurance is available through FEMA's NFIP program. New or proposed homes in a flood zone must still meet additional flood zone requirements. Flood coverage must cover the lesser of the total loan amount or maximum allowed by NFIP.Maximum deductible is $1000 or 1% of the face amount of the policy HAZARD INSURANCE: Maximum deductible is $1000 or 1% of the face amount of the policy BUILDINGS/LAND: The subject property cannot contain any land or buildings that will be used principally for income. Minimal income producing activity is allowed (a garden, but not a farm). The value of the buildings no longer needs to be deducted from the appraised value. RESUBMISSION POLICY: Any request to release GUS for data updates after the issuance of a Conditional Commitment will be treated as a new request, processed in date order of applications received. RETAINING A DWELLING: Current homeowners are eligible for a guaranteed loan if ALL of the following are met: Applicants are not financially responsible for another RD direct or guaranteed loan at closing. Current home no longer meets applicants' needs. Occupy the subject as primary residence. Applicants are without resources or credit to obtain home. Only one home may be retained. Applicants must be financially qualified to own more than 1 home. The commuting area restriction has been removed. In order to meet the above requirement for the current home no longer meeting applicants' needs, the borrower must document a significant status change that requires immediate remedy. For example: Severe overcrowding - Defined as more than 1.5 household members per room (not bedroom, just room)*, document overcrowding has existed for more than 90 days and will persist for 9 months into the future. *Based on USDA's clarification of 1.5 per room, we do not anticipate many of these scenarios being acceptable and approved. TRADELINE REQUIREMENT: One borrower must have 3 trade lines that have existed for 12 months. If this requirement cannot be met, an accept decision must be downgraded to a refer and treated as a manual underwrite. VERIFICATION OF RENT: Scores 680 and above OR GUS accept = No VOR required. Scores 679 and below = VOR required. COLLECTIONS: Determine if the total outstanding balance of all collections accounts and charge offs of all applicants is equal to or greater than $2,000. Unless excluded by state law, collection accounts and charge offs of a non-purchasing spouse in a community property state are included in the cumulative balance of all collections and charge offs. Remove all medical collections and medical charge off accounts from the total balance. Medical collections and medical charge off accounts must be clearly identifiable on the credit report. If the remaining outstanding balance of collection accounts and charge offs are equal to or greater than $2,000, any of the following actions will apply: Payment in full of all collection accounts and charge offs at or prior to closing. Payment arrangements are made with each creditor for each collection account and charge offs remaining outstanding. A letter from the creditor or evidence on the credit report is required to validate the payment arrangements. The agreed upon monthly payment for each outstanding collection account and charge off will be included in the borrower's debt-to-income ratio. In the absence of a payment arrangement, the lender will utilize in the debt-to-income ratio a calculated monthly payment. For each collection and charge off utilize 5% of the outstanding balance to represent the monthly payment. STUDENT LOANS: Include the greater of 1% of the outstanding loan balance or the verified fixed payment reflected on the credit report. Exception: Monthly payment amounts listed on the credit report, which are less than one percent of the outstanding balance may be used when evidence from the loan servicer is obtained indicating; 1)the applicant is on a fixed repayment plan not subject to change under the terms of the current agreement and 2) and the monthly payment amount due. Fixed payments have a monthly amount that is not subject to change through the fixed repayment time frame. Income Based Repayment (IBR) plans, graduated plans, adjustable rates, interest only and deferred plans are examples of repayment plans that are subject to change and do not qualify for the exception. EXCLUDING INSTALLMENT PAYMENTS: Long-term obligations with more than 10 months repayment remaining, including all installment loans, revolving charge accounts, alimony, child support or separate maintenance payments, student loans and other continuing obligations. GUS will determine if the debt can be excluded. If GUS does not exclude the debt, we cannot override it and exclude. DEBT WITH NO PAYMENT REPORTED: Use the greater of 5% of the balance or $10. Current payment from current monthly statement. TRANSCRIPTS: All household members must have 2 years IRS tax return transcripts pulled even if they are not a borrower on the loan. Transcripts for all household members are required prior to submission to USDA for conditional commitment. If the household member(s) is not a borrower on the loan, a separate 4506T form will be required. If any adult member of the household is not presently employed but there is a recent history of such employment, that person's income will be considered in the calculation of annual household income. If the person involved is not presently employed and does not intend to resume employment in the foreseeable future, or if interest assistance is involved, during the term of the Interest Assistance Agreement, the applicant(s) and the person involved must sign a statement to such. The statement will be filed in the permanent loan file. GIFT FUNDS: Household members now can provide gifts. TAX EXEMPT INCOME: May be grossed up 25% for repayment income, cannot be grossed up for household income. PROPERTY: 30% land value restriction has been removed. Cannot include income producing land or buildings that use used principally for income purposes. No reduction of value is required for outbuildings. No active farms are commercial enterprises. Home based operations are allowed (home daycare). Shared Driveways and private roads must have a recorded agreement/easement. If any of these items exist on the credit report or other documentation provided, the loan is ineligible for USDA financing with Platinum Mortgage. Foreclosure within 3 years of application date Chapter 7 BK within 3 years of application date Chapter 13 BK within 12 months of application date Late mortgage payments if any mortgage trade line during the most recent 12 months of application date shows 1 or more late payments of greater than 30 days. Late rent payments paid 30 or more days late within the last 12 months of application date. CREDIT SCORE: A minimum of 2 scores required per borrower. SELLER CONCESSIONS: USDA has placed a limit of 6% for seller concessions. DOCUMENT EXPIRATION: All documents expire after 120 days for both existing and new construction. POC ITEMS PAID BY CREDIT CARD: If the applicant pays for application fee/closing cost/appraisal with a credit card and new charges are not reflected in the credit report balance these new charges must be included in the total balance and the payment must be recalculated. The new payment must be included in the DTI. About Me I have helped over 589 Kentucky families buy or refinance their home over the last 18 years. Realizing that this is one of the biggest, most important financial transactions a family makes during their lifetime, I always feel honored and respected when I am chosen to originate their personal home loan. You can count on me to deliver on what I say, and I will always give you honest, up-front personal attention you deserve during the loan process. I have several advantages over the large banks in town. First, I can search and negotiate for your loan options through several different mortgage companies across the country to get you the best deal locally, as opposed to banks that will offer you their one set of loan products. I work for you not the bank. I have access to over 10 different mortgage companies to broker your loan through to get you the best pricing and loan products that may not fit into the bank's program due to credit, income, or other underwriting issues. You will not get lost in the shuffle like most borrowers do at the mega banks; you're just not a number at our company, you are a person and we will treat you like one throughout the entire process. Give us a try or let us compare your options on your next mortgage transaction. Call me locally at 502-905-3708. Free Mortgage Pre-Qualifications same day on most applications. I specialize in Kentucky FHA, VA ,USDA, KHC, Conventional and Jumbo mortgage loans. I am based out of Louisville Kentucky. For the first time buyer with little money down, we offer Kentucky Housing or KHC loans with down payment assistance. Customer Testimonials We just moved here the first of January in 2017 from Ohio to the Louisville, KY area and we found Joel's website online. He was quick to respond to us and got back the same day on our loan approval. He was very knowledgeable about the local market and kept us up-to date throughout the loan process and was a pleasure to meet at closing. Would recommend his services. Angela Forsythe "We were searching online for mortgage companies in Louisville, Ky locally to deal with and found Joel's website, and it was a godsend. He was great to work with, and delivered on everything he said he would do. I ended up referring my co-worker at UPS, and she was very pleased with his service and rates too. Would definitely vouch for him." September 2016 Monica Leinhardt "We contacted Joel back in July 2011 to refinance our Mortgage and he was great to work with. We contacted several lenders locally and online, and most where taking almost 60 days to close a refinance, Joel got it done in 23 days start to finish,I would definetly recommmend him. He got us 3.75% with just $900 in closing costs on our FHA Streamline loan. Kayle Griffin “Joel is one of the best Mortgage Brokers I have ever worked with in my sixteen years in the real estate and mortgage business.” May 25, 2010 Tim Beck “Joel has always worked very hard to keep his word and to work out seasonable solutions to difficult problems. He is truly an expert in FHA and other type loans.” September 1, 2010 Nancy Nalley “I have worked with Joel since 1998. He is a great loan professional.” I refer most of my Louisville, Kentucky area home buyers to him and he always take special care of them. August 23, 2012 Jon ClarK “Joel Lobb is a real professional in the lending industry, with many years of experience, he is the one to go to for any mortgage lending needs.” August 22, 2011 RICHARD VOLZ , Residential Sales , Remax Foursquare Realty “When looking to purchase our new home in 2006, I had the pleasure of meeting Joel Lobb. Not only was he personable and easy to reach, he was extremely knowledgable in his field and made sure to find us the best rate and a top notch mortgage company. We were able to complete the process in less than 3 weeks with his expertise. I find Joel to have the utmost high integrity and I recommend him to anyone who say's they are need of mortgage assistance. He is also fantastic and keeping everyone up to date on the latest in the housing industry through his twitter posts. He provided great results for our family and we still communicate to this day!” August 21, 2010 Stacie Drake "We first use Joel on our new home purchase in 2007 in St Matthews, Kentucky area and he was great to work with. We have since refinanced our home with him in 2010 when rates got really low and he has always delivered on what he says. I could not imagine using anyone else." Melody Glasscock March 2014 Absolutely Amazing!! I emailed Joel after I had just got a denial from a bank and just thought i would try to get some advice on what my next steps would be to get a house. I honestly didn't expect to even get a reply because my credit is not great. That was about a week and a half ago. I just signed a contract on a house last night. ONLY because of Joel Lobb. He even worked with us throughout the weekend, which shocked me. Best decision I have ever made. THANK YOU SO MUCH FOR WORKING WITH US THROUGHOUT THE ENTIRE PROCESS. Kentucky USDA Current Rates KY USDA Mortgage for Free Pre Approal Website Fine Print The content provided on this website is presented or compiled by Joel Lobb and is provided for informational purposes only. It does not necessarily represent the views or opinions of his employer. Joel Lobb or his employer assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information disclosed, or represents that its use would not infringe privately owned rights. The mortgage or financial services or strategies mentioned in this website may not be not suitable for you. This website is an Equal Opportunity Lender. All rights Reserved. Legal Disclaimer This web site is not the FHA, VA, USDA, HUD or any other government organization responsible for managing, insuring, regulating or issuing residential mortgage loans. All approvals and rates are not guaranteed, and are only issued based on standard mortgage qualifying guidelines. Full Disclosure Policy This blog is a sponsored blog created or supported by a company, organization or group of organizations. For questions about this blog, please contact Joel Lobb 502-905-3708 or email [email protected] NMLS# 57916. This blog does not accept any form of advertising, sponsorship, or paid insertions. We write for our own purposes. However, we may be influenced by our background, occupation, religion, political affiliation or experience. This blog abides by word of mouth marketing standards. We believe in honesty of relationship, opinion and identity. The compensation received may influence the advertising content, topics or posts made in this blog. That content, advertising space or post will be clearly identified as paid or sponsored content. The owner(s) of this blog is not compensated to provide opinion on products, services, websites and various other topics. The views and opinions expressed on this blog are purely the blog owners. If we claim or appear to be experts on a certain topic or product or service area, we will only endorse products or services that we believe, based on our expertise, are worthy of such endorsement. Any product claim, statistic, quote or other representation about a product or service should be verified with the manufacturer or provider. This blog does contain content which might present a conflict of interest. This content will always be identified. Kentucky Refinance Rural Development Pilot Program 2013 Kentucky USDA Pilot program is designed to assist existing Rural Development S... Equal Housing Lender Search This Blog Privacy Policy We take our clients' financial privacy very seriously. During the course of processing your application, we accumulate non-public personal financial information from you and from other sources about your income, your assets, and your credit history in order to allow a lender to make an informed decision about granting you credit. We restrict access to nonpublic personal information about you to those employees who need to know that information to provide products or services to you. We maintain physical, electronic, and procedural safeguards that comply with federal regulations to guard your nonpublic personal information. We collect nonpublic information about you from the following sources: (i) information we receive from you on applications or other forms; (ii) information about your transactions with us, our affiliates, or others; and (iii) information we receive from a consumer reporting agency. We do not disclose any nonpublic information about our customers or former customers to any third party, except as permitted by law. | Mid | [
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DEEPGEN™HIV monitors the success of anti-HIV treatment by determining drug resistance and the ability of the virus to infect different cells based on deep genetic sequencing. University Hospitals Case Medical Center has signed an agreement with ARUP Laboratories, a major national clinical reference laboratory that offers an extensive menu of highly complex and unique medical tests to hospitals, medical schools, and other nonprofit and commercial organizations throughout the United States. Under the agreement, ARUP will include in its menu of tests an HIV diagnostic test invented at University Hospitals’ Translational Laboratory by Miguel Quinones-Mateu, PhD, scientific director at the UH lab and assistant professor at the Department of Pathology, Case Western Reserve University School of Medicine. The novel test, DEEPGEN™HIV, monitors the success of anti-HIV treatment by determining drug resistance and the ability of the virus to infect different cells based on deep genetic sequencing. ARUP, a nonprofit enterprise of the University of Utah, will include DEEPGEN in its menu of tests and will nationally market the assay. Clinical samples will then be referred to UH Translational Laboratory (UHTL, www.uhtl.org) in Cleveland from all 50 states. DEEPGEN™HIV provides a sensitive platform for HIV physicians and researchers, both in the academia and industry. The assay allows the detection of minority variants at frequencies unimaginable with current HIV genotypic tests based on standard (Sanger) sequencing. “Although the clinical relevance of these minority members of the viral population is still under debate, it is reasonable to assume that the earlier these mutant viruses are detected, the sooner the proper strategy can be defined to control their growth,” said Dr. Quiñones-Mateu. “DEEPGEN™HIV is now the primary HIV genotyping assay used by HIV physicians at the Case Western Reserve University/University Hospitals AIDS Clinical Trials Unit, and we have been analyzing clinical specimens from other institutions around the region. This agreement with ARUP will expedite the use of this innovative and highly sensitive assay nationwide, which will allow us to enhance the care and treatment of HIV-infected individuals across the country.” “I am excited about our relationship with ARUP, as it appears to be a natural synergy that we both may leverage to expand the quality of diagnostic testing and care provided to patients with HIV nationally,” said Ronald E. Dziedzicki, chief operating officer at UH Case Medical Center. “Our relationship with UH Case Medical Center enables ARUP to offer this innovative test to our clients for the management of patients with HIV,” said Jerry Hossong, MD, DDS, ARUP’s chief medical officer and director of laboratories. “We are very pleased to include this test as part of our comprehensive menu of services.” Join For Free Access to this exclusive content is for Technology Networks Premium members only. Join Technology Networks Premium for free access to: Exclusive articles Presentations from international conferences Over 4,000+ scientific posters on ePosters More than 5,300+ scientific videos on LabTube 35 community eNewsletters Sign In Forgotten your details? Click Here If you are not a member you can join here *Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy. | High | [
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Key Feature Occasion Specification Material for Jewellery Material : Alloy Color Set Details Color Family : White Plating Specification Plating : Gold Plated Stone Specification Stone : NA Design Specification for Jewel Design : Bridal/Wedding Exclusive Gold Plated Material . Golden polished finishing & many precious stones presents in it. Beautiful Design, Unique style & intricate workmanship make this set true masterpiece. This set can be worn on any special occasions. | High | [
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This document applies in particular to ArchLinux on an HP Pavilion ze5600 laptop. It may also apply to the entire ze5600 series on any modern Linux system (using at least kernel 2.6.39), and dependent upon what BIOS your system has. + This document applies in particular to ArchLinux on my HP Pavilion ze5615CA laptop. It also applies to the entire ze5600 series on any modern Linux system (using at least kernel 2.6.39). Feel free to contact me if any problems or suggestions (lagagnon at gmail.com) (English or Spanish). − Feel free to contact me if any problems or suggestions (lagagnon at gmail.com) (English or Spanish). Three of the upper multimedia keys, fn+f12, wireless off switch at front right of laptop, audio switches at right front side of laptop. Three of the upper multimedia keys, fn+f12, wireless off switch at front right of laptop, audio switches at right front side of laptop. − ==Not Yet Tested== + ==Not Tested== PCMCIA port, Modem. PCMCIA port, Modem. Line 42: Line 41: ==Configurations== ==Configurations== − '''Video:''' The older ATI chip in this laptop requires the xf86-video-ati "radeon" open-source driver. Apparently the latest "catalyst" drivers from ATI do not work with this chip. The radeon driver however, is fine. + <b>Wireless:</b> The older Broadcom wireless chip in this laptop requires the <b>b43legacy</b> module to function properly. Also, you must specifically follow the instructions on how to install the firmware - this is explained here: [[Broadcom wireless]] , in the "b43legacy" section of that wiki entry. + + <b>Video:</b> The older ATI IGP 330M video chip in this laptop requires the xf86-video-ati "radeon" open-source driver. Apparently the latest "catalyst" drivers from ATI do not work with this chip, but I have not tested this. The radeon driver, however, works well, but runs a bit hot (see below). <b>Kernel boot parameters:</b> It <i>might</i> make some difference to your power consumption if you add the following kernel parameters to the "kernel" of your boot config file (for those using grub this is /boot/grub/menu.lst): <b>Kernel boot parameters:</b> It <i>might</i> make some difference to your power consumption if you add the following kernel parameters to the "kernel" of your boot config file (for those using grub this is /boot/grub/menu.lst): + <code>acpi_enforce_resources=lax pcie_aspm=force</code> <code>acpi_enforce_resources=lax pcie_aspm=force</code> − + <b>Suspend/Hibernate:</b> The "pm-suspend" and "pm-hibernate" scripts from the [[pm-utils]] package work well but you need to bind keys to access these scripts because fn+f12 has no scancode. − <b>Wireless:</b> The older Broadcom wireless chip in this laptop requires the <b>b43legacy</b> module to function properly. Also, you must specifically follow the instructions on how to install the firmware - this is explained here: [[Broadcom wireless]] , in the "b43legacy" section of that wiki entry. − − <b>Suspend/Hibernate:</b> The "pm-suspend" and "pm-hibernate" scripts from the [[pm-utils]] package work just fine but you need to bind keys to access these scripts because fn+f12 has no scancode. <b>Function Keys:</b> Only two of the upper keyboard silver multimedia keys have scancodes. For information on how to bind keycodes please read [[Extra Keyboard Keys]]. <b>Function Keys:</b> Only two of the upper keyboard silver multimedia keys have scancodes. For information on how to bind keycodes please read [[Extra Keyboard Keys]]. − <b>Audio:</b> Should just work. Read the "alsactl" man page to find out how to store alsamixer settings between reboots. to get the CPU temperature. Using ArchLinux with kernel 2.6.39 I find that the laptop runs quite hot. It starts at about 32degC and then continues to climb to 50deg C, with the fan on past 40degC, even at idle, with less than 2% CPU activity. I have attempted many energy saving tools as per [[Laptop]] but to little avail. The laptop consumes about 25 watts at idle with the screen on at about mid brightness. I suspect some of the heat may be generated by the video chip as I have heard that the "radeon" module can run the video chip hotter than necessary. I have been unable to get energy saving features of this video chip activated as per https://wiki.archlinux.org/index.php/Ati#With_KMS_enabled . As I have never run any other operating system on this laptop, I would be interested to hear if other owners have success in dropping the power usage and temperature level of this laptop. to get the CPU temperature. Using ArchLinux with kernel 2.6.39 I find that the laptop runs quite hot. It starts at about 32degC and then continues to climb to 50deg C, with the fan on past 40degC, even at idle, with less than 2% CPU activity. I have attempted many energy saving tools as per [[Laptop]] but to little avail. The laptop consumes about 25 watts at idle with the screen on at about mid brightness. I suspect some of the heat may be generated by the video chip as I have heard that the "radeon" module can run the video chip hotter than necessary. I have been unable to get energy saving features of this video chip activated as per https://wiki.archlinux.org/index.php/Ati#With_KMS_enabled . As I have never run any other operating system on this laptop, I would be interested to hear if other owners have success in dropping the power usage and temperature level of this laptop. ==Considerations== ==Considerations== − This laptop is by present standards mediocre hardware. Out of the box it has only 446MB RAM available. It is suggested you stay away from the Gnome or KDE desktop environments as you will then constantly be using your swap partition. I use the Fluxbox window manager. My ArchLinux system boots from cold button press to a ready desktop in just 38 seconds, including a SLiM graphical login page. It shuts down in about 8 seconds and resumes from suspend in about 2 seconds. Immediately after desktop ready and with one urxvt terminal open it has used just 47MB, excluding buffers and cache! The Opera browser launches from cold within 4 seconds. I have seen very modern laptops running Windows 7 perform much worse than this. Have fun with it... + This laptop is now older hardware. Out of the box it has only 446MB RAM available. It is suggested you do not install the Gnome or KDE desktop environments as you will then constantly be using your swap partition and you can therefore expect sluggishness. I use the Fluxbox window manager. My ArchLinux system boots from cold button press to a ready desktop in just 35 seconds, including a SLiM graphical login page. It shuts down in about 7 seconds and resumes from suspend in about 2 seconds. Immediately after desktop ready and with one urxvt terminal open it has used just 47MB, excluding buffers and cache! The Opera browser launches from cold within 9 seconds. I have seen very modern laptops running Windows 7 perform much worse than this. Have fun with it, it is still an incredibly usable laptop with the right operating system and window manager installed. + + Also, many owners have commented how annoying all those bright blue multimedia key LED lights are as they are located immediately beneath the screen. I have placed black electrical tape over them and then with a razor knife cut around the tape to form the tape to the grill edges. It now looks as if those silly lights were never there and reading the screen is much easier on the eyes! − Also, many owners have commented how annoying all those bright blue LED lights are as they are located immediately beneath the screen. I have placed black electrical tape over them and then with a razor knife cut around the tape to form the tape to the grill edges. It now looks as if those silly lights were never there and reading the screen is much easier on the eyes! + The leftmost upper multimedia key can be used as an on/off switch and a resume from suspend/hibernate key. This is useful because the default on/off button for this laptop is poorly designed and often fails or requires significant pressure to work properly. ==Upgrading your BIOS== ==Upgrading your BIOS== − The BIOS upgrade download at the HP support website is a Windows only executable file and is designed to create bootable floppies. This is about as useless as tits on a bull because this laptop has no floppy drive (yes, it is really hard to understand the stupidity of HP sometimes)! To get it to flash under Linux you need to: + It is possible that a BIOS upgrade may fix some of the missing key scancodes and missing hardware control function as listed above. But probably not ;-). Nonetheless if you wish to upgrade your BIOS this is how to do it in Linux. The BIOS upgrade download at the HP support website ( http://tinyurl.com/629wd38 ) is a Windows only executable file and is designed to create bootable floppies. This is about as useless as tits on a bull because this laptop has no floppy drive! To get it to flash under Linux you need to: <ol> <ol> <li>Run the Windows BIOS upgrade file as an executable under a MS Windows operating system <li>Run the Windows BIOS upgrade file as an executable under a MS Windows operating system <li>Rather than inserting a floppy use Windows Explorer to navigate to the directory where the extracted image file (rom.img) was stored. <li>Rather than inserting a floppy use Windows Explorer to navigate to the directory where the extracted image file (rom.img) was stored. − <li>Copy the rom.img file to a USB thumb drive and then copy the file from the drive into your Linux system + <li>Copy the rom.img file to a USB thumb drive and then copy that file from the thumb drive into your Linux system This procedure should be foolproof yet did not work for me. The Phlash software started up but hangs at reading the .bin file. I suspect that it balks at reading data from USB. Someone needs to test this with an external floppy drive device and see if a BIOS flash upgrade really does work on this laptop. Please let me know if you are successful with either method and I will include further details here. This procedure should be foolproof yet did not work for me. The Phlash software started up but hangs at reading the .bin file. I suspect that it balks at reading data from USB. Someone needs to test this with an external floppy drive device and see if a BIOS flash upgrade really does work on this laptop. Please let me know if you are successful with either method and I will include further details here. Revision as of 04:16, 15 July 2011 This document applies in particular to ArchLinux on my HP Pavilion ze5615CA laptop. It also applies to the entire ze5600 series on any modern Linux system (using at least kernel 2.6.39). Feel free to contact me if any problems or suggestions (lagagnon at gmail.com) (English or Spanish). What Works With Configuration? What Does Not Work? Three of the upper multimedia keys, fn+f12, wireless off switch at front right of laptop, audio switches at right front side of laptop. Not Tested PCMCIA port, Modem. Configurations Wireless: The older Broadcom wireless chip in this laptop requires the b43legacy module to function properly. Also, you must specifically follow the instructions on how to install the firmware - this is explained here: Broadcom wireless , in the "b43legacy" section of that wiki entry. Video: The older ATI IGP 330M video chip in this laptop requires the xf86-video-ati "radeon" open-source driver. Apparently the latest "catalyst" drivers from ATI do not work with this chip, but I have not tested this. The radeon driver, however, works well, but runs a bit hot (see below). Kernel boot parameters: It might make some difference to your power consumption if you add the following kernel parameters to the "kernel" of your boot config file (for those using grub this is /boot/grub/menu.lst): acpi_enforce_resources=lax pcie_aspm=force Suspend/Hibernate: The "pm-suspend" and "pm-hibernate" scripts from the pm-utils package work well but you need to bind keys to access these scripts because fn+f12 has no scancode. Function Keys: Only two of the upper keyboard silver multimedia keys have scancodes. For information on how to bind keycodes please read Extra Keyboard Keys. to get the CPU temperature. Using ArchLinux with kernel 2.6.39 I find that the laptop runs quite hot. It starts at about 32degC and then continues to climb to 50deg C, with the fan on past 40degC, even at idle, with less than 2% CPU activity. I have attempted many energy saving tools as per Laptop but to little avail. The laptop consumes about 25 watts at idle with the screen on at about mid brightness. I suspect some of the heat may be generated by the video chip as I have heard that the "radeon" module can run the video chip hotter than necessary. I have been unable to get energy saving features of this video chip activated as per https://wiki.archlinux.org/index.php/Ati#With_KMS_enabled . As I have never run any other operating system on this laptop, I would be interested to hear if other owners have success in dropping the power usage and temperature level of this laptop. Considerations This laptop is now older hardware. Out of the box it has only 446MB RAM available. It is suggested you do not install the Gnome or KDE desktop environments as you will then constantly be using your swap partition and you can therefore expect sluggishness. I use the Fluxbox window manager. My ArchLinux system boots from cold button press to a ready desktop in just 35 seconds, including a SLiM graphical login page. It shuts down in about 7 seconds and resumes from suspend in about 2 seconds. Immediately after desktop ready and with one urxvt terminal open it has used just 47MB, excluding buffers and cache! The Opera browser launches from cold within 9 seconds. I have seen very modern laptops running Windows 7 perform much worse than this. Have fun with it, it is still an incredibly usable laptop with the right operating system and window manager installed. Also, many owners have commented how annoying all those bright blue multimedia key LED lights are as they are located immediately beneath the screen. I have placed black electrical tape over them and then with a razor knife cut around the tape to form the tape to the grill edges. It now looks as if those silly lights were never there and reading the screen is much easier on the eyes! The leftmost upper multimedia key can be used as an on/off switch and a resume from suspend/hibernate key. This is useful because the default on/off button for this laptop is poorly designed and often fails or requires significant pressure to work properly. Upgrading your BIOS It is possible that a BIOS upgrade may fix some of the missing key scancodes and missing hardware control function as listed above. But probably not ;-). Nonetheless if you wish to upgrade your BIOS this is how to do it in Linux. The BIOS upgrade download at the HP support website ( http://tinyurl.com/629wd38 ) is a Windows only executable file and is designed to create bootable floppies. This is about as useless as tits on a bull because this laptop has no floppy drive! To get it to flash under Linux you need to: Run the Windows BIOS upgrade file as an executable under a MS Windows operating system Rather than inserting a floppy use Windows Explorer to navigate to the directory where the extracted image file (rom.img) was stored. Copy the rom.img file to a USB thumb drive and then copy that file from the thumb drive into your Linux system This procedure should be foolproof yet did not work for me. The Phlash software started up but hangs at reading the .bin file. I suspect that it balks at reading data from USB. Someone needs to test this with an external floppy drive device and see if a BIOS flash upgrade really does work on this laptop. Please let me know if you are successful with either method and I will include further details here. | Low | [
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Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences. The objective of this study was to evaluate etiology and consequences of neutropenic fever in AML patients. Two hundred and ninety neutropenic periods following chemotherapy in 84 AML patients were retrospectively evaluated. Neutropenic fever was found in 280 periods (97%). Severe sepsis developed in 35 occasions (13%) and 9 patients (11%) died due to severe sepsis. In 165 episodes with neutropenic fever (59%), the potential causative organism was found in blood cultures. Gram-negative bacteria were more commonly found in patients who developed severe sepsis (40% vs. 23%, p = 0.03). CRP after 2 - 3 days from start with fever was higher in patients with severe sepsis (190 mg/L vs. 96 mg/L, p < 0.001) but the rise in CRP rather coincided than preceded with the development of severe sepsis. Severe sepsis is associated with significant mortality in AML patients. Earlier methods than CRP are needed to predict development of severe sepsis. | Mid | [
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23 June 2015 – Allegheny Mound Ant The Allegheny mound ant (Formica exsectoides Forel) is a field ant that found on the refuge. It ranges along the Atlantic Coast of North America from Nova Scotia to Georgia. Although they are not highly regarded by some people, they are a fascinating and even arguably beneficial species. 23 June 2015 Unlike most field ants, they can have multiple queens. Their tunnels can reach three feet below ground level and their mounds reach up to four feet high. The tunnels can be complex and may link several mounds. 23 June 2015 They are noted for killing woody vegetation up to about 40 feet away from their mounds. They do this by injecting formic acid into the plants. But, according to the Maine State Extension Service, this damage is minor in comparison to the role of a pest control that they perform. Dwarf Dandelion – 3 May 2014 Allegheny mound ants have been observed scavenging upon honeydew produced by aphids and leafhoppers, dead vertebrates and arthropods, and seeds; and preying upon most small arthropods they encounter. They also prey on caterpillars, beetles, treehoppers, grasshoppers, crickets, wasps and flies. Dwarf Dandelion – 3 May 2014 On the refuge, they also help to spread certain plant species like the Dwarf Dandelion (Krigia virginica (L.) Willd.) and the Canada Toadflax (Nuttallanthus canadensis (L.) D.A. Sutton.) The ants harvest the seeds of these plants and feed on a fat-rich accessory in the seeds called an elaiosome. Dwarf Dandelion – 3 May 2014 Then they discard the still viable seed next to their mound. On the refuge, you can see this behavior in action. The photos seen here are from the Dwarf Dandelion which were seeded by the ants next to their mounds. Dwarf Dandelion – 3 May 2014 The ants are aggressive when disturbed and will bite. Their bite is irritating, but not harmful. When taking pictures on the refuge, I have had more than a few encounters with this fascinating critter. | Mid | [
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854 N.E.2d 1205 (2006) GOVERNMENT PAYMENT SERVICE, INC., Appellant-Defendant/Counter-Plaintiff, v. ACE BAIL BONDS, American Bail Bond Company, Bertholet Bail Bond, and Express Bail Bond, Appellees-Plaintiffs/Counter-Defendants. No. 49A02-0507-CV-656. Court of Appeals of Indiana. October 11, 2006. *1206 Mark R. Waterfill, James B. Chapman II, Dann Pecar Newman & Kleiman, P.C., Indianapolis, IN, for Appellant. Douglas M. Grimes, Gary, IN, for Appellees. *1207 OPINION KIRSCH, Chief Judge. Government Payment Service, Inc. ("GPS") appeals the trial court's decision in favor of Ace Bail Bonds, American Bail Bond Company, Bertholet Bail Bond, and Express Bail Bond (collectively, the "Bail Agents"). Specifically, GPS appeals the trial court's decision to permanently enjoin GPS from facilitating cash bail in Indiana. GPS also appeals the trial court's denial of its counterclaim for damages. On appeal, GPS raises the following dispositive issues: I. Whether the trial court's findings of fact and conclusions support the permanent injunction entered against GPS. II. Whether the trial court erred in denying GPS's counterclaim for damages sustained as a result of being wrongfully enjoined or restrained. We reverse in part and affirm in part. FACTS AND PROCEDURAL HISTORY[1] GPS is an Indiana company that was incorporated in 1997 to help credit card holders access their credit in order to make payments to government agencies and small businesses. GPS has approximately 950 customers in thirty-one states, 800 of which are government agencies. This dispute arises from actions taken by GPS in connection with its contracts with Lake County, Hammond City Court, and Hobart City Court ("the Contracts"). Under the Contracts, GPS facilitated the payment of cash bail, a fine, or other fee by means of a client's credit card. On March 27, 2003, the Bail Agents filed a "Complaint for Temporary Restraining Order, Preliminary and Permanent Injunction and Damages," claiming that GPS had tortiously interfered with the Bail Agents' business by issuing bail bonds in violation of IC XX-XX-X-X.[2] On March 27, 2003, the Lake Superior Court entered a temporary restraining order ("TRO") enjoining GPS both from posting cash bail for incarcerated defendants and from advertising its services. The TRO expired April 7, 2003. On July 7, 2003, the Lake County Superior Court granted GPS's motion to transfer venue to Marion County. Thereafter, GPS filed a counterclaim against the Bail *1208 Agents for damages sustained as a result of being wrongfully enjoined by the TRO. In turn, the Bail Agents filed an amended complaint on March 1, 2004, which requested the same relief as the initial complaint but sought to add Express Bail Bond, Inc. as a party and remove American Bail Bond as a party. On July 30, 2004, GPS filed its motion for summary judgment on the Bail Agents' amended complaint. The Bail Agents responded in opposition to GPS's motion, and GPS, in turn, filed a reply in support of summary judgment. On September 30, 2004, GPS filed a motion to dismiss asking the trial court to dismiss the amended complaint based on the Bail Agents' failure to obtain leave of court to add Express Bail Bond as a party and dismiss American Bail Bond as a party. The trial court conducted a hearing on GPS's motion for summary judgment on October 5, 2004. During that hearing, the trial court, in an effort to align the parties to the pleadings, obtained the parties' consent to keep all four Bail Agents as plaintiffs in the case. Tr. at 7, Appellant's App. at 106. This action effectively denied GPS's motion to dismiss the amended complaint and denied GPS's motion for default judgment. Appellant's Br. at 4. On November 18, 2004, the trial court denied GPS's motion for summary judgment. GPS then filed amended counterclaims against the Bail Agents to change the caption to include all four of the Bail Agents. The trial court conducted a bench trial on the Bail Agents' amended complaint on December 13 and 14, 2004. On July 12, 2005, the trial court entered its judgment (1) permanently enjoining GPS from facilitating cash bail in Indiana or advertising its services, and (2) denying GPS's counterclaim for damages, attorney fees, and costs. GPS now appeals. Additional facts will be added as needed. DISCUSSION AND DECISION The trial court issued special findings of fact and conclusions pursuant to Ind. Trial Rule 52(A). When reviewing a judgment based on such findings, this Court must determine first, whether the evidence supports the findings, and second, whether the findings support the judgment. Town of New Ross v. Ferretti, 815 N.E.2d 162, 166 (Ind.Ct.App.2004); Ratliff v. Ratliff, 804 N.E.2d 237, 244 (Ind. Ct.App.2004). This Court may set aside findings of fact only if they are clearly erroneous. Collections, Inc. v. Wolfe, 818 N.E.2d 14, 16 (Ind.Ct.App.2004). Findings are clearly erroneous only when the record contains no facts to support them either directly or by inference. Id. In order to determine that a finding or conclusion is clearly erroneous, our review of the evidence must leave us with the firm conviction that a mistake has been made. Id. Here, the trial court granted a permanent injunction, which is an extraordinary equitable remedy that should be granted only with caution. Crawley v. Oak Bend Estates Homeowners Ass'n, Inc., 753 N.E.2d 740, 744 (Ind.Ct.App.2001), trans. denied (2002). To properly analyze the issues before this court, we must first address the nature of the claim, i.e., whether the Bail Agents are pursuing a private cause of action to enjoin GPS from violating IC XX-XX-X-X or a claim for tortious interference with a business relationship. The Bail Agents' amended complaint alleged in part: (1) GPS is engaged in the practice of charging fees to post cash bail; (2) GPS is not a licensed bail agent in the State of Indiana; (3) the actions of GPS have tortiously interfered with the business of the plaintiffs, all of whom are licensed bail agents in the State of Indiana; (4) GPS is guaranteeing the funds which are transmitted to the clerk's office within three business days which results in the release *1209 of a person without ever having actually posted the cash or given any assurance that they will post the bail; (5) as a result of GPS's unlawful actions, plaintiffs have suffered damages; and (6) the actions of GPS are contrary to IC XX-XX-X-X, which provides that only a licensed bail agent may charge a fee to post a bail bond. Appellant's App. at 51-52. GPS understood the claim as being one for tortious interference with business relationships.[3] When questioned at oral argument, Douglas Grimes, counsel for the Bail Agents, agreed. I. GPS contends that the evidence does not support the findings and, in turn, the findings do not support the judgment granting a permanent injunction on a claim of tortious interference with a business relationship. This Court may set aside findings of fact if they are clearly erroneous. The elements of tortious interference with a business relationship are: (1) the existence of a valid relationship; (2) the defendant's knowledge of the existence of the relationship; (3) the defendant's intentional interference with that relationship; (4) the absence of justification; and (5) damages resulting from defendant's wrongful interference with the relationship. Felsher v. Univ. of Evansville, 755 N.E.2d 589, 598 n. 21 (Ind.2001) (citing Levee v. Beeching, 729 N.E.2d 215, 222 (Ind.Ct.App.2000)); Rice v. Hulsey, 829 N.E.2d 87, 91 (Ind.Ct.App.2005); AutoXchange.com, Inc. v. Dreyer and Reinbold, Inc., 816 N.E.2d 40, 51 (Ind.Ct.App.2004). Additionally, our Supreme Court has held that "this tort requires some independent illegal action." Brazauskas v. Fort Wayne-South Bend Diocese, Inc., 796 N.E.2d 286, 291 (Ind.2003), cert. denied, 541 U.S. 902, 124 S.Ct. 1602, 158 L.Ed.2d 244 (2004); see also Watson Rural Water Co., Inc. v. Ind. Cities Water Corp., 540 N.E.2d 131, 139 (Ind.Ct.App.1989), trans. denied ("In the State of Indiana, an element necessary to prove this cause of action is that a defendant acted illegally in achieving his end."). The first element of a cause of action for tortious interference with a business relationship is the existence of a valid business relationship. Computers Unlimited, Inc. v. Midwest Data Systems, Inc., 657 N.E.2d 165, 169 (Ind.Ct.App.1995); Comfax v. N. Am. Van Lines, 587 N.E.2d 118, 124 (Ind.Ct.App.1992). Bail Agents contend that GPS interfered with the relationship that they and their clients had with the local governmental entities. However, there is no evidence that either Bail Agents or their clients had any such relationship. There is no evidence of a contract between the Bail Agents, their clients, and the governmental entities. There is no evidence of property or other rights held by the Bail Agents. Although Bail Agents claim that they had access to the incarcerated defendants in the jails prior to the Contracts with GPS, there is no evidence that such access was a matter of right or flowed in any way from a business relationship between the Bail Agents and the governmental entities. Similarly, there is no evidence of any consideration paid by Bail Agents for such access. There is also no evidence that GPS intentionally interfered, or could interfere, with the relationship which Bail Agents claim to have had with the governmental entities. It was the governmental entities, not GPS, who adopted the cash bail program. *1210 It was the governmental entities, not GPS, who restricted the access of the Bail Agents to the jails and the incarcerated defendants. Nothing in the Contracts here at issue restricts, limits, or interferes with the rights or business activities of Bail Agents in any way. To be sure, the Bail Agents may have lost business in writing traditional bail bonds when the governmental entities adopted a cash bail system and when they entered into a contract with GPS to facilitate that program by providing credit access to incarcerated defendants. That loss results not from intentional interference by GPS, but from the choice that the governmental entities decided to give incarcerated defendants through the cash bail program. Indiana law permits licensed bail agents to write bonds for incarcerated defendants. It also permits a cash bail program. Facilitating the access of incarcerated defendants to credit which they in turn post as cash bail is not engaging in the writing of bail bonds, and it is not tortious interference with the business relationships of the Bail Agents. The trial court erred in concluding that GPS intentionally interfered with the business relationships of the Bail Agents and in enjoining GPS from facilitating cash bail. Accordingly, we reverse the trial court's judgment and permanent injunction.[4] II. On December 9, 2004, GPS filed an amended counterclaim against the Bail Agents, which requested attorney fees, costs, expenses, and damages incurred by lost business due to the TRO. Appellant's App. at 114-15. Citing to Trial Rule 65(C)which suggested that GPS was suing to collect on the bond maintained by the trial court as security for the TRO the nature of GPS's counterclaim was malicious prosecution on the basis that GPS had to defend against the wrongful request for a TRO. Id. at 114. The trial court denied this counterclaim and granted the Bail Agents' request for a permanent injunction in the same July 12, 2005 order. Id. at 18. GPS contends that because GPS was wrongfully enjoined, the trial court erred in denying this amended counterclaim against the Bail Agents for damages that arose through the trial court's issuance of the TRO. GPS further contends, "upon a reversal of the trial court's permanent injunction, the Court should remand this matter to the trial court for a calculation and an award of damages pursuant to Rule 65(C)." Appellant's Br. at 26. Where a temporary injunction is dissolved and not replaced by a permanent injunction, the enjoined party is generally entitled to compensation for the damages it incurred. H & G Ortho, Inc. v. Neodontics Int'l, Inc., 823 N.E.2d 718, 733 (Ind.Ct. App.2005); Hampton v. Morgan, 654 N.E.2d 8, 9 (Ind.Ct.App.1995). While it is true that this TRO expired ten days after it was issued and it was not immediately replaced by a permanent injunction, the trial court eventually did grant the Bail Agents' request for a permanent injunction. The decision to deny the counterclaim was made in conjunction with that decision to grant the permanent injunction. To prove malicious prosecution, GPS had to prove: (1) the Bail Agents instituted or caused to be instituted an original action against GPS; (2) the Bail Agents acted maliciously in so doing; (3) the Bail Agents had no probable cause to *1211 institute the original action; and (4) the original action was terminated in GPS's favor. City of New Haven v. Reichhart, 748 N.E.2d 374, 378 (Ind.2001); Crosson v. Berry, 829 N.E.2d 184, 194 (Ind.Ct.App. 2005), trans. denied. Here, the Lake Superior Court issued the TRO in favor of the Bail Agents. On the merits, the Marion Superior Court issued a permanent injunction also in favor of the Bail Agents. Because the original action was not terminated in GPS's favor, GPS failed to prove malicious prosecution. The trial court did not err in denying GPS's counterclaim. Reversed in part and affirmed in part. SULLIVAN, J., and DARDEN, J., concur. NOTES [1] Oral argument was heard on this case on June 14, 2006 in Indianapolis. We commend counsel on the quality of their written and oral advocacy. [2] IC XX-XX-X-X, in pertinent part, provides: (a) A person may not act in the capacity of a bail agent or recovery agent or perform any of the functions, duties, or powers prescribed for bail agents or recovery agents under this article unless the person is qualified and licensed as provided in this article. However, none of the terms of this section shall prohibit any individual or individuals from: (1) pledging real or other property as security for a bail bond in judicial proceedings and where the individual does not receive, or is not promised, money or other things of value; or (2) executing any bail bond for an insurer, pursuant to a bail bond service agreement entered into between the insurer and any automobile club or association, financing institution, insurance company, or other organization or association, and on behalf of a person required to furnish bail in connection with any violation of law arising out of the use of a motor vehicle. (b) A license: (1) may not be issued except in compliance with this article; and (2) may only be issued to an individual. However, upon an affirmative showing to the commissioner in writing by an individual that the individual is an all lines fire and casualty insurance producer, a surety bail agent license shall be issued to the individual without further qualification or fee to represent an insurer the individual is licensed to represent. The individual shall be subject to and governed by laws and rules relating to bail agents when engaged in the activities of a bail agent. [3] Prior to trial, GPS filed a trial brief reiterating its understanding that the Bail Agents' claim alleges, "GPS is tortiously interfering with [the Bail Agents'] business in that GPS is acting as an unlicensed bail bondsman in violation of IC XX-XX-X-X." Appellant's Supp. App. at 161. [4] On July 21, 2005, GPS filed Emergency Motion to Stay Enforcement of the Permanent Injunction Pending Appeal. The trial court heard oral argument on the motion to stay and took the matter under advisement on August 15, 2005. There is no evidence in the record before us that this matter was ruled on by the trial court. | Low | [
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Q: Understanding Sieve of Eratosthenes in Python I've found an example code in python that gives out all prime numbers upto n but I simply don't get it, Why does it does what it does? I've read the wikipedia article about the Sieve of Eratosthenes but simply have no idea about how this works. pp = 2 ps = [pp] lim = raw_input("Generate prime numbers up to what number? : ") while pp < int(lim): pp += 1 for a in ps: if pp%a==0: break else: ps.append(pp) print set(ps) An explanation of how the loop works would be appreciated. EDIT - Figured out that the code's all wrong for it denotes 25 as a prime and through more intensive searching found that this ain't no sieve, can someone show an generator which utilizes the sieves in python and explain it A: Since no one has yet to show a true sieve or explain it, I will try. The basic method is to start counting at 2 and eliminate 2*2 and all higher multiples of 2 (ie 4, 6, 8...) since none of them can be prime. 3 survived the first round so it is prime and now we eliminate 3*3 and all higher multiples of 3 (ie 9, 12, 15...). 4 was eliminated, 5 survived etc. The squaring of each prime is an optimization that makes use of the fact that all smaller multiples of each new prime will have been eliminated in previous rounds. Only the prime numbers will be left as you count and eliminate non-primes using this process. Here is a very simple version, notice it does not use modulo division or roots: def primes(n): # Sieve of Eratosthenes prime, sieve = [], set() for q in xrange(2, n+1): if q not in sieve: prime.append(q) sieve.update(range(q*q, n+1, q)) return prime >>> primes(100) [2, 3, 5, 7, 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73 79, 83, 89, 97] The simple approach above is surprisingly fast but does not make use of the fact that primes can be only odd numbers. Here is a generator based version that is faster than any other I have found but hits a Python memory limit at n = 10**8 on my machine. def pgen(n): # Fastest Eratosthenes generator yield 2 sieve = set() for q in xrange(3, n+1, 2): if q not in sieve: yield q sieve.update(range(q*q, n+1, q+q)) >>> timeit('n in pgen(n)', setup="from __main__ import pgen; n=10**6", number=10) 5.987867565927445 Here is a slightly slower but much more memory efficient generator version: def pgen(maxnum): # Sieve of Eratosthenes generator yield 2 np_f = {} for q in xrange(3, maxnum+1, 2): f = np_f.pop(q, None) if f: while f != np_f.setdefault(q+f, f): q += f else: yield q np = q*q if np < maxnum: np_f[np] = q+q >>> timeit('n in pgen(n)', setup="from __main__ import pgen; n=10**6", number=10) 7.420101730225724 >>> list(pgen(10)) [2, 3, 5, 7, 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47] To test if a number is prime just do: >>> 539 in pgen(539) False >>> 541 in pgen(541) True Here are some hints as to how this more memory efficient version works. It uses a dict to store only the bare minimum of information, the next non-prime numbers (as keys) along with their factors (as values). As each non-prime is found in the dict, it is removed and the next non-prime key is added with the same factor value. A: That code is an attempt at using trial division to produce a sequence of primes. To correct it: pp = 2 ps = [pp] lim = raw_input("Generate prime numbers up to what number? : ") while pp < int(lim): pp += 1 for a in ps: if pp%a==0: break else: # unindent ps.append(pp) # this To make it much more efficient (in fact, optimal) trial division: pp = 2 ps = [pp] lim = raw_input("Generate prime numbers up to what number? : ") while pp < int(lim): pp += 1 for a in ps: if a*a > pp: # stop ps.append(pp) # early break if pp%a==0: break | Mid | [
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Flipside Announces New CS:GO Roster FlipSid3 Tactics is happy to announce its new CS:GO Roster. With this signing we are further advancing our interests in CS:GO and want to give these guys the opportunity to compete against the best. “So here we are, a lot of missed out talents from several other teams gathering up to make this top team,” Andreas ‘Schneider’ Lindberg told HLTV.org. “Me and the rest of the players in the team felt that we are not done yet, so we are here to show everyone what we are made of. “After a lot of back and forth with organizations I stumbled across F3 and since it’s not a familiar organisation for me and a lot of other CSGO players we were skeptical. We decided to hear them out anyway, as it turned out they were not what I expected. They had good sponsor agreements and good economic funding. The whole staff was really honest and kind with the will to get bigger and better.” Andreas “MODDII” Fridh Andreas “schneider” Lindberg Jacob “pyth” Mourujärvi Simon “twist” Eliasson Martin “cENTRYZ” Brandal “I want to thank FlipSid3 Tactics and Flexible Gaming for believing in our team. I look forward to representing them in the future. Be sure to show your support by going to www.flexiblegaming.com.” Read more at: http://www.hltv.org/news/12807-moddii-returns-in-flipside-tactics Barsic and Hydrox will remain apart of Flipside Tactics as they figure out their next plans for CS:GO. | Mid | [
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Amazonas Baroque Ensemble Amazonas Baroque Ensemble - ABE is a period instruments group based on Manaus, Amazonas, Brasil. Its members join themselves in Amazonas State University as Music and Musicology teachers and former students. Their aims included restoration of ancient Brazilian and Portuguese repertory, in a historically inspired approaching. Many of them joined Musicological research and practical performance projects sponsored by local and federal government agencies, such as Fundação de Amparo à Pesquisa do Amazonas, Petrobrás, Eletrobrás, among others. At this moment ABE performed in many Brazilian and European cities, including festivals (opera, sacred music) and stage productions. Musicians Mirian Abad - soprano Thelvana Freitas - contralto Fabiano Cardoso - tenor Roberto Paulo Silva - bass Gustavo Medina (Spalla), Tiago Soares, Juliana Lima Verde, Andreza Viana - baroque violin 1 Manoella Costa, Silvia Raquel Lima, Raúl Gustavo Falcón - baroque violin 2 Gabriel Lima, Elcione Santos - baroque viola Edoardo Sbaffi - baroque cello Diego Soares, Laércio Gomes - double bass Mário Trilha - harpsichord Vanessa Monteiro - organ Arley Raiol - baroque flute Márcio Páscoa, baroque flute and musical direction Repertoire Anonymous (Chiquitos, Bolivian Amazonia, 18th century) Trio Sonata Anonymous 18th century, Credo de São José do Tocantins Antonio Leal Moreira (1758–1819) - In te confida (Mardocheo recitative and aria from Ester (1786) Antonio Leal Moreira (1758–1819) Ah cangiar può d'affetto (Ismene aria in Gli eroi spartani, 1788) Antonio Leal Moreira (1758–1819) Amor di questa impresa (Alcibiade aria in Gli eroi spartani, 1788) Antonio Teixeira (1707–1774), Guerras do Alecrim e Mangerona (1737) opera jocoseria (in two acts) -Libretto by Antonio José da Silva (1705-1739) Carlos de Seixas (1704–1742). Symphony movement Corelli, Arcangelo (1653–1713). Concerto Grosso (Op. 6 nº 8) Fatto per la notte di Natale Corelli, Arcangelo (1656–1713). Concerto Grosso (Op. 6, nº10) Corelli, Purcell, Handel and J.S.Bach. Trio Sonates David Perez (1711–1778). Trio sonata in D minor David Perez (1711-1778): Semplicetta tortorella, (Barsene aria in Demetrio, 1766) Dietrich Buxtehude (1637–1707). Jesu Meines Lebens Leben Giovanni Battista Pergolesi (1710–1736). Stabat Mater Dolorosa (from Stabat mater)*+ Gluck, C. W. (1714–1787). Que farei sem o consorte. (Rozaura aria from A mulher amoroza) Haydn, Joseph (1732–1809). Die himmel erzahlen João de Deus do Castro Lobo (1794–1832). Seis Responsórios Fúnebre João de Sousa Carvalho (1745–1799). Con tanto riprove de tenere affeto (duet Giulietta e Armidoro in L'amore industrioso, 1769) João de Sousa Carvalho (1745–1799). Trio (Penelope, Ulisse and Icario in Penelope nella partenza da Sparta, 1782) João de Sousa Carvalho (1745–1799). Se l'interno affano mio (Alcione ária in Alcione, 1787) João de Sousa Carvalho. Padre, amico, non piangete (Isacco aria, from Isacco figura del redentor) José Maurício Nunes Garcia (1767–1830). Lauda Sion (1809) José Mauricio Nunes Garcia (1767–1830). Laudate Dominum José Mauricio Nunes Garcia (1767–1830). Laudate Pueri José Maurício Nunes Garcia (1767–1830). Creator alme siderum José Maurício Nunes Garcia (1767–1830). Te Christe solum novimus (1800)* José Palomino (1755–1810). Concert for violin (ca.1804, first movement) José Palomino (1755–1810). Harpsichord concerto Niccolo Jommelli (1714-1774): Ah, non son io che parlo (Fulvia aria in Ezio, 1772) Niccolò Jommelli (1714–1774). Nasce al bosco in rozza cuna, (Varo aria in Ezio, 1772) Nicolò Porpora (1686–1768). Lungi dal ben che s'ama (aria from Or che d'orrido verno)* Telemann, Georg Phillip (1681–1767). Ouverture e minor for flute and strings Videos 1. Antonio Leal Moreira (1858-1819). Ismene Aria "Ah cangiar non puo d'affetto" from opera "Gli Eroi Spartani" (Lisboa, 1787) - libreto by Gaetano Martinelli 2. José Palomino (1755-1810). Harpsichord concerto (1785) - 1st part 3. José Palomino (1755-1810). Harpsichord concerto (1785) - 2nd part 4. José Maurício Nunes Garcia (1767-1830). "Te Christe Solum Novimus" 5. Niccolò Jommelli (1714-1774). Aria "Nasce al bosco in rozza cuna" from opera "Ezio in Roma" (Bolonha, 1772) - libreto by Pietro Metastasio Gallery References Category:Baroque music groups Category:Brazilian musical groups | High | [
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/* * Part of Very Secure FTPd * Licence: GPL v2 * Author: Chris Evans * banner.c * * Calls exposed to handle the junk a typical FTP server has to do upon * entering a new directory (messages, etc), as well as general banner * writing support. */ #include "banner.h" #include "strlist.h" #include "str.h" #include "sysstr.h" #include "tunables.h" #include "ftpcmdio.h" #include "filestr.h" #include "session.h" #include "sysutil.h" /* Definitions */ #define VSFTP_MAX_VISIT_REMEMBER 100 #define VSFTP_MAX_MSGFILE_SIZE 4000 void vsf_banner_dir_changed(struct vsf_session* p_sess, int ftpcode) { struct mystr dir_str = INIT_MYSTR; /* Do nothing if .message support is off */ if (!tunable_dirmessage_enable) { return; } if (p_sess->p_visited_dir_list == 0) { struct mystr_list the_list = INIT_STRLIST; p_sess->p_visited_dir_list = vsf_sysutil_malloc(sizeof(struct mystr_list)); *p_sess->p_visited_dir_list = the_list; } str_getcwd(&dir_str); /* Do nothing if we already visited this directory */ if (!str_list_contains_str(p_sess->p_visited_dir_list, &dir_str)) { /* Just in case, cap the max. no of visited directories we'll remember */ if (str_list_get_length(p_sess->p_visited_dir_list) < VSFTP_MAX_VISIT_REMEMBER) { str_list_add(p_sess->p_visited_dir_list, &dir_str, 0); } /* If we have a .message file, squirt it out prepended by the ftpcode and * the continuation mark '-' */ { struct mystr msg_file_str = INIT_MYSTR; if (tunable_message_file) { (void) str_fileread(&msg_file_str, tunable_message_file, VSFTP_MAX_MSGFILE_SIZE); } vsf_banner_write(p_sess, &msg_file_str, ftpcode); str_free(&msg_file_str); } } str_free(&dir_str); } void vsf_banner_write(struct vsf_session* p_sess, struct mystr* p_str, int ftpcode) { struct mystr msg_line_str = INIT_MYSTR; unsigned int str_pos = 0; while (str_getline(p_str, &msg_line_str, &str_pos)) { vsf_cmdio_write_str_hyphen(p_sess, ftpcode, &msg_line_str); } str_free(&msg_line_str); } | Mid | [
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Weyler Hildebrand Weyler Hildebrand (4 January 1890 – 17 November 1944) was a Swedish actor, film director and writer. He appeared in over 35 films between 1924 and 1944. He also directed over 20 films between 1932 and 1944 and wrote scripts to 30 films between 1925 and 1944. Selected filmography Konstgjorda Svensson (1929) Söderkåkar (1932) Anderssonskans Kalle (1934) Munkbrogreven (1935) He, She and the Money (1936) Pensionat Paradiset (1937) Klart till drabbning (1937) Whalers (1939) Landstormens lilla Lotta (1939) Kyss henne! (1940) Fröken Vildkatt (1941) Löjtnantshjärtan (1942) Mitt folk är icke ditt (1944) Lilla helgonet (1944) References External links Category:1890 births Category:1944 deaths Category:Swedish male film actors Category:Swedish film directors Category:20th-century Swedish male actors | Mid | [
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Q: Add left and right arrows to scroll slider? Is it possible to add left and right arrows to a jQuery UI Slider in addition to the default scrollbar? The particular example I am using is this -> http://jqueryui.com/slider/#side-scroll As you can see it comes with the drag slider at the bottom of the content. However, I would like to add also a left and right arrow when mouse hover over, it will incrementally scroll the scrollbar left and right respectively. Any insights on this is appreciated! A: you were missing a small detail. The slider widget by itself does not control the position of the content. Its slide method takes care of that. When you updated the value of the slider programmatically, this method was not called, because no user interaction occurred. I refactored your code to make the slide no longer be an anon function. i call it from the hover handers: http://jsfiddle.net/j4WY6/13/ | High | [
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It is obvious that electricity disruptions are bad for business and the economy. Smaller businesses can counter the effects of load shedding for a few hours by using standby generators – at a cost – but large enterprises simply cannot operate without steady and adequate power. In fact, the Reserve Bank (Sarb) noted in its latest quarterly bulletin that the prime reason for the recovery in economic activity in the second quarter (Q2) of 2019 was the absence of severe electricity disruptions that hampered output in Q1 2019. “Real gross domestic product (GDP) advanced at an annualised rate of 3.1% in the second quarter, after contracting by a similar magnitude in the previous quarter,” say the bank’s economists in their review. The ongoing problems at Eskom have had such a huge effect on the economy that it urged the Reserve Bank to look into it closely, with an analysis showing that electricity disruptions during the three months to end March were the worst ever, barring Q2 2015. The Reserve Bank set about devising a quantitative measure to gauge the intensity of load shedding. The measure is based on the number of days of electricity disruptions in each quarter and the level of load shedding, with a higher stage of load shedding given a higher weighting to quantify the intensity of electricity disruptions. For example, three days of Stage 1 load shedding equal an intensity of 3, while three days of Stage 2 load shedding equal an intensity of 6. In Q1 2008, the calculation yielded a figure of 34 when SA had three days of Stage 1 load shedding, three days of Stage 2, seven days of Stage 3 and one day of stage 4. Incidence and intensity of electricity load shedding Number of days per quarter Intensity Quarter Stage 1 Stage 2 Stage 3 Stage 4 2008 Q1 3 3 7 1 34 2014 Q1 1 0 0 0 1 Q2 2 0 0 0 2 Q4 1 1 1 0 6 2015 Q1 6 5 0 0 16 Q2 38 15 1 0 71 Q3 12 11 0 0 34 2018 Q2 2 1 0 0 4 Q3 1 0 0 0 1 Q4 5 7 0 0 19 2019 Q1 1 7 2 5 41 * The table only reflects quarters in which load shedding occurred Source: Sarb Quarterly Bulletin, September 2019 Sarb rated load shedding in Q1 2019 at an intensity of 41, due to five days of Stage 4 load shedding. The result was that the economy shrunk by 3.1% in Q1 and recovered by 3.1% in Q2 after Eskom received a tongue-lashing from the president’s office and got its act together. The indicator shows that SA experienced the worst intensity of load shedding in Q2 of 2015, when 38 days of Stage 1 load shedding and 15 days of Stage 2 disruptions pushed the intensity to a count of 71. Economic growth in Q2 2015 was a negative 1.3% as measured by the real GDP, but it’s noteworthy that load shedding did not reach Stage 4 then. The analysis of the effect of load shedding in the Quarterly Bulletin clearly states that there are lots of factors that can impact economic activity, besides the shortage of electricity. Sarb points out that the economy suffered in certain quarters when there was no load shedding as well. It listed the various other factors that probably impacted economic growth, such as a number of long labour strikes, maintenance and safety stoppages in the mining sector and weak domestic and and global demand, as well as political and policy uncertainty, which affected business and consumer confidence. However, there seems to be an uncanny correlation between load shedding and a declining economy. The economy posted negative growth in all the quarters in which load shedding occurred – except for Q1 in 2008 when load shedding was actually quite severe. Paging through a few older economic reports shows that power failures were blamed for the lacklustre performance of the mining and manufacturing industries in every quarter characterised by electricity shortages. Sarb notes in its analysis of the effect of electricity shortages on the economy that the electricity-intensive mining and manufacturing sectors have often been affected the most, with agricultural and transport sectors also affected. All the SA mining companies blamed disruptions in electricity supply for their bad results in Q1 2019 and attributed the strong recovery in production levels in Q2 to a steady supply of electricity. Sarb noted that the real gross value added (GVA) by the primary and secondary sector sector increased notably in Q2 2019, following several quarters of contraction. “The marked turnaround in mining output was fairly broad-based and contributed the most to overall real GDP growth in the second quarter. “Following a sharp contraction in the first quarter of 2019, the real output of the secondary sector increased moderately in the second quarter as continuous electricity supply was restored, supported by Unit 3 of Eskom’s Medupi power station becoming operational. The real GVA by the manufacturing sector as well as the sector supplying electricity, gas and water reverted from sharp contractions to expansions,” says the bulletin. The intensity of load shedding and analysis notes that the impact of load shedding on real GDP was also tested by using a regression model, basically to see if the calculations are of statistical importance. The results show that as the intensity of load shedding increases, the decrease in SA’s real GDP growth is statistically significant by 0.06%. The real GVA of all the economic sub-sectors displayed a (negative) correlation to the intensity of load shedding. Load shedding had the biggest impact on growth in the agriculture, mining and manufacturing sectors, with statistically significant correlations. In short, the report proves what everybody already knows: businesses cannot operate without electricity and without operating businesses the economy cannot grow. Solving Eskom’s problems will solve a lot of other problems too. Hopefully the managers at Eskom will read the report too. | Mid | [
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Introduction {#s1} ============ CP (CP) is a movement disorder caused by an upper motor neuron (UMN) lesion in the developing brain [@pone.0040686-Rosenbaum1]. There are a range of prenatal, perinatal, and postnatal causes of CP and it is often associated with periventricular leukomalacia [@pone.0040686-Reddihough1]. CP covers a spectrum of severities and is the most common childhood movement disorder with a prevalence of 3.6 cases per 1000 in the US that has not decreased with medical advances [@pone.0040686-YearginAllsopp1]. While the UMN lesion that initiates CP is non-progressive, many secondary changes occur within the musculoskeletal system that are progressive and debilitating [@pone.0040686-KerrGraham1]. Among the hallmarks of CP is muscle spasticity, in which the muscle contracts in a velocity dependent resistance to stretch that results, in part, from reduced inhibition of the stretch reflex [@pone.0040686-Crenna1]. While the disability that results from spasticity is variable [@pone.0040686-Kim1], [@pone.0040686-Lin1] patients with spastic CP may also develop muscle contractures secondary to the lesion. Fixed muscle contractures represent a unique muscle adaptation in which muscles detrimentally limit the range of motion around a joint without being activated. These muscle contractures limit mobility, may be painful, and represent a major disability among those affected by CP or anyone with an UMN lesion [@pone.0040686-Bache1]. There are a variety of treatments designed to inhibit muscle activity in CP and prevent contracture formation. Physical therapy techniques, oral muscle relaxants, intrathecal placement of medication (baclofen), chemical neurectomies with phenol or alcohol, chemodenervation using neurotoxins, and surgical neurectomies have all been employed to decrease spasticity in children with CP [@pone.0040686-Koman1]. However, despite best clinical practices, contractures still develop and often require surgery to correct [@pone.0040686-Tilton1]. It should also be noted that all of these therapies reduce muscle strength in a condition in which strength is already compromised. Clearly current therapies are not ideal. There are no known genetic defects in patients with CP and their muscles, as it is a direct consequence of the UMN lesion [@pone.0040686-Hankins1]. Although skeletal muscle is known to be highly adaptive in response to neurological input, muscle contractures that develop are part of an adaptive mechanism that is not fully understood. Contracture does not develop in animal models of increased muscle use, which could be present from decreased motor neuron inhibition, or even decreased muscle use, which could result in decreased functionality [@pone.0040686-KerrGraham1]. Indeed UMN contractures are not readily reproducible in animal models, thus necessitating research on human subjects [@pone.0040686-Foran1]. The underlying transcriptional alterations have important consequences in the development of increased passive mechanical properties and pathologic contracture. Understanding the precise nature of transcripts differential regulation can delineate the mechanisms that accompany contracture, including but not limited to increased passive tension. Previous research demonstrated that muscle stiffness in contracture is independent of active muscle contraction [@pone.0040686-Lorentzen1], [@pone.0040686-Sinkjaer1]. Recent mechanical measurements of biopsies from pediatric hamstring muscles indicate that the increased muscle stiffness is due to alterations in extracellular matrix (ECM) rather than the stiffness of muscle fibers themselves [@pone.0040686-Smith1]. Multiple studies have also shown an increase in sarcomere length of muscle in contracture, demonstrating contractured muscle experiences high intrinsic strain [@pone.0040686-Lieber1] due to dramatic, but unknown structural alterations. These results suggests a decrease in the serial sarcomere number despite conflicting evidence as to whether muscle fascicle length decreases [@pone.0040686-Malaiya1]--[@pone.0040686-Shortland1]. Studies have shown that muscle and muscle fiber cross sectional area are reduced, which decreases force production, and even that the remaining muscle has decreased force generating capacity [@pone.0040686-Elder1]--[@pone.0040686-Stackhouse1]. These mechanical and architectural changes in muscle implicate a disruption of the biological components involved in myogenesis, force generation, force transmission, extracellular matrix maintenance, and perhaps additional pathways. Recent microarray data from the upper extremity supports the assertion that CP muscle is altered transcriptionally and that in addition to the pathways listed above, neuromuscular junction activity, excitation-contraction coupling, and energy metabolism are also deranged [@pone.0040686-Smith2]. As a purely adaptive muscle disorder, contractures are believed to have an altered transcriptional profile. The current study has taken advantage of a large surgical population of both children with CP and typically developing children to conduct a robust microarray analysis correlated to mechanical parameters. Our previous study was limited by a very small control subject population which was not age matched, (N = 2) [@pone.0040686-Smith2], and microarray studies in humans subjects generally require larger sample sizes to identify differences due to the higher variability present in human tissues compared to most inbred animal strains. Additionally the same biopsies reported here have been used to collect mechanical data that was recently published, allowing the comparison of our transcriptional data to functional parameters [@pone.0040686-Smith1]. We also took advantage of recent additions of muscle specific gene ontologies and muscle specific gene networks to probe the muscle and compare the pathology to microarrays from other published muscle conditions ([@pone.0040686-Feltrin1]; Smith et al. in press). A mechanistic understanding of muscle adaptation to contracture may lead to discovery of possible therapeutic targets that can delay or even reverse the debilitating effects of CP or other UMN lesions. Results {#s2} ======= For this transcriptional study, a cohort of 20 subjects were recruited. 10 patients with cerebral palsy were undergoing hamstring lengthening surgery, making biopsies of gracilis and semitendinosus accessible. The disease parameters of these subjects are listed in [Table 1](#pone-0040686-t001){ref-type="table"}. Gracilis and semitendinosus are synergistic muscles that both create a knee flexion moment, and thus their surgical release facilitates knee extension. Surgery is required because both muscles studied are in the state of pathologic muscle contracture. As control subjects, 10 typically developing pediatric patients who were approximately age matched were included, who were undergoing ACL reconstruction surgery with a hamstring autograft that made gracilis and semitendinosus muscles accessible. A separate microarray was used for each muscle biopsy, resulting in a total of 40 microarrays. 10.1371/journal.pone.0040686.t001 ###### Subject parameters. {#pone-0040686-t001-1} Cerebral Palsy Subjects Typically Developing Subjects ------------------------- ------------------------------- ---- --- ---- ----- ---- --- ---- 8 M 16 Q V 90 1 M 14 9 M 11 H II 110 2 F 16 30 M 4 D II 125 5 F 13 32 F 8 D II 95 6 F 15 34 M 15 D II 120 10 M 15 35 M 6 Q V 130 12 M 16 37 M 9 H II 95 18 F 17 38 M 9 D II 100 28 M 15 39 M 15 D II 120 31 M 14 40 M 10 D II 120 33 M 13 The parameters for each subject is specified. Region indicates the regions of the body effected: (Q) quadriplegic, (H) hemiplegic, and (D) Diplegic. Gross Motor Function Classification System (GMFCS) score is a functional parameter ranging from I (least severe) to V (most severe). Popliteal angle is a measure of knee extension and represents the maximum angle of the upper leg to lower leg when the hip is flexed at 90°. Significantly altered genes {#s2a} --------------------------- Among the 22,283 probesets on the microarray, 13,787 were considered present for further analysis. Of those 1,398 genes were identified as significantly different in CP (2,836 for Microarray Suite Version 5.0 (MAS5), 3,954 for Robust Multiarray Analysis (RMA), and 4,009 for GC-RMA; [Table S1](#pone.0040686.s001){ref-type="supplementary-material"}). Of these genes, 533 had expression increased in CP while 865 genes had expression decreased. The 2×2 ANOVA yielded only 3 genes (*MAB21L1*, *SIM1*, and *EN1*) with unknown roles in muscle as significantly different between muscles, demonstrating that both muscles have similar expression profiles. There were also no genes that produced a significant interaction between muscle type and disease state, indicating that both muscles undergo similar changes in CP. Condition tree clustering {#s2b} ------------------------- The condition tree was conducted based on all present genes on the microarray and resulted in a clustering of CP subject biopsies distinct from typically developing subject biopsies, with the exception of one mild CP subject ([Figure 1](#pone-0040686-g001){ref-type="fig"}). The condition tree also shows that biopsies from the two muscles of the same patient cluster together. This result indicates that the two hamstring muscles, gracilis and semitendinosus, have less variability within a subject than the variability between subjects with the same condition. With a large sample size there was an expectation that biopsies from patients with similar clinical severity scores would cluster together. This trend was not observed in the data. {#pone-0040686-g001} Quantitative Real Time PCR {#s2c} -------------------------- As a quality control measure, qRT-PCR was performed on a subset of relevant genes, 2 significantly up-regulated, 2 not significantly altered, 2 significantly down regulated, and 2 genes of interest not present on the microarray. We chose these representative genes since they are commonly studied in muscle physiology. Comparison of qRT-PCR to microarray datasets revealed a significant correlation (p\<0.05) in all 6 genes examined ([Figure 2A--F](#pone-0040686-g002){ref-type="fig"}). qRT-PCR was also conducted on 2 genes of interest involved in the muscle atrophic process that do not have corresponding probesets on the microarray that had expression ratios of (0.48) *TRIM63* and (0.79) *FBXO32*. *TRIM63* expression had a significant main effect of CP (p\<0.01) ([Figure 2G--H](#pone-0040686-g002){ref-type="fig"}). {#pone-0040686-g002} Categorical analysis {#s2d} -------------------- Secondary analysis was performed using predefined gene sets for Gene Ontology allowing the categorization of significantly altered genes in CP. There were 87 gene ontologies over-represented from the list of significantly genes up-regulated in CP ([Table S2](#pone.0040686.s002){ref-type="supplementary-material"}, [Table 2](#pone-0040686-t002){ref-type="table"}). Of note are a large portion of extracellular matrix ontologies as well as those for calcium ion binding and cytoskeleton ontologies. Categories discussed are presented in [Table 2](#pone-0040686-t002){ref-type="table"}. Among genes that were down-regulated in CP, 85 ontologies were significantly over-represented ([Table S2](#pone.0040686.s002){ref-type="supplementary-material"}, [Table 2](#pone-0040686-t002){ref-type="table"}). These ontologies primarily fell into the categories of metabolic processes and ubiquitin related pathways and also interestingly included skeletal muscle contraction. 10.1371/journal.pone.0040686.t002 ###### Highlighted gene ontologies significantly over-represented in genes significantly altered in CP. {#pone-0040686-t002-2} Gene Ontology GO\# Category Observed Expected p-value ----------------------------------------------- ------------------- ---------- ---------- ---------- ---------- *Biological Process* *Increased in CP* extracellular matrix organization 0030198 86 20 3.57 1.55e-07 collagen metabolic process 0032963 38 8 1.58 0.0044 actin cytoskeleton organization 0030036 213 22 8.85 0.0044 *Molecular Function* calcium ion binding 0005509 680 64 28.22 3.91e-08 collagen binding 0005518 32 8 1.33 0.0005 growth factor binding 0019838 97 14 4.02 0.0006 *Cellular Component* collagen 0005581 31 12 1.31 4.60e-08 cytoskeleton 0005856 1008 75 42.73 1.58e-05 basal lamina 0005605 15 6 0.64 0.0003 *Biological Process* *Decreased in CP* ubiquitin-dependent protein catabolic process 0006511 190 33 12.18 9.76e-06 glucose metabolic process 0006006 116 19 7.43 0.0041 skeletal muscle contraction 0003009 15 6 0.96 0.0073 *Molecular Function* ligase activity 0016874 281 43 18.12 6.48e-06 ubiquitin-protein ligase activity 0004842 107 23 6.90 1.39e-05 zinc ion binding 0008270 1447 128 93.32 0.0028 *Cellular Component* proteasome complex 0000502 54 11 3.35 0.0047 cis-Golgi network 0005801 12 5 0.74 0.0056 nuclear lumen 0031981 1203 101 74.65 0.0081 (Category) is the number of genes on the reference list or in this case on the microarray that fall under the ontology. (Observed) is the number of genes on either the significantly up or down-regulated in CP list. (Expected) is the number of genes expected to be in the significantly altered list based on the relative sizes of lists. Network analysis {#s2e} ---------------- We recently created networks of genes related to muscle function to enable detailed investigation of muscle-specific gene expression. A heatmap, using expression ratios, is created with genes listed in their 9 respective functions with genes in those determined as significantly different in CP according to previous analysis ([Figure 3](#pone-0040686-g003){ref-type="fig"}). Some genes appear in multiple functions and some genes are listed within gene complexes ([Table S3](#pone.0040686.s003){ref-type="supplementary-material"}). {ref-type="supplementary-material"} in which case geometric means of multiple genes determine expression ratio. Gene symbols found to be significantly different in CP are colored based on direction of regulation. Gene families are colored if any individual gene in the family is significantly altered in CP. Genes with N/A were either not present on the chip or did not have expression to qualify as present in analysis.](pone.0040686.g003){#pone-0040686-g003} Most of the networks had a selection of genes that were both up and down regulated in CP. These include: the neuromuscular junction, excitation contraction coupling, cytoskeleton elements, and muscle signaling. Other networks had transcripts that were altered in a more uniform manner. Most strikingly, the extracellular matrix had 14 out of 20 transcripts with increased transcription. On the other hand muscle metabolic factors had 11 out of 37 transcripts down regulated and only one up regulated. Unfortunately only 7 of the inflammatory markers were present and available for analysis on the microarray. Some proteins function with a different isoform in fast or slow muscle that is transcribed from a separate gene. There was no significant change in expression among the slow isoforms, however 5 out of the 11 transcripts for fast isoforms were significantly down regulated. This indicates a relative shift to slow fibers that corresponds to the myosin heavy chain protein content of the muscles [@pone.0040686-Smith1]. mRNA correlations to passive stiffness {#s2f} -------------------------------------- A unique aspect of this study was the corresponding mechanical measurements from the same muscle biopsies in 17 of the 20 subjects. Individual fibers were isolated and mechanically tested to determine stiffness [@pone.0040686-Smith1]. Fiber bundles, consisting of a group of approximately 20 fibers and their constituent extracellular matrix, were tested in the same way. Mechanical stiffness for fibers and fiber bundles was correlated with each of the significant genes in CP. 27 genes had a significant (p\<0.05) positive correlation with fiber stiffness and 50 genes had a significant negative correlation ([Table 3A, 3B](#pone-0040686-t003){ref-type="table"}; [Figure 4](#pone-0040686-g004){ref-type="fig"}; [Table S4](#pone.0040686.s004){ref-type="supplementary-material"}). These gene lists were used for categorical gene ontology analysis with the total significantly altered in CP gene list as the reference set to determine which categories were over-represented ([Table S5](#pone.0040686.s005){ref-type="supplementary-material"}). From the genes positively correlated with fiber stiffness there were no categories significantly up-regulated. However among the negatively correlated genes, 29 ontologies were significantly (p\<0.05) over-represented, with most ontologies related to ubiquitin ligase activity. This suggests that when genes in the ubiquitin protease system are most active muscle fibers lose mechanical stiffness. When fiber bundle mechanics are considered, 141 genes had a positive and 95 genes a negative significant correlations with stiffness values ([Table 3C, 3D](#pone-0040686-t003){ref-type="table"}). There were 36 ontologies significantly over-represented with a positive correlation to bundle stiffness. These consisted almost exclusively of ontologies related to the extracellular matrix, indicating the matrix plays an important role in the stiffness of fiber bundles. Only 2 ontologies were significantly over-represented among genes negatively correlated with bundle stiffness. Those related to mitochondrial structure, suggesting a relationship between muscle stiffness and energy production. {#pone-0040686-g004} 10.1371/journal.pone.0040686.t003 ###### Gene ontology of transcripts correlated with stiffness. {#pone-0040686-t003-3} Gene Ontology Observed Expected p-value ----------------------------------------------- ----------------------------------------- ---------- ---------- *Biological Process (selection from 21)* *Positive Bundle Stiffness Correlation* extracellular matrix organization 13 2.25 5.54E-06 collagen fibril organization 8 1.07 7.53E-05 collagen biosynthetic process 5 0.54 1.40E-03 *Molecular Function (selection from 5)* extracellular matrix structural constituent 12 2.25 2.58E-05 growth factor binding 8 2.25 2.56E-02 proteoglycan binding 3 0.32 2.60E-02 *Cellular Component (selection from 10)* proteinaceous extracellular matrix 22 5.46 1.65E-07 fibrillar collagen 6 0.75 2.00E-04 basement membrane 8 1.93 4.70E-03 *Cellular Component* *Negative Bundle Stiffness Correlation* mitochondrial intermembrane space 4 0.36 6.70E-03 organelle envelope lumen 4 0.43 1.00E-02 *Biological Process (selection from 20)* *Negative Fiber Stiffness Correlation* ubiquitin-dependent protein catabolic process 7 1.34 2.54E-02 cellular protein catabolic process 9 2.89 3.18E-02 proteasomal protein catabolic process 4 0.60 3.81E-02 *Cellular Component (selection from 9)* nucleus 28 16.61 1.44E-02 proteasome complex 4 0.48 2.16E-02 membrane-bounded organelle 35 25.73 2.76E-02 Gene ontologies that were over-represented among genes that had a significant correlation (p\<0.05) with either fiber or fiber bundle passive stiffness measurements. (Category) is the number of genes on the reference list or in this case significantly altered in CP. (Observed) is the number of genes significantly correlated with mechanical stiffness that fall into the category. (Expected) is the number of genes expected to be in the significantly altered list based on the relative sizes of lists. Discussion {#s3} ========== The objective of this study was to describe the transcriptional adaptations that occur in skeletal muscle of patients with CP and incorporate functional data to determine the cellular mechanisms that drive the muscle pathology secondary to the upper motor neuron lesion. This research has seen little prior work, as there is no commonly accepted animal model necessitating the challenges of direct human research [@pone.0040686-Foran1]. Without any genetic defect in the muscle, it is clear that the pathology has a large transcriptional component across many genes ([Figure 1](#pone-0040686-g001){ref-type="fig"}). The large number of altered transcripts fall into a variety of gene ontologies and biological pathways, as well as important functional networks within skeletal muscle. Some of these vital muscle systems such as the extracellular matrix have a correlation between transcript levels and tissue stiffness. The condition tree clustering demonstrates the difference between the transcriptional profile of muscles from patients with CP or typically developing ([Figure 1](#pone-0040686-g001){ref-type="fig"}). This separation was nearly 100% as only a single CP patient clustered more closely with the controls. It should be noted that this was one of the more mild cases of CP and the highest popliteal angle of the entire group (120°, least amount of contracture). The clustering algorithm did not, however, group the CP muscle by the clinical severity scores, age, or even muscle. The patients themselves had both biopsies clustered together consistently indicated that the variation from subject to subject is higher than that between muscles of the same subject. This finding was described in a previous study using multiple muscles from a single subject [@pone.0040686-Smith2]. Categorical analysis {#s3a} -------------------- To determine the various functions that are altered in CP we first established a list of genes with altered transcription. We sought to narrow our results by using a more stringent analysis that uses the congruence of three summarization algorithms as well as a restrictive false discovery rate of 1%. This still produced a large gene list due to the large sample size, but we chose not to implement a fold change cutoff as this assumes an arbitrary level of change is required to be functionally important [@pone.0040686-Klebanov1]. We used categorical analysis to determine altered functional gene categories in CP. Among the up-regulated transcripts there were a total of 87 gene ontologies over-represented, but they generally fell into only a few categories. The increase in extracellular matrix transcripts has been well documented in muscle from CP [@pone.0040686-Smith2], [@pone.0040686-Booth1], [@pone.0040686-Lieber2]. However the structure of the extracellular matrix increases is not well known. This study shows how extensive the increase in extracellular matrix is with categories ranging from fibrillar collagen, basal lamina and even collagen metabolic process. Increased structural categories continue through the cell with ontologies including integrin binding, cytoskeletal binding protein, and cytoskeleton. This could have an effect on individual fiber stiffness, but the stiffness of fibers in CP is inconsistent [@pone.0040686-Smith1], [@pone.0040686-Friden1]. There were ontologies important in muscle function that had over-representation as well with calcium ion binding. A disruption of calcium handling had been suggested previously, where *PARV* was drastically altered in CP muscle [@pone.0040686-Smith2], however here *PARV* was unchanged. The impact of growth factor binding is also crucial in skeletal muscle, with many of the transcripts being IGF binding proteins known to be important in skeletal muscle. Contrastingly, there were 62 ontologies that were over-represented in down-regulated genes. The most extensive of these were related to metabolic processes and ubiquitin ligases. Skeletal muscle is a very metabolically active tissue and these results suggest that, despite spasticity, the muscle has less metabolic machinery. This decrease was also seen in the previous transcriptional study in CP, however this was accompanied by a shift to faster fiber types, which was not the case here [@pone.0040686-Smith2]. The ubiquitin ligase role is surprising here as it is generally accepted that muscle in CP has decreased mass [@pone.0040686-Elder1], [@pone.0040686-Barrett1]. This result suggests that decreased muscle mass is not due to active muscle degradation. The obvious importance of the skeletal muscle contraction ontology is also represented. Together these results imply that muscle protein turnover is decreased in CP. Network analysis {#s3b} ---------------- Categorical analysis provides an avenue to analyze vast gene lists into manageable pieces. However, we also sought to investigate more deeply into networks of genes critical to muscle function using a recently established gene networks (Smith et al., in press). As CP is neurological in origin, the neuromuscular junction could be altered and has indeed been shown to have a disorganized nature in CP [@pone.0040686-Theroux1]. The results did not show overwhelming changes in the neuromuscular junction, the acetylcholine receptor (*CHRN*) was down-regulated. *CHRN* is dramatically up-regulated when muscle is denervated [@pone.0040686-Tsay1], which our results clearly show is not the case in CP muscle. Most of the changes were associated with extracellular matrix proteins localized to the neuromuscular junction. However, unlike the majority of extracellular matrix transcripts *COL4* was down-regulated as was *UTRN* an important link to the extracellular matrix of the neuromuscular junction. It is unclear how these adaptations change the function of the neuromuscular junction, but it does support evidence for disorganization [@pone.0040686-Theroux1]. Excitation-contraction coupling has been largely unexplored in CP, but has been shown to be altered and is also the target of therapeutic intervention [@pone.0040686-Smith2], [@pone.0040686-Verrotti1]. The transcripts altered in this study were unique however, and primarily down-regulated in CP. Genes such as *ASPH* and *DHPR* which have a role in activating the -ryanodine receptor are down-regulated. As are mechanisms for pumping calcium back in to the sarcoplasmic reticulum with *ATP2A* and its regulator *SLN*. Further, a decrease in transcripts of calcium binding proteins of *CALM1* and downstream *CAMK2* suggest that there is less calcium cycling in CP muscle. The only up-regulated transcript was *RYR3*, which is a ryanodine receptor expressed in immature muscle, and reinforces the theme that there are a number of immature transcripts in these muscles. That theme is also observed in the contractile transcripts of skeletal muscle. The only up-regulated genes are immature isoforms embryonic myosin heavy chain (*MYH3*) and embryonic myosin light chain (*MYL4*). Many of the contractile elements have well defined isoforms that have genes expressed in either fast or slow muscle [@pone.0040686-Schiaffino1]. Many of the down-regulated transcripts are isoforms of the fast isoforms, which will be discussed with respect to fiber type. Interestingly, both thin filament Z-disc capping protein *CAPZ* and titin filament Z-disc capping protein *TCAP* are down-regulated in CP. This could lead to Z-disc disorganization and *TCAP* itself is associated with destabilization in limb girdle muscular dystrophy 2G [@pone.0040686-Olive1]. The force generated in the sarcomere is transmitted through the cytoskeleton to the cell periphery, but the effects in CP have been largely unexplored. Our results are somewhat difficult to interpret with many genes both up and down-regulated. Of those associated with the dystroglycan complex, sarcoglycans (*SGC*) and snytrophins (*SNT*) as well as *UTRN* are down-regulated. This is while many crosslinking transcripts of the cytoskeleton are up-regulated (ankyrin (*ANK*), sprectrin (*SPT*), filamin (*FLNC*)) along with an important connector to the Z-disc (*MYOZ2*). What role these increased cytoskeletal filament connections may play is unknown, but they did not lead to increased fiber stiffness [@pone.0040686-Smith1]. The cytoskeletal connection to the nucleus is interesting as *EMD* and *LMNA*, which both lead to Dreifuss-Emery muscular dystrophy when absent are not co-regulated with *EMD* decreased and *LMNA* increased [@pone.0040686-Brown1], [@pone.0040686-Maraldi1]. One aspect that is consistent is that *VIM* is up-regulated, which is the primary immature muscle intermediate filament that is replaced with desmin (*DES*) during development. The force generated in the cell is ultimately transferred to the extracellular matrix, which is significantly altered in various analyses here as well as numerous other studies of CP [@pone.0040686-Smith2], [@pone.0040686-Booth1], [@pone.0040686-Lieber2]. This alteration is nearly uniformly up-regulated, with the exception of the *COL4* isoforms in the neuromuscular junction previously described. It is important to note that the increase includes many categories, fibrillar collagens, laminar collagens, proteoglycans, matrix metalloproteinases, matrix metalloproteinase inhibitors, and extracellular matrix growth factors. This uniform increase does not permit speculation on how the extracellular matrix may be prolific, yet disorganized as speculated in CP muscle [@pone.0040686-Lieber2]. With all the increase in extracellular matrix components it would be expected that *TGFB1*, an important fibrosis signal in muscle, would be increased [@pone.0040686-Zhu1]. Although it did have higher expression in CP it was not significant and shows that ECM alterations can occur independent of a large *TGFB1* autocrine increase and may be more closely tied to TGFβ activation locally. Another network with broad regulation was metabolic transcripts, which were down-regulated in CP. This was observed in gene ontologies, pathways, as well as previous studies [@pone.0040686-Smith2]. The fold change values on many of the transcripts were relatively low. It should be noted that this change occurred despite a decrease in fast muscle isoforms that have fewer mitochondria present. The only increased transcript was *LPL* associated with fat metabolism that is more prevalent in slow muscle. Despite an increase in non-voluntary muscle contractions associated with spasticity [@pone.0040686-Ivanhoe1], the muscle is not producing more metabolic machinery. This could be a result of the muscle being in the state of contracture and thus have decreased functionality which contributes to disuse [@pone.0040686-Pohl1]. While the state of damage within a static muscle contracture is relatively unknown, it is known that inflammation is present within damaged muscle [@pone.0040686-Smith3]. Wound healing and inflammatory pathways were up-regulated in categorical analysis, but unfortunately few inflammatory transcripts were able to be analyzed in this study. Of those that were altered were p38 (*MAPK14*) and a heat-shock transcription factor (*HSF2*). The role of muscle damage in pathologic CP muscle is not discernable from these data. The critical aspect of muscle growth is a complicated system of many genes and viewed the lack of muscle growth is considered the primary cause of contracture [@pone.0040686-Tardieu1]--[@pone.0040686-Clavet1]. However there are many transcripts altered to induce muscle growth including down-regulation of myostatin (*MSTN*) a critical muscle growth inhibitor, its receptor (*ACVR2B*), and up-regulation of natural inhibitor (*FST*). *FGF2* also plays a role in stimulating muscle growth and differentiation [@pone.0040686-Husmann1]. The muscle atrogene program is also decreased with a drop in MURF1 (*TRIM63*) and its transcription factor *FOXO* [@pone.0040686-Sandri1]. This *MSTN* signal is in contrast to the previous study in CP muscle and is a candidate for being responsible for blocking the growth signal in these muscles. The question of what limits muscle growth in CP is not apparent from these results. The role of fiber type has been discussed in regard to multiple networks. The results here show clearly that while slow isoform levels remain unchanged many fast isoforms have significant decreases in transcription. The role of fiber type in upper motor neuron lesions has been inconsistent [@pone.0040686-Ponten1], [@pone.0040686-Scelsi1], but these results imply a proportional shift to slower muscle. This can be important functionally, but is also very important in terms of a transcriptional study. Many of the changes observed could be the result in transcriptional changes from fast to slow muscle, such as the decrease in glycolytic transcripts. However it is clear that the pathology of muscle in CP is not purely a secondary effect of a shift in fiber type. mRNA correlations to passive stiffness {#s3c} -------------------------------------- Having mechanical stiffness measurements for both the muscle fibers and the muscle fiber bundles with their extracellular matrix was a unique aspect of this study. There is literature to support the role of the giant protein titin (*TTN*) in being the major contributor to passive tension of individual fibers [@pone.0040686-Neagoe1]. When considering the muscle bundle much of the passive stiffness is believed to arise from collagen, especially at larger sarcomere lengths [@pone.0040686-Ducomps1]. Certainly many transcriptional factors could contribute to the production of these important proteins or other proteins that have a direct impact on the passive mechanical stiffness. Indeed 77 genes were correlated with fiber stiffness and 236 with bundles stiffness. To determine the fundamental nature of these transcripts we again used categorical analysis. It should be noted that since only significantly altered genes were considered that was the gene set used as a reference set, meaning correlated genes had to be enriched beyond the significant gene list be over-represented. For individual fiber there were actually no ontologies that had a significant positive correlation with stiffness. However many ontologies were associated with decreasing fiber stiffness, the vast majority of which were related to ubiquitin ligases. This supports the idea that as ubiquitin ligases become active and begin degrading the muscle filaments, particularly titin, causing a loss of passive stiffness [@pone.0040686-Mrosek1]. When bundle stiffness is considered there are many more ontologies over-represented ([Table 3](#pone-0040686-t003){ref-type="table"}). Fittingly the most prevalent ontologies are related to extracellular matrix, however there are many more transcripts than fibrillar collagens thought to provide the passive stiffness to bundles [@pone.0040686-Kovanen1]. For example one of the most highly correlated genes was *COL21A1*, which is a fibril associated collagen that is found with collagen I and serves to maintain the integrity of the extracellular matrix. This illustrates the complex nature and the many factors that lead to tissue stiffness and that could be contributing to fibrosis in CP. Additional ontologies were over-represented including immune system process. This is an indicator of damage in bundles that are stiffer and supports the claim that muscle tissue damage leads to fibrosis in CP. Conversely there were only two ontologies negatively correlated to bundle stiffness, related to mitochondria. It is difficult to speculate in too much detail from this small data set, but this suggests that more metabolically active tissue, with increased mitochondria, is more compliant. Perhaps this is simply a secondary effect of decreased area fraction in myofilaments occupied by mitochondria. Comparison to upper extremity {#s3d} ----------------------------- This study is similar to one conducted in the upper extremity of muscle from patients with CP [@pone.0040686-Smith2]. There are some important differences in that the current study has a much larger sample size, especially in terms of controls (10 in this study compared to 2 in the previous). Additionally the typically developing control subjects in the current study were injured months prior to surgery and thus did not have recent acute trauma as a confounding factor. Regardless, we expected to see many similar results between the two studies. However this was not the case with only 19 genes significantly altered in the same direction between the two studies ([Table S6](#pone.0040686.s006){ref-type="supplementary-material"}). A possible explanation for this is the change in fiber type, which was opposite in the studies, was driving many of the transcriptional changes. Fast fibers have a more extensive calcium cycling apparatus thus offering an explanation other than a disruption of typical calcium handling in CP [@pone.0040686-Smith2]. It is still important to look at the similarities between the studies. The obvious similarity is an increase in extracellular matrix in both upper and lower extremity contracture, shown with ontology analysis of genes altered in both studies. This is important in placing fibrosis as a consistent property of muscle contractures in CP. It should also be noted that both studies had an increase in genes related to immature muscle, another possible hallmark of muscle in a contractured state. Implications {#s3e} ------------ Despite CP being a spectrum disorder that is non-homogenous in our subjects there are many common attributes [@pone.0040686-Dzienkowski1]. This study is valuable in highlighting many functions of skeletal muscle that are disrupted in contractures caused by CP and detailing the gene transcripts involved. It does not directly answer which programs are inducing contracture or contributing to the lack of muscle growth. However the most dramatic changes were seen in the drastic increases in extracellular matrix, which could blunt the intracellular growth signals observed. Indeed it has been shown that the extracellular stiffness can modulate skeletal muscle satellite cells proliferation and differentiation [@pone.0040686-Boonen1], [@pone.0040686-Gilbert1]. Further matrix digestion has been shown to have a positive effect on muscle growth through satellite cell activation [@pone.0040686-Chen1]. Combining previous knowledge with this study establishes the extracellular matrix as a novel treatment target for CP. Summary {#s3f} ------- Skeletal muscle undergoes significant transcriptional alterations secondary to upper motor neuron lesion in CP in which we have identified many transcripts. These genes fall into several ontologies with increases extracellular matrix components along with decreases in metabolic, and muscle degradation systems. Muscle specific network analysis recapitulates the increase in extracellular matrix components along with an increase in muscle molecules signaling for muscle growth. These are overlaid on a decrease in fast muscle isoform transcripts and an increase in immature muscle isoforms. The increases in extracellular matrix were seen to be associated with an increase in the passive stiffness of the muscle tissue and one of the few components consistent with previous transcriptional studies into CP muscle. This work will assist future research into CP muscle and aid the design of novel therapies for these patients. Materials and Methods {#s4} ===================== Muscle Biopsy Collection {#s4a} ------------------------ Ethical approval for this study conformed to the standards of the Declaration of Helsinki and was approved by the Institutional Review Board at the University of California, San Diego Human Research Protection Program. Age appropriate assent from the patient as well as consent of the parent or guardian was obtained. After obtaining consent, subjects with spastic CP (n = 10) were recruited into the study based on undergoing distal hamstring lengthening surgery involving both the gracilis and semitendinosus muscles such that 2 muscle biopsies could be acquired per subject. "Control" subjects (n = 10) were pediatric patients undergoing ACL (anterior cruciate ligament) reconstructive surgery of the knee with hamstring autograft using gracilis and semitendinosus tendons that were excised along with a distal portion of the muscle that was obtained prior to trimming of the tendon. Control patients did not have any neuromuscular disorders and were ambulatory prior to surgery suggesting no damage to the hamstring muscle from the injury. Their index injury occurred at least 6 weeks before their surgery. However, because they were having surgery to repair a torn ligament we acknowledge that these are not truly normal muscles. However, given the ethical constraints associated with taking muscle biopsies, we believe that this is the best possible comparison group that can be envisioned. Patients with CP had developed a fixed contracture requiring surgery and were classified based on the clinical measures of Gross Motor Function Classification System [@pone.0040686-Palisano1], popliteal angle, and limb(s) affected. Patients had not received any neurotoxin injection or previous surgical lengthening within the 2 years prior to surgery. All muscle biopsies (n = 40) were snap frozen in liquid nitrogen (−159°C) within ∼1 minute of excision and stored at −80°C. RNA extraction {#s4b} -------------- RNA was extracted using a combination of standard Trizol (Invitrogen, Carlsbad, CA) and RNeasy (Qiagen, Valencia, CA) protocols. Briefly, approximately 30 mg of frozen muscle tissue was homogenized using approximately 50 mg of RNase free 0.5 mm zirconium oxide beads (Next Advance, Averill Park, NY) in 0.5 ml Trizol using a Bullet Blender (Next Advance, Averill Park, NY). 0.1 ml of chloroform was added to the solution, then vigorously vortexed for 15 seconds, then centrifuged at 4°C for 15 min. The upper aqueous layer was removed and mixed with an equal volume of 70% ethanol before being added to the RNeasy spin column. The column was washed and then incubated with RNAse-free DNAse (Qiagen) for 15 minutes and then washed again three times prior being eluted as described in the manufacturer\'s protocol. RNA concentration was determined by absorbance at 260 nm, and the 260 nm-to-280 nm absorbance ratios were calculated to define RNA purity. Microarray processing {#s4c} --------------------- Affymetrix microarrays (HG-U133A 2.0; Affymetrix, Santa Clara, CA) were used for each individual muscle biopsy (n = 40 chips). RNA processing including cDNA synthesis, cDNA labeling, microarray hybridization, microarray scanning, and stringent quality control measures were performed by the Gene Chip Core at the Department of Veterans Affairs San Diego Health Care System, (San Diego, CA). The raw data are available (.cel files) at the Gene Expression Omnibus (GEO) under accession number GSE31243. Quantitative real time PCR {#s4d} -------------------------- Quantitative real-time PCR (qRT-PCR) was conducted to validate the expression levels of select genes (*DMD*, *COL1A2*, *MSTN*, *IGF1*, *COL4A2*, and *MYH1*) and also to provide expression values for two transcripts of interest not present on the microarray (*FBXO32* and *TRIM63*). The same RNA extracted for microarray analysis was used for qRT-PCR. Isolated RNA was diluted 1∶5 with DNase/RNase free water (Invitrogen) and 1 µl of each sample was reverse transcribed using standard protocols (Superscript III; Invitrogen). cDNA was amplified with the Cepheid SmartCycle (Sunnyvale, CA) with primers designed specific to each gene of interest ([Table S7](#pone.0040686.s007){ref-type="supplementary-material"}) using nBLAST and Oligo (version 6.6; Molecular Biology Insights, Cascade, CO). Each sample was run in triplicate along a standard curve. The PCR reaction tube contained 1×PCR buffer, 2 mM MgCl~2~ (Invitrogen), 0.2 mM sense and antisense primers, 0.2 mM dNTP, 0.2×SYBR green, and 1 U of platinum Taq polymerase (Invitrogen). Amplification conditions included an initial hold at 95°C for 2 minutes with 40 cycles of denaturing at 95°C for 15 seconds, followed by annealing and extension phases adjusted for each transcript. Success of each the reaction was determined based on observation of a single reaction product on an agarose gel and a single peak on the DNA melting temperature curve determined after the 40 cycles. The results of qRT-PCR were expressed using a standard curve method with the "cycles to threshold" values represented the number of PCR cycles at which the SYBR green signal was increased above threshold. The triplicate measures were normalized to the housekeeping gene *GAPDH* and then averaged. qRT-PCR data were normalized to the median value of the gene to facilitate comparisons to microarray data. Microarray analysis {#s4e} ------------------- Data files were processed with GeneSpring Software (version 11.5.1; Agilent Software, Santa Clara, CA) for determination of significantly altered genes and clustering analysis. Present genes were determined from the MAS5 (Affymetrix) probe set algorithm based on a 12.5% (5/40) present call. Each sample was clustered based on MAS5 for present genes based on Pearson Correlation similarity score and average linkage clustering algorithm. To provide a conservative choice of significantly altered genes in CP, three independent probe set algorithms were used: MAS5, RMA, and GCRMA. Requiring concordance among different probe set algorithms has recently been used as an approach to reduce false positives in data sets specific to any individual algorithm. Each probe set was normalized to the median of the microarray and then to the median of that probe set on all chips. The probe set data were then condensed into gene level data in GeneSpring by calculating the median value of all probe sets belonging to a single gene. Gene values were analyzed by 2×2 Welch ANOVA based on pathology (CP vs. Control) and muscle (gracilis vs. semitendinosus) with a Benjamini and Hochberg False Discovery Rate for multiple testing correction setting the required statistical significance to (p\<0.01). For each algorithm significant genes were separated into lists for increased or decreased expression with CP, so that concordances of significant genes were all in the same direction.Accordingly, 1% of the genes deemed significant for an individual probeset algorithm are suspected to be false positives and genes that passed in all three algorithms were designated as significantly different for further analysis. Microarray categorical analysis {#s4f} ------------------------------- After the significantly altered genes were defined, categorical analysis was used to provide information on over represented subsets of genes. Enrichment analysis was performed on up-regulated and down-regulated genes independently with WebGausalt (<http://bioinfo.vanderbilt.edu/webgestalt/>) on Gene Ontology, KEGG Pathways, transcription factor targets, and microRNA targets [@pone.0040686-Zhang1], [@pone.0040686-Zhang2]. The hypergeometric statistical method was used with a Benjiman-Hochberg multiple testing correction with a significance level of (p\<0.01) requiring a minimum of 3 genes per category. Network analysis was also conducted to determine the proportion of significantly altered genes present in a recently-published muscle gene network (L. Smith, G. Meyer, and R. Lieber, submitted). As these networks are specific to skeletal muscle function, each gene in the network was also investigated in order to avoid arbitrary cutoffs. The networks were visualized using Cytoscape (Version 2.8.1; Cytoscape Consortium) [@pone.0040686-Cline1] and the nodes colored based on expression level defined as the average expression in CP:average expression of controls. For complexes, the geometric mean of expression ratios is reported and significance is denoted if at least one gene in the complex was significantly different. mRNA correlations to passive stiffness {#s4g} -------------------------------------- The same biopsies used for microarray analysis also underwent mechanical experiments, published separately, that allowed matching of microarray data to mechanical function [@pone.0040686-Smith1]. Briefly, all biopsies underwent passive mechanical testing of muscle fibers and muscle fiber bundles. Fibers and bundles were isolated and stretched with the result of the mechanical tests yielding a tangent stiffness (kPa/µm sarcomere length). For fibers, this represents the stiffness of components within the cell and for fiber bundles includes cellular components as well as extracellular components. Collagen concentration was also measured in fiber bundle samples. Correlations analysis was performed using MATLAB software (Mathworks; Natick, MA). Each gene that was considered significantly altered in children with CP from the analysis above was correlated with each of the physical parameters measured. Correlations were considered significant with p\<0.05. No multiple testing correction was used in determining genes significantly correlated with mechanical data. Supporting Information {#s5} ====================== ###### **A list of each gene that was significantly altered in CP.** Gene_ID is affymetrix microarray spot ID. Ratio is expression ratio of CP to typically developing controls. P-values are listed for all 3 summarization algorithms used. (XLSX) ###### Click here for additional data file. ###### **Significantly over-represented ontologies from genes significantly up-regulated (A) or down regulated (B) in CP.** Category (C), Observed (O), Expected (E), Ratio of observed over expected (R), raw p-value (rawP), and multiple testing adjusted p-value (adjP). (XLSX) ###### Click here for additional data file. ###### **List of gene families and complexes used for** [**Figure 3**](#pone-0040686-g003){ref-type="fig"} **.** Complexes are separated by the functional muscle network. (XLSX) ###### Click here for additional data file. ###### **Genes significantly correlated with passive stiffness measurements on fibers and fiber bundles.** (XLSX) ###### Click here for additional data file. ###### **Primer pairs used for quantitative real-time PCR analysis.** (XLSX) ###### Click here for additional data file. ###### **Significantly over-represented ontologies from genes with positively or negatively significantly correlated with fiber or bundle passive stiffness.** Category, Observed, Expected, and multiple testing adjusted p-value (adjP). (XLSX) ###### Click here for additional data file. ###### **Similarity between upper and lower extremity transcriptional studies of skeletal muscle in ceregbral palsy.** The list of genes that are significantly regulated in the same direction with cerebral palsy between the current study in hamstring muscle and a previous study in wrist muscle. Only 13 genes were up-regulated in both and only 6 down regulated in both. The 13 up-regulated genes were significantly over-represented in the 4 extracellular matrix gene ontologies listed. (XLSX) ###### Click here for additional data file. We would like to acknowledge the contributions of Dr. Eric Edmonds for assistance in procuring biopsies. We would also like to thank Austin Carr for performing the PCR experiments and Shannon Bremner for technical assistance. [^1]: **Competing Interests:**The authors have declared that no competing interests exist. [^2]: Conceived and designed the experiments: LRS HGC SS RLL. Performed the experiments: LRS HGC. Analyzed the data: LRS SS RLL. Contributed reagents/materials/analysis tools: HGC SS. Wrote the paper: LRS SS HGC RLL. | High | [
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Colin Myler Colin Myler is a US-based British journalist. Early life Myler grew up in the Hough Green area of Widnes, Cheshire. He was raised Catholic, served as an altar boy and attended SS John Fisher and Thomas More Roman Catholic High School, at the time a secondary modern school, in Widnes. Career Myler started his career working for the Catholic Pictorial in Liverpool, before joining West Lancs Press Agency in Southport The Sun and later the Daily Mail. He was appointed news editor of the Sunday People, then moved to Today in 1985, before its launch, again as news editor. He was later appointed as Deputy Editor of the Sunday Mirror. In 1992, he succeeded his boss Bridget Rowe as editor of the Sunday Mirror. In 1994, he moved to edit the Daily Mirror. He was made managing director of both the Daily and Sunday Mirror in 1995, but soon left to run Super League of Europe, the rugby league marketing body. He returned to the Sunday Mirror in 1998, but resigned in 2001 after Judge David Poole ruled that an article he had published regarding accusations of assault against Leeds United F.C. footballers Lee Bowyer and Jonathan Woodgate risked prejudicing their trial. Shortly after, Myler moved to the United States and was appointed executive editor of the New York Post. He returned to London in 2007 to become editor of the News of the World and remained in post until the paper ceased publication on 10 July 2011. On 22 July 2011, Myler and former News of the World lawyer, Tom Crone, wrote to the Parliamentary Select Committee to clarify evidence given by James Murdoch in respect of the News International phone hacking scandal which had resulted in the closure of the News of the World. They appeared before the Committee to answer further questions on 6 September 2011. In January 2012, Myler was appointed editor-in-chief of the New York City Daily News. Personal Myler is a practising Catholic and a second cousin of rugby player Frank Myler. References External links Myler's speech to News of the World staff on the occasion of the publication of the final edition of the paper. Category:Living people Category:English newspaper editors Category:English male journalists Category:British rugby league administrators Category:News of the World people Category:People associated with the News International phone hacking scandal Category:Sportspeople from Widnes Category:Daily Mirror people Category:English Roman Catholics Category:News Corporation people Category:Year of birth missing (living people) | Mid | [
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Escaping Boredom on the Noordam - Long Review "There is no such thing as a BAD CRUISE" ..... unless of course you were on the Titanic (or other recent fiascos at sea) The more we cruise, the more we learn about ships, crews, cruise lines, itineraries, entertainment, cabins, etc.... so naturally we are more opinionated. If this were my first cruise... I would say WOW. This being my 12th cruise ... I will start by saying... ....I love HAL. Prior to the end of this cruise, we happily put down a deposit for a future cruise. Why? Mainly because HALs overall service meets or exceeds our expectations. If there is a problem, they bend over backwards to try and resolve it for you. The food is very good. There is no nonsense in the way of dining room antics, PA system announcements (that are unnecessary) the cruise director does his job ... and doesn't overstay his welcome. There are lots of interesting people on board and enrichment More offerings that other cruise lines don't offer. I guess it's like trying to find the perfect person... you will never be 100% satisfied. Personally we would like it if there was just a little more liveliness on board in the later evening, but it's the passengers of each sailing that determine this. The longer the cruise, the older the passengers. Embarkation: HAL in Ft Lauderdale was swift and easy. We had all our check in documents complete ahead of time and the line moved quickly. (15 minutes at the most around 1:00 pm) The gentlemen who checked us in was friendly and charming and seemed to be working side by side with his other half. When he finished checking us in, he leaned over to share a kiss with the agent next to him who had also just finished checking her passengers in. It was adorable. We boarded before 2:00 pm and were able to go straight to our cabin (unlike many other cruise lines that require you to roam around the Lido deck with your carry on baggage until the cabins are ready). Cabin: This was our 2nd aft veranda cabin. Previously we were on deck 4. We love the aft cabin experience. Watching the seas off the back of the ship is wonderful. Going northbound you get a lot of sun out there (and a little bit of ash from the ships stacks!) What we did not factor in when we booked this cabin was that on the Navigation deck (8) under the Lido deck, there is a lot of noise in the mornings and the afternoons when the deck chairs are being brought out and rearranged. There was also a noise that we never identified. My husband is a very light sleeper and if he wakes up he is up for hours. There was some kind of noise that was an intermittent loud bang. We ruled out doors slamming, chairs being dropped, toilets flushing. It would happen all through the day and night but not at regular intervals. We reported it to the front desk and they bent over backwards trying to figure it out. Short of having a crew member camp out in our room, there was no way to tell what it was. For 4 days we kept trying to explain it and finally gave up. The front desk was very apologetic and sent us a bottle of wine as a gesture of goodwill. In the end we think it may have had something to do with the HVAC system relieving itself of some pressure or the Lido pool/spa filtration system. That was our only cabin complaint. On the good side .. Our bathroom was spacious enough for a bathtub which I used on several occasions . We did notice there was a little less counter space than we would have liked and we wished we had booked a cabin with a full sized eating table on the deck. Next time. Cabin Stewards: Weebee and Hadi from the Philippines were about as good as they come. They were always there when we needed them. They kept our rooms in tip top shape, kept our ice bucket full and their ability to communicate with us was a welcome treat. By day 2 they remembered our names, even if we saw them way down the hall or around the corner away from the cabin they associated us with. Amazing. It took us 4 days to remember their 2 names. Kudos. I will say that I think it's time for the Noordam to change out the carpeting. Cocktails: We preplanned this trip to enjoy cocktails in our cabin and ordered through HAL the gin and tonic package and a bottle of vodka. One bottle showed up, the other we had to call the front desk to remind them of our order, but it arrived shortly thereafter. Of course we did not finish either bottle, but it was nice to mix a cocktail each evening before going to the dining room and enjoy them on our balcony. We also pre ordered the Navigator wine package. 10 nights - 5 bottles of wine worked perfectly for us. We still took advantage of the lounges about the ship. On sail away day we had champagne at the Atrium Bar "hip hip hooray" before our life boat drill, we had a bucket of cold beer (5 for the price of 4) on the night of Lido Deck Party, Pina Coladas at the Crows Nest one afternoon, Kir Royal and Cognac another evening before my husband enjoyed a cigar in the Oak Room. I thought the drink prices on this cruise were fair. My only pet peeve about cocktails on ships these days (not exclusive to HAL) is that I detest drinking out of plastic glasses and stemware. I know it's a safety issue, but I heard quite a few coffee cups in the Lido dining room hit the floor and break .. so why use plastic for cocktails? For me, it deters me from wanting to buy one outside. I like to be treated like an adult. (note to self: next cruise I plan on asking my cabin steward to empty out the servi-bar completely so we can use it for keeping our own things chilled. (including suntan lotion!) Sail Away: We dropped our bags and went to the Lido for a late lunch. There were plenty of options for my husband. I was dieting and also found a wonderful salad bar. I only wish there were more fat free salad dressing options. As I mentioned above, we had champagne in the Atrium Bar "hip hip hooray" before the life boat drill. The drill was conducted on promenade deck and quite efficiently (especially following recent events on the seas) It would have gone very quickly if it hadn't been for 3 cabins who had to be paged repeatedly to show up. 48 hour rule: HAL now does a hands-off policy for the first 48 hours of a cruise. The buffet in the Lido is not self serve until after 48 hours have passed. Salt and pepper shakers are off the tables and you must use paper packets and they have staff to serve you from the buffet, coffee, water, iced tea machines. Frankly I would be thrilled if they kept this policy the entire cruise. (The things you see at a buffet line!!) I asked a crew member and he told me it takes 6 extra crew to serve the buffet rather than have it self serve. Small price to pay for keeping an outbreak of Norovirus. Pools: Much to my surprise the aft pool was fresh water. I never stepped into the main pool, but I am guessing it was also fresh water. By the end of 10 days it did look like it needed to be drained as it got a little murky. The aft hot tubs were about 100-101 degrees. One worked, the one on port side had no bubbles. These aft tubs and pool are supposed to be Adults Only. There were a few kids in the tub on the first couple of days. I hate to be the cranky lady who complains, but I really don't understand why parents can't respect this signage. We also mentioned this to the front desk and it seemed to stop occurring after a few days. There weren't that many children on this cruise, but I just don't like getting into a hot tub when kids are splashing around. It's a place for adults to congregate and enjoy adult conversation and adult beverages. My suggestion to HAL is to post better signage by the entrance to the hot tubs and enforce the rules. Towels: On the plus side ...... Ship towels were available at the pool, both main and aft, on the Promenade deck and on disembarking to shore. They were freely available. Not distributed with a sign out sheet. (again, I like being treated like an adult). On the minus side, when we anchored at Half Moon Cay and tendered in, they were completely out of towels. We assumed there would be towels on the beach and there were not. So we spent the day on the beach with no towels. Greenhouse Spa: We signed up for the week of Thermal Suites. I love this and it offers you a chance to use the Hydro Therapy Pool (aka the hot tub with no kids). I think it is over priced, but I am willing to spend the money. (perfect marketing strategy!!) We also had a couples massage on the second sea day. It was really nice, but when it was over they push you to buy another service and we were caught up in the moment and did. Later that week our sunburns prevented us from desiring another massage, so we cancelled and they were kind enough to do that without charge. We gave them 24 hrs... or close to it. I also had a Fire and Ice Pedicure. It was very nice and after a 10 day cruise and a week home, my nail polish still has not chipped! Dining: We had main seating 8:00 p.m. in the Vista Dining Room on the upper floor, table #56. For some reason I never learned the name of our head waiter. I recognized him, but his name did not stick. He was very nice and remembered after the first night that we enjoy an espresso and a cappuccino after dinner and we never had to ask again. The menu each night was different and varied and I liked that they had items each night that were available if you did not want to venture off the beaten path. I always enjoy trying all the exotic soups (hot and chilled) they are wonderful and the escargot and caviar and seared delicacies they offer. Sometimes we order two of something or have special requests and they are always pleased to indulge our gluttony. We dined in the Vista Dining Room 6 nights. The food ranged from very good to not so good. First night's prime rib was undercooked to order and very thin. Some of the seared items were room temperature and some chilled appetizers had been sitting out too long.Also the service was slow between the last appetizer and the entree and so slow a few nights that we missed the show if we stayed for dessert. Again, I would love it if HAL would offer some healthier choices. Wine Steward: Also I did not remember his name. He was efficient and never lost our wines even as we moved to different dining rooms throughout the cruise. We don't like our wines poured in the glass in large quantities. We like "an inch" of wine so that we can swirl and open up the flavors. It always takes 3-4 days for us to convince our wine stewards of this. I think they just want you to finish the bottle so you can feel like you need another. Pinnacle: $25 extra per person. We have done this before and enjoyed it. The decor and service exceeds that of the dining room, but the choices and quality of the food were not overly superior this time. I had Steak Diane and mushrooms, but when I asked for a lobster for us to split, the answer was no .. unless we wanted to pay extra for the entree. It wasn't much $10, but it seemed petty. We have eaten in other "specialty" restaurants and never heard of this. We rarely ask for 2 of anything, but from time to time you can't decide what to order or want to try something. It's standard operating procedure to order this way in the Vista dining room. The amount of waste that goes on in the Lido could save a small country. Le Cirque: $39 extra per person. We had pre reserved this before the cruise. It was paid for or else we would have cancelled it after the Pinnacle experience. Supposedly the dining room was to be "transformed into the legendary Le Cirque of New York" ... all we noticed was the change of the china and linens. The menu was about the same as the Pinnacle in choice and quality. Don't get me wrong.. it tasted pretty darn good, but in our opinion it definitely did not warrant $78 + gratuity. We can get that at home. We did meet a really nice couple both nights while dining and the service is much more attentive, but I think next time we might only try the Pinnacle. Canaletto: No extra charge, reservations only. On the Lido at the end of the Lido buffet. Linen covered tables and personal service. The food is prepared and set up behind one of the Lido buffet areas, but not available for self service. The food was fabulous, piping hot and the service was wonderful. I think the waiters there are hoping to work their way out of the Lido and into the main dining room, so they work extra hard to be friendly. We found this to be the same in the Lido all hours of the day. Very friendly wait and service staff. Breakfast: Room Service: We ordered room service 3 times and it always came right on time and exactly what we ordered. You can actually order a full breakfast. The coffee was not very good in our opinion, but we classify ourselves as coffee snobs. Lido: Lido had lots of choices, poached eggs for eggs Benedict, waffles, omelet chef, and standard scrambled eggs and meats, oatmeal, and even some ethnic choices from Asia. Vista Dining Room: Plenty of choices, but each day we were told the wait for an omelet would be 30-45 minutes. We could never figure that out. We usually had eggs Benedict or oatmeal, fresh fruit, etc. Coffee was slow and rarely refilled without seeking out a waiter and asking for it. Other foods: There was a pretty good sushi bar in the afternoon offering maki and noodles. The Lido BBQ Party was fun and we ate like we were planning for a famine that night. It was perfect weather and the smells got the best of me.... I blew my diet that night! Entertainment: We enjoyed the HAL singers and dancers on 2 nights, a magician/comedian another night, a fabulous violinist another night. We always found a seat in the show. We went to the late show and it was never full. We skipped a few nights and went to try other venues of entertainment. The Adagio Strings were a nice touch, but we did not enjoy the dance music of the HAL Cats or the folk music in the Crows Nest Lounge. The Northern Lights played the usual popular fare, but the crowds were nonexistent after 11:00 pm. The whole ship basically shuts down at 11:00 except for the Northern Lights Club and the casino. The Piano Bar was full each night. The piano man was quite talented as a pianist and a singer, but a little too full of himself and over-the-top for my taste. I don't recall hearing much of the pool band, we must have been on the other side of the ship while they were playing. Normally the main pool would have the noise and the music and the aft pool (adults only) would be more mellow and quiet. This cruise the music was in the aft pool. Activities: We watched a movie one night in the Culinary Arts Center with popcorn and we attended part of a demonstration on how to make creme br'lee ... very interesting. Public Rooms: The Explorers Lounge is wonderful. Huge library you can check books out, magazines, puzzles. Someday I will take a long enough cruise that I won't feel guilty for spending time down here out of the sun. Restrooms throughout the ship: Nicely appointed and always clean Casino: What can you say about a casino? You win some. You lose some. We did both and enjoyed our time spent there. Special shout out to Rey who was training to be a dealer but spent most of his time in the cashiers cage. Very personable and entertaining. We enjoyed having fun with you each night! Cruise Director: Shane. Great job. I love a cruise director who actually does their job without being annoying over the PA system. He had funny jokes to start his introductions out to other entertainers and had the perfect blend of information and not being overbearing. Kudos. Mariners Society: Very nice upgrade from the usual champagne toast and canape ... to a full on luncheon in the Vista Dining room. Excellent. Cocktails with the Captain: We aren't sure why we were invited, but we attended a really nice cocktail party toward the end of the cruise in the Crows Nest Lounge. We had actual one-on-one conversations with the Captain John Scott as well as his lovely wife and the 2nd in command, hotel manager and other officers. Shore Calls: Getting off and off the ship was very organized and easy in port. Even on the tender days the wait was short. Half Moon Cay: Wonderful day. Only wish they had not run out of towels before we left the ship. Medical Center: We did stop by here once because of a sting my husband got while snorkeling in Bonaire. It was irritating him and the nurse looked at it and advised us to return when the ships doctor was back at 5:00 pm, but we didn't return as the sting began to dissipate. Friendly, good service. Disembarkation: Easy. We had a shore excursion booked on the ship and then to the airport Thank you HAL for another memorable cruise. Time to start planning our next sailing Less | Mid | [
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566 F.2d 104 Lake Livingston Washateria, Inc.v.Hasty*** No. 77-2769 United States Court of Appeals, Fifth Circuit 12/29/77 1 S.D.Tex. AFFIRMED * Summary Calendar case; Rule 18, 5 Cir.; see Isbell Enterprises, Inc. v. Citizens Casualty Co. of New York et al., 5 Cir., 1970, 431 F.2d 409 ** Local Rule 21 case; see NLRB v. Amalgamated Clothing Workers of America, 5 Cir., 1970, 430 F.2d 966 | Low | [
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Jim Sanders' Craigslist Diamond Sale Goes Horribly Wrong (VIDEO) A Washington resident was killed in late April after his attempt to sell a diamond ring on Craigslist went terribly awry. Jim Sanders and his wife, Charlene Sanders, posted the ring, a family heirloom, on Craigslist. They were contacted by people, believed to be posing as interested buyers, who told the Sanders they wanted to come to their home to see the ring. As ABC News reports, Jim Sanders opened the door to the prospective buyers, who forced their way into the family's home, then tied up Jim and Charlene, and their two sons. Jim Sanders "watched his family beaten before he was shot and killed in cold blood," says ABC News. | Low | [
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Atypical chronic myeloid leukemia: a rare entity with management challenges. The aim of our study was to review the clinicopathologic features and management of atypical chronic myeloid leukemia (aCML). Relevant manuscripts published in English were searched using PubMed. aCML is diagnosed as per WHO 2016 classification in the presence of leukocytosis ≥13 × 109/l with circulating neutrophil precursors ≥10%, monocytes less than 10%, minimal basophils, hypercellular bone marrow with granulocytic proliferation and dysplasia, bone marrow blast less than 20% and absence of BCR/ABL fusion gene. Common cytogenetic features and mutations include trisomy 8, and mutations in SETBP1 and ETNK1. Median survival is 1-2 years. Hematopoietic stem cell transplant may be the only curative option. Ruxolitinib and dasatinib are emerging therapeutic options. Thus, aCML is a rare entity with poor survival. Novel therapies are needed. | High | [
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_________________Choyo Chagas is Chairman of the Big Four, the ruler of the planet from "The Bull's Hour" ( Russian: Час Быка), a social science fiction novel written by Soviet author and paleontologist Ivan Yefremov in 1968. Six months after its publication Soviet authorities banned the book and attempted to remove it from libraries and bookshops. "Lo, How A Rose E'er Blooming" lyricsLo, how a Rose e'er blooming from tender stem hath sprung!Of Jesse's lineage coming, as men of old have sung.It came, a floweret bright, amid the cold of winter,When half spent was the night. Isaiah 'twas foretold it, the Rose I have in mind;Mary we behold it, the Virgin Mother kind.To show God's love aright, she bore to us a Savior,When half spent was the night. The shepherds heard the story proclaimed by angels bright,How Christ, the Lord of glory was born on earth this night.To Bethlehem they sped and in the manger they found Him,As angel heralds said. This Flower, whose fragrance tender with sweetness fills the air,Dispels with glorious splendor the darkness everywhere;True man, yet very God, from sin and death He saves us,And lightens every load. | Low | [
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Transcription of the FMR1 gene in individuals with fragile X syndrome. Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 x 10(-3)), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered. | High | [
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Q: value of input field bind in angularjs I have a strange behavior in my browser with an input field. When I inspect it in developer console it looks like this: <input type="text" name="siteName" ng-model="model.name" minlength="3" maxlength="40" ng-disabled="!model.isEditable || disableUpdate" required="" class="ng-pristine ng-untouched ng-empty ng-valid-namevalidation ng-invalid ng-invalid-required ng-valid-minlength ng-valid-maxlength"> After the page is rendered, in chrome developer console, I select this input field like this: var x = document.querySelector('input[name="siteName"]') and I get it in console. This input field has a value in UI (a string, not empty) - is filled by angularjs in this way: ng-model="model.name". model.name has a valid string value. when I call x.value in console, I get an empty string. More, in chrome developer console, when inspect an element, I can access it using $0. And $0.value returns me the correct value. Anyone had such issue? Any idea how to get using query selector the value for the input field? Thank you. A: If you are trying to access the angular scope from the chrome developer console, try angular.element(document.querySelector("<selectors>")).scope() you can get more information about this query in the following answer How do I access the $scope variable in browser's console using AngularJS? | Mid | [
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Empress Xiaoyixiang Empress Xiaoyixiang (died 1646) was a Chinese Empress consort of the Southern Ming Dynasty, empress to the Longwu Emperor. Notes Sources |- Category:Ming dynasty empresses Category:Southern Ming Category:1646 deaths Category:Year of birth unknown Category:17th-century Chinese women | High | [
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Alexander Marx Alexander Marx (1878–1953) was an American historian, bibliographer and librarian. Biography Born in Elberfeld, Germany, son of George Marx, a banker, and Gertrud Marx-Simon, a published poet. Alexander Marx grew up in Königsberg (East Prussia). He spent a year in a Prussian artillery regiment where he excelled in horsemanship. Later he studied at the University of Berlin and at the Rabbiner-Seminar (Berlin), marrying in 1905 Hannah the daughter of R' David Zvi Hoffmann, rector of the Seminar. In 1903, Marx accepted Solomon Schechter's invitation to teach history at the Jewish Theological Seminary of America and be its librarian. Marx came to Jerusalem in the 1950s to give Ben Gurion the prize from the J.T.S. His siblings include Moses Marx, another librarian, and Esther Marx, wife of S.Y. Agnon. Works Marx published articles in many languages and was at home in both classical and Semitic languages. Marx contributed monographs and articles to journals on a wide variety of subjects, published two volumes of collected essays (Studies in Jewish History and Booklore (1944); Essays in Jewish Biography (1947)), and with Max L. Margolis wrote A History of the Jewish people (Jewish Publication Society of America, 1927, 1962). This pioneering work, stressed economic and social life, organization and legal status. It offers the reader a soundly researched, authoritative, and objective Jewish history in one volume. In later years he also served as a member of the publications committee of the Jewish Publication Society of America. As librarian The JTS library on his arrival in 1903 contained 5,000 volumes and 3 manuscripts. At his death it possessed 165,000 books and over 9,000 Hebrew, Samaritan, Aramaic, and Yiddish manuscripts, comprising the largest Judaica collection in the world. Much of Marx's research in early Jewish printing remains unpublished. References External links https://www.jewishvirtuallibrary.org/jsource/judaica/ejud_0002_0013_0_13362.html Encyclopaedia Judaica, Alexander Marx Category:1878 births Category:1953 deaths Category:American Jews Category:American librarians Category:German emigrants to the United States Category:German Jews Category:Historians of Jews and Judaism Category:Jewish Theological Seminary of America faculty Category:Prussian Army personnel Category:People from Wuppertal Category:People from the Rhine Province Category:Humboldt University of Berlin alumni Category:Fellows of the Medieval Academy of America | High | [
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10.05.2007 are you getting fat? so i have one set of grandparents. my dad's. (my mom's parents both passed away a long time ago) the living ones are starting to get up there in age. my grandma's in her 80's & in my opinion still kicking pretty good, although in recent years, her body is slowing down. sometimes i think her mind might be a little, too. (this is to be expected, right? too bad in my world, it started slowing down around 25, maybe 26) ok, enough of this background knowledge. i don't talk to my grandma often, maybe once or twice a month. but for some reason, when i call & she answers, she's always known my voice, based on my "grandma?!" she always says, "hayley!" this week, when i called, she paused & said, "who is this? melissa?" (melissa is a cousin) I said, "no grandma, its hayley." so then she caught on to my game & said "where are you going?" cause apparently i only call her in the car. but - its a good place to call people, cause if i'm home, i'm often doing something - not on the phone. and i told her that i was on my way home from dinner with a friend. she said, "are you getting fat?" getting? i swallowed hard, cause you know that when your grandma tells you enough is enough, you've really dropped the ball. i said (honestly, in my opinion, so don't yell at me dad) "well, i'm a fat version of what i should be, but i'm not fat compared to the norm, i'd say." and she said "oh, cause it seems like you eat out a lot & when you eat out a lot, you gain weight." OH SO THAT'S MY PROBLEM. (actually, i kinda already knew that.) but the thing is, i seriously only talk to her monthly or less... Folks, here's my lesson this week, my grandma can actually hear me getting fatter. (that's a line from tommy boy) sad. and maybe i should call her sometime from home. while i'm exercising! | Low | [
0.483402489626556,
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17O NMR spectroscopy of sulfolenes (2,5-dihydrothiophene-1,1-dioxides) and sultines (3,6-dihydro-1,2-oxathiin-2-oxides)--experiment and quantum calculations: synthesis of 4,9-dioxo-1,2-oxathiacyclodecane-2-oxide, a new heterocycle The products of hetero-Diels-Alder reactions (sultines) and cheletropic addition reactions (sulfolenes) between 1,3-dienes and sulfur dioxide can be distinguished by their 17O NMR shifts. Experimental data have been collected for derivatives of 3,6-dihydro-1,2-oxathiin-2-oxide and of 2,5-dihydrothiophene-1,1-dioxide. This data was then compared with that calculated by the gauge independent atomic orbital (GIAO) method at the HF/6-31 + G(d,p) and HF/6-311 + G(3df, 2p) levels of theory with geometries optimized by MP2/6-31G(d) calculations. GIAO-MBPT(2) calculations were also performed with the 6-31 + G(d,p) basis set. The adduct between (E)-1-methoxybutadiene and SO2 is sulfolene 3, the ozonolysis of which in SO2 followed by work-up with ethanol provided (2RS,3SR,6SR)-(31), (2RS,3RS,6SR)-(32), and (2RS,3RS, 6RS)-2,6-diethoxy-3-methoxy-1,4-oxathiane-4,4-dioxide (33). Single-crystal X-ray diffraction studies are reported for 32 and 33. Ozonolysis of the hetero-Diels-Alder adduct of SO2 with 1,2-dimethylidenecyclohexane produced 4,9-dioxo-1,2-oxathiacyclodecane-2-oxide (34), the first member of a new class of sulfur heterocycles. | High | [
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Razer Megalodon 7.1 Surround sound gaming headset TOG Score Members (av.) The Good The Bad x64 installation issues USB only, can’t be used on a conventional stereo Reviewed by okkervil A lavish and indulgent treat for your gaming ears. Initial thoughts The first thing you’ll notice about this headset is how hard Razer have worked on the packaging. A slick cardboard arrangement slides then unfolds to reveal a faux carbon fibre hardcase which contains the headset, control pod and some marketing propaganda in one neat, shiny package. The case is something you’d definitely hang on to in the event you were off to a lan, as the headset fits snugly inside and the protection provided could save you more than a few pennies in repairs or replacements. The cloth covered cord which is at an estimate around 3 metres long is also a nice touch. Plenty of length, and no cold plastic anywhere. Though for the time being, this is where the fun ended. My experience plugging this in and trying to get it to work on my new i5 system running Windows 7 64 bit was a nightmare. The specs and website state that it’s compatible with x64, which turned out to be true, but I did not discover the truth until a good solid hour of googling had lapsed. In order to get it to work, I had to uninstall the drivers that Windows thought were appropriate for this product, then update the firmware - a tricky operation that requires you to hold down a button on the control pod, whilst re-inserting the headset into a USB port. Following a reboot, the headset still wasn’t working, so some USB slot shuffling took place and at last one of the twelve I have allowed the headset to actually play sound. Sound They say that those who are patient get the rewards and I must say that even with the steam coming out of my ears after my installation experience I was well rewarded. Truth be told, I thought the 7.1 was a bit of a gimmick before I purchased the headset, and I purchased on the promise of a headset at last comfortably fitting my giant bonce. I got the fit right, and as a bonus I got excellent gaming sound. Tested on Team Fortress 2, Live for Speed, Trackmania, Call of Duty: Black Ops, Battlefield: Bad Company 2 and Starcraft 2, the Megalodon headset performs really well. Positional audio works as well as they claim on the website, which is a rare event indeed and I’m convinced it provides an edge, particularly in the FPS games over stereo headsets. The sound is crystal clear, with gamer thrilling, punchy bass. A game with plenty of pew pew or vroom vroom and cowbell will see the Megalodon puff it’s chest out and flex all of it’s muscle. The great humbler for gaming headsets is always music. It seems you can’t have a gaming headset that’ll do a great job of music, or a music headset that’ll do gaming really well. The Megalodon fits into this stereotype. Music performance is pretty good, but not thrilling. Treble and mids are crisp and as good as my not-cheap-either Sennheiser headphones, but the bass even after performing so admirably in games, feels slightly loose and disconnected, leading to an overall ho-hum experience with your music player doing it’s thing. That being said, how often do audiophiles listen to MP3 files from a computer anyhow? As I’m writing this review, I’m tweaking the settings and trying to get my music to sound better and rather embarrassingly I’ve just discovered the button that switches the 7.1 mode over to 2.0 and not surprisingly music sounds considerably better now. Forehead slap. Individual channel volume is adjustable easily and quickly via the control pod, as is overall volume - which at 2/3 is more than enough, even for these seasoned live gig ears. Also at your fingertips is are handy mic mute, mic sensitivity and mic level control features. I found being able to adjust tidbits on the fly without alt tabbing to be most useful. These headphones aren’t noise cancelling, so provided you’re at an acceptable level you’ll at least hear people in your presence, though you might not be able to make out what’s said, so unfortunately cup of tea or hanging out the washing duties can not be completely avoided. Without the noise cancelling, they also leak a little noise, but in our road test we found the levels of noise leaked to be perfectly acceptable. Microphone The boom swivels 270 degrees, and has a little bendy section which should be adjustable enough to get the microphone close enough to the mouth on even the most unconventional of faces. While it’s not detachable, it can be easily swung above so that it’s out of the way if required. Traditionally I’ve struggled with voice communications. Like a turtle on it’s back, I’ve never been able to get the settings right, it’s at times been that bad that I’ve heard people sigh as they’ve seen my tag light up on Ventrilo. It turns out that my struggles have must have been hardware related. Previously having used a $2 desktop microphone, then a Creative Fatal1ty gaming headset and finally a Microsoft Lifecam VX1000 as a voice communications tool, I’m not surprised. I’m delighted to say that this microphone just works, straight out of the box. Tested on Ventrilo, Mumble, Teamspeak and the previously mentioned games via in-game voice, all have come up trumps. If you take the plunge, expect to have people say “I didn’t know that’s what you sounded like.” Samples taken from Windows Sound Recorder are crisp, clear and punchy. Very satisfying indeed if you’ve been through microphone hell as I have. Overall Besides the nightmare setting it up, I’m very happy with this purchase. Build quality, comfort, gaming sound, the control system and the microphone are excellent, as previously mentioned, music isn’t quite up to the standard of the previously mentioned attributes, but again - it’s a gaming headset not an audiophile headset. The dollars invested are justified in my view when performance is considered, however the real test of value will come with time. If I get two good years of gaming out of this thing, the investment will be an excellent one, working out roughly at a few cents per hour of gaming, which for the enhanced experience, I’m more than happy to pay. If it falls short of the two year mark, it will have been a lavish and indulgent treat, perhaps a little over the top but not a complete waste, if this makes sense. Nice review Okkervil. I like the way you seem to talk and test at the same time (discovering the switch partway through discussing music sound). Very true to life and makes the review seem more honest imo. I'm looking for a new headset, and this sounds like a good option to keep in mind. Don't suppose you tested it on skype? I use the program a lot to chat with family OS. Cheers! True to razer products they have produced a very fancy product with great gaming credentials only to let themselves down in the ease of use department. My Razer Lachesis mouse was a case in point - fantastic once I set it up but ohhh my god the issues getting setup right. I have used a Megalodon and was impressed by the sound, but in the end I bought a Logitech G35 headset for $50 less, ran the disc, plugged it in and was blown away. Added bonus - G35 is closed ear and blocks out Mrs Rapid and the Rapidlets. Good review but a bit pricey for me. As a matter of interest I downloaded the product demo and listened to it through my Zalman 5.1 headset. The positional effects were very good as was the demo of speaker position. I note that the headset costs AUD$249 at Razers AU site and on checking that price varied over a few Australian suppliers the best being AUD$189 here http://www.bttech.com.au/razer-megalodon-surround-sound-gaming-headset-p-70723.html. Quite a big difference between the RRP and the lowest. Thanks for the review- was good read :) I'm hanging out for the Turtle Beach ear force z6a (being re-released in november as a MW3 tie in, with the PC version being called "Ear Force Charlie"). http://www.reghardware.com/2011/08/30/ten_gaming_headsets/ They got a 10/10, as well as being real 5.1 (4 speakers per ear).. I had real problems finding a headset that was comfortable for long durations, and good quality too. After reading your review I took the plunge and got a Megalodon. This is the best headset I've ever used! My old Plantronics 777 never did surround sound properly, and they became uncomfortable on my big lugs after a few minutes. The Megalodon is the best surround I've ever heard on headphones, voice quality is excellent, and I can play for hours in comfort. I also gave some music a go the other night in 2.0 mode and I was very impressed. I had the same issues with firmware updates and needing to change USB port to make it work (I hear a powered hub solves this) but got it working fine in minutes. 5/5 Bought a pair of Megalodons recently - they sound great and fit well, but I just can't seem to get them to work consistently with The Elder Scrolls: Skyrim. I have read a lot of other comments online about a powered USB hub being helpful in stabilising the audio, so will try that and post here if it works out. i do like this headset but i am waiting for the new head set to come out it can switch between the headset and speakers you allready have, and has 5 drivers for what i belive to be a better sound we will see when they come out here soon i hope I've had one of these for quite a while now, maybe as long as a year. It shipped with cloth ear pads, which I had to replace after a few months due to, well they got a bit smelly. Bought the faux leather which are easy to clean and have been great since. Overall I am very happy with it. One improvement would be better noise cancelling, but it's not a big issue. Had to admitt had a similar experience with setting it up. Also ran into troubles with audio and mic running at the same time. But after the pain of getting it working it has been nothing but value for money. Love the sound quality (the 7.1 is great in games), comfortable as...something really comfortable (and I too have a big noggin), and just looks plain cool. 5 stars Well it's been about a month since I got these and to keep it short they are great, get some. I had no dramas setting them up like some other people have and I'm running 64 bit. I did however find them quite uncomfortable AT FIRST. I'm not sure whether this was just from wearing them for hours or what but they eventually got better and now I wouldn't play BF3 without them. Recommended @seraphim & ramon.. Feel free to post pictures and / or a review of your own of your suggested products. Otherwise, go piss on someone else's parade. Your contributions aren't in any way shape or form productive. I have a pair of G35 7.1 surround from Logitech and apart from having to re-install the software every other day i think they are as good as the Razor, but i do have a Razor left handed mouse which is awesome! | Low | [
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10 N.J. Super. 475 (1950) 77 A.2d 483 THE STATE OF NEW JERSEY, PLAINTIFF-RESPONDENT, v. CLARENCE ILLARIO, DEFENDANT-APPELLANT. Superior Court of New Jersey, Appellate Division. Argued November 20, 1950. Decided December 6, 1950. Before Judges JACOBS, EASTWOOD and BIGELOW. Mr. Myron L. Levy argued the cause for the appellant. Mr. Charles A. Reid, Jr., argued the cause for the respondent. *476 The opinion of the court was delivered by JACOBS, S.J.A.D. This is an appeal from an order entered by the Magistrate of the Municipal Court of the Township of Bridgewater adjudging the defendant guilty of contempt of court. On April 9, 1950, words passed between the defendant Clarence Illario and his neighbors, the Blackfords. A complaint was filed by the Blackfords charging the defendant with using vile, profane and insulting language in violation of an ordinance of the Township of Bridgewater which declared such action to be disorderly conduct. At the hearing the Blackfords testified that the defendant had used the improper language and they were supported by Kathryn Brennan who lived next door. On the other hand, the defendant testified that he had not used any vile, profane and insulting language and he was supported by his wife Helen. At the close of the testimony on defendant's behalf the magistrate, on his own motion, called for testimony by Mrs. Brennan, clerk of his court and mother of Kathryn Brennan; she corroborated her daughter. The magistrate found the defendant guilty of disorderly conduct and assessed a fine and costs which were paid. Thereafter, the magistrate issued an order directing the defendant to show cause why he should not be adjudged guilty of contempt of court for having falsely testified when, in the course of his defense on the disorderly conduct charge, he denied he had used the improper language. Hearing was held, the Blackfords and Brennans again testified that the defendant had used the improper language, the defendant and his wife Helen again testified to the contrary, and the magistrate again disbelieved the defendant's denial. This time he adjudged the defendant guilty of contempt and the present appeal is from this action. The problem as to when the giving of false testimony in a judicial proceeding constitutes contempt has given courts much concern. As Justice Black said in Matter of Michael, 326 U.S. 224, 227, 90 L.Ed. 30, 33 (1945), it is clear that "all perjured relevant testimony is at war with justice, since it *477 may produce a judgment not resting on truth" and as a crime it is indictable and triable by jury with constitutional and traditional safeguards. However, when dealt with as contempt it becomes subject to the awesome power of the court to deal with it in its discretion, summarily and without fixed limit of punishment a power described by Justice Depue as, at best, "an arbitrary power, and liable to great abuses." Rhinehart v. Lance, 43 N.J.L. 311, 321 (Sup. Ct. 1881). In the light of the foregoing the Supreme Judicial Court of Maine in Ex parte Holbrook, 133 Me. 276, 177 A. 418 (1935), denied to itself power to deal with the giving of perjured testimony as contempt, declaring that while perjury is an abhorrent crime it would be "unsafe and unwarranted" to deal with it in any manner other than as a crime triable by jury. See State v. Lazarus, 37 La. Ann. 314 (1885). Similarly, the United States Supreme Court has declined to sanction contempt proceedings based solely on the giving of false testimony. See Ex Parte Hudgings, 249 U.S. 378, 63 L.Ed. 656 (1919); Clark v. United States, 289 U.S. 1, 11, 77 L.Ed. 993, 998 (1933); Matter of Michael, supra. In the Clark case Justice Cardozo expressed the Supreme Court's doctrine in the following language: "Perjury by a witness has been thought to be not enough where the obstruction to judicial power is only that inherent in the wrong of testifying falsely. * * * For offenses of that order the remedy by indictment is appropriate and adequate. On the other hand, obstruction to judicial power will not lose the quality of contempt though one of its aggravations be the commission of perjury." Recent applications of this doctrine may be found in United States v. Goldstein, 158 F.2d 916 (7th Cir. 1947), and Howard v. United States, 182 F.2d 908 (8th Cir. 1950). In several states, courts have taken the position that although the power to treat the giving of false testimony as contempt exists it will not be exercised unless the court has "judicial notice of the falsity," e.g., where it is admitted by the contemnor or otherwise appears incontrovertibly. See People v. Harrison, 403 Ill. 320, 86 N.E.2d 208 (1949); *478 Hegelaw v. State, 24 Ohio App. 103, 155 N.E. 620 (1927); McInnis v. State, 32 So.2d 444 (Miss. Sup. Ct. Div. A 1947). In the Hegelaw case the court said: "In nearly every case issues of fact are made up by the pleadings, each side seeking by testimony to maintain its side. The court or jury, in rendering judgment or verdict, bases its finding upon the testimony which seems the more probable. Merely because the court chose to believe the one side in preference to the other as to an issue of fact, upon grounds of greater probability, would not justify the court in holding the witness who supported the losing side guilty of contempt of court. To justify such action by the court the falsity of the witness' testimony, given in open court, must be a matter of judicial knowledge, not merely of opinion. In other words, it must be a patent falsehood upon which there can be no difference of opinion. If the alleged false statement is merely a matter of the court's opinion, as distinguished from its knowledge, contempt proceedings will not lie." In this connection the notion which once prevailed in King's Bench that the denial under oath by the alleged contemnor, although indictable if false, constituted a bar to further prosecution of the contempt is worthy of mention. See Curtis, "The Story of a Notion in the Law of Criminal Contempt, 41 Harv. L. Rev. 51 (1927). Although the notion had ceased to be a defense in England by 1796 and had been discarded by the United States Supreme Court in United States v. Shipp, 203 U.S. 563, 51 L.Ed. 319 (1906), it was apparently accepted by our former Supreme Court in In re Gonzales, 88 N.J.L. 536, 544 (Sup. Ct. 1910). However, the notion never prevailed in our Court of Chancery and we may safely state that it does not, in its comprehensive form, represent our present law. Cf. Attorney General v. Verdon, 90 N.J.L. 494 (E. & A. 1917); In re Merrill, 88 N.J. Eq. 261, 282 (Prerog. 1917); In re Baer, 13 N.J. Misc. 148, 151 (Sup. Ct. 1935). In New Jersey the giving of false testimony has been generally considered to constitute a contempt of court punishable as such. Thus, in In re Caruba, 139 N.J. Eq. 404 (Ch. 1947); affirmed, 140 N.J. Eq. 563 (E. & A. 1947); cert. denied, 335 U.S. 846, 93 L.Ed. 396 (1948), the Court of Chancery adjudged a witness who had testified falsely guilty *479 of contempt and cited prior New Jersey decisions to support the view that perjury or false swearing is a "contempt of court and may be punished, notwithstanding an indictment for perjury as a crime will also lie." In the Caruba case the contemnor had admitted the falsity of his testimony and in all of the cited cases, with the possible exception of Edwards v. Edwards, 87 N.J. Eq. 546 (Ch. 1917), the falsity of the testimony likewise appeared incontrovertibly. In the Edwards case Vice-Chancellor Lane found that the husband petitioner in a divorce proceeding testified falsely and engaged in other misconduct, adjudged him guilty of contempt, and said: "The power to punish for contempt is an arbitrary power, and should be used only when absolutely necessary in the interest of justice, and then with great care and discretion. Courts will not ordinarily, when the facts are in dispute, punish perjury as a contempt, not because of lack of power, but because sound public policy requires that the offender should be left to the criminal law. But where the facts are admitted or demonstrated, it seems to me that the court would be shirking a clear duty if it did not act. And circumstances may arise which would make it the duty of the court to act even if it was obliged to weigh evidence. Perjury committed by a petitioner which has induced the court to grant a decree of divorce presents one of this class of cases." See Zimmerman v. Zimmerman, 11 N.J. Super. ___ (App. Div. 1950); Swanson v. Swanson, 10 N.J. Super. 513 (App. Div. 1950). Unlike the petitioner in the Edwards case who voluntarily sought affirmative relief from the court and then imposed upon it, the case before us deals with a defendant in a proceeding essentially criminal in nature. State v. Yaccarino, 3 N.J. 291, 295 (1949). As such defendant he testified and conducted himself in respectful fashion and his denial of the offense could be true although the court as trier of the facts disbelieved him and his wife and determined that the witnesses in support of the charge against him were telling the truth. Finkel v. McCook, 247 App. Div. 57, 286 N.Y. Supp. 755, 761 (1936); affirmed, 271 N.Y. 636, 3 N.E.2d 460 (1936). In none of the cases which have been brought to our attention has conviction for an alleged contempt by a defendant under *480 comparable circumstances been sustained. Cf. People v. Tomlinson, 296 Ill. App. 609, 16 N.E.2d 940 (1938), where the Appellate Court of Illinois reversed a contempt conviction in the municipal court of a defendant charged with a motor vehicle violation whose testimony was found by the magistrate to be false on the basis of testimony to the contrary. We assume that municipal courts established pursuant to P.L. 1948, c. 264, are vested with adequate power to punish contempt committed in open court. See Rule 8:9. But cf. In re Kerrigan, 33 N.J.L. 344 (Sup. Ct. 1869); Rhinehart v. Lance, supra. Nevertheless, under P.L. 1948, c. 333, a person convicted of such contempt in a municipal court is entitled to a trial de novo in the Appellate Division which is expressly empowered to "give such judgment as it shall deem to be lawful and just under all the circumstances of the case." Zimmerman v. Zimmerman, supra. Our de novo examination of the record in the instant matter has led us to the conclusion that judgment of acquittal of contempt would be the lawful and just one under all the circumstances of the case. When the defendant was charged with disorderly conduct he defended in orderly fashion as was his natural and lawful right. He was duly tried, convicted of the ordinance violation, and sentenced, when the magistrate disbelieved him and his witness on the basis of the testimony to the contrary. Under similar circumstances our courts have ordinarily permitted the proceeding to terminate without the suggestion of contempt. We have not been advised of any reasons for departure in the instant matter and no unusual circumstance has been presented other than that the court clerk had been called by the magistrate as a witness to contradict the defendant's denial. It seems to us, however, that this circumstance might well have been considered as special cause for permitting the defendant's perjury, if any, to be dealt with in regular course by other authorities rather than by contempt proceedings before the magistrate. It must be borne in mind that, in the effectual maintenance of a strong and independent court system, the appearance as well as the actuality of fair *481 and impartial judicial administration must at all times be sought. While there undoubtedly was sufficient proof, as a matter of weight of evidence, to justify the magistrate in his belief that the defendant had committed perjury, the record before us nonetheless indicates that the defendant has, with his wife's corroboration, consistently and steadfastly maintained his denial of the ordinance violation, and perhaps it was not untruthful. We cannot bring ourselves to the belief that upon such directly controverted showing the contempt conviction of this defendant, unaccompanied by the constitutional and traditional safeguards which would surround his trial by jury for the crime of perjury or false swearing, would be lawful and just or that it would not, in its implications, serve to retard rather than advance the proper administration of justice according to law. Cf. Pound, "Justice According to Law," 13 Col. L. Rev. 696, 709 (1913). Judgment of acquittal of contempt will be entered, without costs. | Low | [
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Meta Sumit SinghalSumit Singhal loves modern architecture. He comes from a family of builders who have built more than 20 projects in the last ten years near Delhi in India. He has recently started writing about the architectural projects that catch his imagination. Restaurant ‘Het Bosch’ by DREISSEN architects in collaboration with JagerJanssen architects is located at a superb location on the Nieuwe Meer lakeside [Amsterdam, NL], a stones throw away from the Southern Amsterdam business district. The Design has to distinct faces: one towards the marina and one facing the Nieuwe Meer lake. Both faces derive their qualities and appearance from the surroundings. The marina side is rough, seeking relation with boat hangar architecture. The lake facade is more horizontal, broad and refined. Large transparent surfaces exhibit the restaurant interior. The characteristic roof intermediates between these two aspects: it morphs from 3-pithced roof to a straight edge. Exterior View - Photo by John Marchall Lewis This space saving configuration makes it possible to fit the desired program into the tight prescribed envelope. A magnificent few from the restaurant is created by lifting the built volume. This intervention gives room to a storage space for 6 sloops underneath the restaurant. By using a durable and prefab construction of laminated wooden elements, the building time is significantly reduced. | Mid | [
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Fatal traumatic air embolism following a stab wound to the chest. Traumatic air embolism is rare in Australia, but must be treated promptly if patients are to survive. A single fatal case of traumatic air embolism due to penetrating trauma is described with attention to the presenting symptoms and signs, the unsuccessful attempts at resuscitation and correlation with the post-mortem findings. Patients with penetrating chest trauma are at high risk of traumatic air embolism and positive pressure ventilation of the affected lung will cause rapid death if the condition is not immediately recognized. Early aggressive treatment is therefore necessary for survival. The diagnosis can be missed at post-mortem if not specifically sought. | High | [
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Congenital aortic regurgitation due to absent aortic cusps and high-degree mitral stenosis. Congenital absence of aortic cusps leads to severe aortic regurgitation. We present a newborn with this rare entity with extreme mitral stenosis. Hemodynamic features were those of hypoplastic left heart syndrome. Surgical management consisted of initial modified Norwood procedure followed by orthotopic heart transplantation. | High | [
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TORONTO – Ontario’s official opposition says the governors of New York, Pennsylvania and Ohio should send Premier Kathleen Wynne thank-you notes for the cheap power they’re getting from the province. Progressive Conservative Leader Patrick Brown says the province sold $9.4 million worth of excess electricity for just $144,000 on Nov. 10, which he suspects is a “record day for this government in terms of wasted power.” Ontario has “given away” $6 billion in surplus electricity since 2009 by selling it at a big loss, said Brown. “This is embarrassing for the province of Ontario,” he said. “We are hurting our businesses. We are subsidizing competitors.” Energy Minister Glenn Thibeault admits the figures showing the low price Ontario gets for surplus electricity can be shocking at first blush. “When you look at that, you do the face palm,” said Thibeault. “But what we have to do is make sure we tell the whole story, not just one day.” Ontario made $230 million in 2015 by selling excess electricity to neighbouring jurisdictions, added Thibeault. “The year before that we made $280 million, the year before that we made $300 million, which we put back to put downward pressure on rates,” he said. Brown said the energy minister was being disingenuous because he knows it cost the province $9.4 million to produce the power it sold for $144,000 on Nov. 10, and that it loses money on its electricity exports. “So it’s a massive net loss, and I use that day because it was particularly suggestive of where we are,” said Brown. “Only in Kathleen Wynne’s world is that a good deal for Ontario.” Ontario suffered through power shortages and brown outs when the Conservatives were last in power, and had to spend up to $500 million a year to buy electricity from its neighbours to keep the lights on, said Thibeault. “We’ve made the investments now to ensure that we don’t have to import electricity, that we’re an exporter,” he said. “We’ve made sure that our system is clean and reliable, and it is something that they left in tatters and we had to fix.” | Mid | [
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300 S.W.3d 14 (2009) Walter Aaron HAMILTON, Appellant, v. The STATE of Texas, Appellee. No. 04-08-00206-CR. Court of Appeals of Texas, San Antonio. August 31, 2009. Rehearing Overruled October 5, 2009. *15 Edward F. Shaughnessy, III, Attorney at Law, San Antonio, TX, for Appellant. Scott Roberts, Assistant Criminal District Attorney, San Antonio, TX, for Appellee. Sitting: REBECCA SIMMONS, Justice, STEVEN C. HILBIG, Justice, MARIALYN BARNARD, Justice. *16 OPINION Opinion by: STEVEN C. HILBIG, Justice. A jury convicted Walter Aaron Hamilton of four counts of aggravated sexual assault, one count of aggravated robbery, and one count of aggravated kidnapping. On appeal, Hamilton contends the trial court erred by: (1) denying his motion to suppress; (2) admitting the complainant's in-court identification; and (3) admitting an expert's testimony regarding DNA evidence. We affirm the trial court's judgment. MOTION TO SUPPRESS In his first issue, Hamilton contends the trial court erred in denying his motion to suppress evidence seized from his vehicle. He argues items removed from his car should not have been admitted into evidence because they were seized without a warrant during an illegal inventory search. Hamilton contends the inventory search was improper, and therefore cannot serve as an exception to the warrant requirement, because the State failed to prove it was conducted "according to standard police procedure." See Gauldin v. State, 683 S.W.2d 411, 415 (Tex.Crim.App.1984) (holding that in absence of testimony regarding "actual adherence to standard police inventory procedure," State does not sustain its burden of proof), overruled on other grounds by State v. Guzman, 959 S.W.2d 631, 633 (Tex.Crim.App.1998). He further argues that because information from the warrantless search was used in part to support the application for the subsequent search warrant, any items seized pursuant to the warrant must also be suppressed. Background At the hearing on Hamilton's motion to suppress, Bexar County Deputy Sheriff George Johnston testified he approached Hamilton's car at 12:42 p.m. in a relatively desolate area in Bexar County. Officer Johnston had seen Hamilton's car parked in the same location an hour earlier. Deputy Johnston stated he thought the driver might have fallen asleep while eating lunch. As Deputy Johnston approached Hamilton's car, he noticed the engine was on and saw Hamilton lying in the driver's seat. Hamilton appeared to be asleep. Deputy Johnston initially knocked, then "banged" on the window in an attempt to gain Hamilton's attention. When this failed, the deputy opened the vehicle and physically shook Hamilton. When Hamilton did not respond, Deputy Johnston called an ambulance. Medical personnel arrived and were unable to awaken Hamilton. They transported him to a hospital for further treatment. Deputy Johnston began to inventory the vehicle and discovered a backpack containing a package of "zip ties," a roll of duct tape, a knife, a B & B pistol, and a ski mask. After discussion with the other deputies, the inventory search was halted so a search warrant could be obtained. Based on items discovered during the inventory, the deputies were concerned items in the car were related to a sexual assault committed nearby a day earlier. Eventually, a search warrant was obtained to search the vehicle. The State presented three witnesses who testified about the sheriff department's policy for impounding and inventorying vehicles. Deputy Johnston explained that because Hamilton was transported to the hospital, the deputy was responsible for the vehicle, and it could not be left at its current location. He stated the sheriff's department has a policy that requires an inventory of any impounded vehicle to safeguard against loss or theft. Deputy *17 Johnston further testified he followed department policy by conducting the inventory, including when he looked inside the backpack. Bexar County Deputy Sheriff Detective Roger Pedraza also testified about his department's policy on inventory searches. Deputy Pedraza stated the policy had been in effect during his nineteen years of service, and explained he ordered the inventory halted when it became apparent evidence of a crime was discovered. Finally, Bexar County Deputy Sheriff Detective John Mahon stated he was the lead investigator in the sexual assault case and was made aware of the items discovered during the inventory. Deputy Mahon testified the sheriff's office has a written inventory policy and that policy or protocol was followed by Deputy Johnston when he inventoried Hamilton's vehicle after Hamilton was taken away by medical personnel. At the conclusion of the suppression hearing, the trial court denied the motion to suppress. The record does not contain any request for findings of fact or conclusions of law. Discussion A trial court's ruling on a motion to suppress is reviewed under an abuse of discretion standard. Swain v. State, 181 S.W.3d 359, 365 (Tex.Crim.App.2005); Perez v. State, 103 S.W.3d 466, 468 (Tex. App.-San Antonio 2003, no pet.). We examine the evidence in the light most favorable to the trial court's ruling and give great deference to the trial court's determinations of historical fact. Corbin v. State, 85 S.W.3d 272, 276 (Tex.Crim.App. 2002); Perez, 103 S.W.3d at 468. When no findings of fact or conclusions of law are entered, we imply findings of fact in support of the trial court's judgment when those facts are supported by the record. State v. Kelly, 204 S.W.3d 808, 818-19 (Tex.Crim.App.2006). We review the application of the law to the facts de novo. Id.; Perez, 103 S.W.3d at 468. "When vehicles are impounded, local police departments generally follow a routine practice of securing and inventorying the automobiles' contents." South Dakota v. Opperman, 428 U.S. 364, 369, 96 S.Ct. 3092, 49 L.Ed.2d 1000 (1976). "These procedures developed in response to three distinct needs: [1] the protection of the owner's property while it remains in police custody; [2] the protection [of] the police against claims or disputes over lost or stolen property; and [3] the protection of the police from potential danger." Id. (citations omitted). "A peace officer's inventory of the contents of an automobile is permissible under both the Fourth Amendment and Article I, section 9 if conducted pursuant to a lawful impoundment." Garza v. State, 137 S.W.3d 878, 882 (Tex. App.-Houston [1st Dist.] 2004, pet. ref'd); see also Opperman, 428 U.S. at 373, 96 S.Ct. 3092 (concluding inventories pursuant to standard police procedures are reasonable); Laney v. State, 117 S.W.3d 854, 858 (Tex.Crim.App.2003) (noting automobile inventory doctrine is an exception to the warrant requirement). The record supports an implied finding that the inventory of Hamilton's vehicle was conducted according to the policy of the Bexar County Sheriff's Department. Because the inventory was proper, any information obtained during the inventory that was subsequently used to obtain the search warrant was not tainted. Accordingly, any evidence found pursuant to the search warrant was admissible. We hold the trial court did not abuse its discretion in denying the motion to suppress, and we overrule Hamilton's first issue. IN-COURT IDENTIFICATION Hamilton next contends the trial court erred in refusing to suppress the complainant's *18 in-court identification. He argues the complainant, who was unable to identify Hamilton from a photographic array near the time of the offense, should not have been permitted to make an in-court identification because it was "tainted by unwarranted suggestiveness" when the complainant was allowed to observe him before jury selection. At the time the complainant saw Hamilton, he was seated at the defense table with his attorneys. Background The complainant, R.C., was a realtor. On the day of the offense, she was working at a sales trailer in a subdivision that was being developed. Around 3:45 p.m., a man came into the sales trailer, and R.C. showed him some floor plans and printed out some listings for him. At approximately 4:45 p.m., R.C. told the man she had to leave. He followed her into an office and assaulted her. R.C. described her attacker as having reddish-blond hair and green eyes. A few days after the incident, R.C. was shown a photographic lineup but was unable to identify Hamilton's picture. No other identification was attempted before trial, which took place more than two years after the crime. Apparently some time before the presentation of evidence, R.C. entered the courtroom and observed Hamilton seated at the defense table. She recognized Hamilton as her attacker. The defense filed a motion to suppress the in-court identification. At a hearing outside the presence of the jury, R.C. testified she always knew she would recognize her attacker when she actually saw him. R.C. stated she was certain Hamilton was the person who assaulted her as soon as she saw him in the courtroom because of his hair color and the shape of his body. When questioned why she did not identify Hamilton from the photo array, R.C. stated she was looking for "a kind of blond, lighter reddish hair," and none of the men in the photographs had lighter hair. She also explained none of the men appeared clean and professional as Hamilton had appeared on the day of the offense, and his photograph was a "bad" photograph. At the conclusion of the hearing, the court denied the motion to suppress. Discussion "An in-court identification is inadmissible when it has been tainted by an impermissibly suggestive pretrial [ ] identification." Loserth v. State, 963 S.W.2d 770, 771-72 (Tex.Crim.App.1998). We apply a two-step analysis when a defendant challenges an in-court identification. Id. at 772. Considering the totality of the circumstances, we determine whether the pretrial identification procedure was impermissibly suggestive. Id. If so, we then determine whether the procedure was so impermissibly suggestive as to give rise to a "very substantial likelihood of irreparable misidentification." Id. It is the defendant's burden to establish these elements by clear and convincing evidence. Loserth v. State, 985 S.W.2d 536, 543 (Tex.App.-San Antonio 1998, pet. ref'd). Reliability is the critical question in determining the admissibility of the in-court identification. Loserth, 963 S.W.2d at 772. "Testimony is reliable if the totality of the circumstance reveals no substantial likelihood of misidentification despite a suggestive pretrial procedure." Loserth, 985 S.W.2d at 543. In assessing reliability, the following five non-exclusive factors enunciated in Neil v. Biggers, 409 U.S. 188, 93 S.Ct. 375, 34 L.Ed.2d 401 (1972), should be weighed against the corrupting effect of the suggestive pretrial procedure: (1) The opportunity of the witness to view the criminal at the time of the crime; (2) the witness's degree of attention; *19 (3) the accuracy of the witness's prior description of the criminal; (4) the level of certainty demonstrated by the witness at the confrontation; and (5) the length of time between the crime and the confrontation. Loserth, 963 S.W.2d at 772 (citing Biggers, 409 U.S. at 199, 93 S.Ct. 375). The foregoing five factors are all issues of historical fact and should be considered deferentially in the light most favorable to the trial court's ruling. Id. at 773. We apply a de novo review in weighing the factors against the corrupting effect of the suggestive pretrial procedure, and we need not assign the same weight or significance to the historical facts as the trial court in deciding the ultimate question of reliability. Id. at 773-74. Applying the Biggers factors, we conclude the trial court did not abuse its discretion in denying the motion to suppress R.C.'s in-court identification of Hamilton. R.C. had an extensive opportunity to view Hamilton during the hour he was in the sales trailer with her discussing houses; her degree of attention was high given the setting and her efforts to sell Hamilton a house; her initial description of Hamilton as having reddish-blond hair and green eyes was fairly accurate; and her explanation for her failure to identify Hamilton from the photographic line-up was plausible. R.C.'s level of certainty was high, and she testified that she always knew that she would be able to identify Hamilton when she saw him. Although the time between the crime and the trial was two years and two months, after weighing all the Biggers factors in the light most favorable to the trial court's ruling, we conclude the totality of the circumstances reveals no substantial likelihood of misidentification despite R.C. viewing Hamilton for a brief period in the courtroom before the trial commenced. Hamilton's second issue is overruled. ADMISSIBILITY OF DNA EXPERT TESTIMONY In his final issue, Hamilton asserts the trial court violated his confrontation rights when it admitted the testimony of Garon Foster regarding Hamilton's DNA. Foster testified based on DNA tests that Hamilton could not be excluded as the donor of the spermatozoa identified on the vaginal and labial swabs taken from R.C. or of the biological material on the breast swabs taken from R.C. Although Foster expressed an opinion based on his evaluation of the data, he also testified over objection to the results of the DNA analysis conducted by Erica Graham, another scientist whose work was supervised by Foster. Hamilton also contends his confrontation rights were violated because Foster, in making his conclusions, relied on the work of Graham and her processing of the DNA material. Background Foster testified he is a forensic scientist supervisor at the Bexar County Criminal Investigation Laboratory, and was the supervisor when Erica Graham performed the serology and DNA analysis on Hamilton's case. At the time of Hamilton's trial, Graham was no longer employed with the Bexar County lab. Graham screened the physical evidence in Hamilton's case for biological material and developed a DNA profile for R.C., Hamilton, and the biological material from the physical evidence. Foster stated he had access to Graham's notes and those notes indicated Graham followed the appropriate protocol and methods to develop the DNA profiles. Foster described for the jury the various steps involved in the creation of the DNA profiles, but stated concluding whether a person's DNA is a "match" with an unknown substance is accomplished by the *20 scientist comparing graphs of each DNA profile. He also testified that as part of the lab's accreditation requirements, two scientists must independently review the data and come to the same conclusion before issuing the report. Foster testified he originally reviewed Graham's work before the report in Hamilton's case was issued, and he agreed with its results. Foster also reviewed his analysis a second time in preparation for trial. Foster testified Graham's reports reflect Hamilton's DNA was not excluded as the donor of the spermatozoa identified on the vaginal and labial swabs taken from R.C. or of the biological material on the breast swabs taken from R.C. Foster further testified the odds of another person having the same DNA profile as Hamilton is approximately one in seven quadrillion. Foster stated he conducted his own review of the data and agreed with the results reported by Graham. Discussion A defendant's right to confrontation under the Sixth Amendment is violated when a witness is permitted to relate out-of-court "testimonial" hearsay statements unless the declarant is unavailable and the defendant had a prior opportunity to cross-examine the declarant. Crawford v. Washington, 541 U.S. 36, 59, 124 S.Ct. 1354, 158 L.Ed.2d 177 (2004); see De La Paz v. State, 273 S.W.3d 671, 680 (Tex. Crim.App.2008). A statement is testimonial if it was made "under circumstances which would lead an objective witness reasonably to believe that the statement would be available for use at a later trial." Crawford, 541 U.S. at 52, 124 S.Ct. 1354. Whether a statement is testimonial is a question of law. Wall v. State, 184 S.W.3d 730, 742 (Tex.Crim.App.2006). Once an objection is made based on Crawford, the proponent of the statement must demonstrate its admissibility. De La Paz, 273 S.W.3d at 680-81. We review de novo the trial court's ruling admitting evidence over a confrontation objection. Wall, 184 S.W.3d at 742. Hamilton asserts that reports of DNA analysis are testimonial. He primarily relies on a case from this court holding a trial court erred in admitting a latent print report prepared by a person who did not testify in court. See Acevedo v. State, 255 S.W.3d 162, 173 (Tex.App.-San Antonio 2008, pet. ref'd). The State counters that Crawford is not implicated because Graham's report was neither offered nor admitted into evidence, and an expert may offer his own opinion based on another person's report even though the report itself may be inadmissible. See Martinez v. State, 22 S.W.3d 504, 508 (Tex.Crim. App.2000). However, Martinez was not decided on confrontation grounds, but on whether an expert may opine before the jury when his opinion is based in part on "hearsay" documents. Furthermore, in Martinez, the court of criminal appeals noted neither the non-testifying expert's data nor his opinion was ever placed before the jury. Here, in contrast, most of the State's evidence centered on the actions and conclusions of Graham, the non-testifying expert. Because the State placed before the jury the work and the conclusions of the non-testifying expert, we must determine whether DNA reports prepared by a forensic scientist employed by Bexar County are testimonial. The State urges this court to adopt the reasoning expressed in Campos v. State, 256 S.W.3d 757 (Tex.App.-Houston [14th Dist.] 2008, pet. ref'd). In that case the Fourteenth Court of Appeals held a DNA report was not testimonial because, in part, the report was neutral, not accusatory, and had the potential to either support a conviction or exonerate the defendant. Id. at 765. However, we are *21 cognizant of the United State's Supreme Court's recent decision in Melendez-Diaz v. Massachusetts, ___ U.S. ___, 129 S.Ct. 2527, 174 L.Ed.2d 314 (2009), which was rendered after the briefs in this matter were filed. In Melendez-Diaz, the court ruled that reports produced by state chemists regarding the results of their analysis of suspected drugs were testimonial. 129 S.Ct. at 2532. In its analysis, the Court rejected the reasoning expressed in Campos that reports of "neutral, scientific testing" somehow fall outside the protections of the Confrontation Clause. Id. at 2536-38. In light of Melendez-Diaz, we hold Graham's reports of her DNA analysis were testimonial. The trial court therefore erred in allowing Foster to testify as to Graham's findings. Hamilton also complains that his right of confrontation was violated when Foster testified as to the procedures and protocols employed by Graham to produce the DNA profiles Foster used to reach his opinion. We disagree. In his testimony, Foster explained the procedures used to create DNA profiles. He essentially told the jury that a series of scientific instruments are used to "crack open" the DNA material, replicate the material, and then separate the DNA according to its size. Foster stated a machine he described as a "genetic analyzer" is used to create a printout with a series of lines or graphs. A scientist will compare the printout produced by the unknown DNA sample with the one produced by the known DNA sample to determine if there is a "match." When a second review of the lab work is conducted as required by the lab protocols and accreditation standards, it is accomplished by looking at the printout, either on paper or on the computer. The precise question here whether an expert witness who offers his opinion based in part on lab work performed by another violates the Confrontation Clause does not appear to be addressed in Melendez-Diaz. However, the Supreme Court noted: [W]e do not hold, and it is not the case, that anyone whose testimony may be relevant in establishing the chain of custody, authenticity of the sample, or accuracy of the testing device, must appear in person as part of the prosecution's case. While the dissent is correct that "[i]t is the obligation of the prosecution to establish the chain of custody," post, at 2546, this does not mean that everyone who laid hands on the evidence must be called. As stated in the dissent's own quotation, ibid., from United States v. Lott, 854 F.2d 244, 250 (C.A.7 1988), "gaps in the chain [of custody] normally go to the weight of the evidence rather than its admissibility." It is up to the prosecution to decide what steps in the chain of custody are so crucial as to require evidence; but what testimony is introduced must (if the defendant objects) be introduced live. Additionally, documents prepared in the regular course of equipment maintenance may well qualify as nontestimonial records. Id. at 2532 n. 1. This passage indicates the Supreme Court would hold records or information created by personnel that play a role in the analysis that leads to the expert's opinion are not testimonial. See id. We are also persuaded by the court's reasoning in United States v. Washington, 498 F.3d 225 (4th Cir.2007), cert. denied, ___ U.S. ___, 129 S.Ct. 2856, 174 L.Ed.2d 600 (2009). In Washington, the court considered this very issue. In that case, the court held an expert witness could express his opinion, without violating the Confrontation Clause, as to whether alcohol and drugs were present in Washington's blood when he was arrested and charged with operating a motor vehicle under the influence of drugs or alcohol. Id. at 231. The court reasoned the raw data produced by the scientific instruments *22 were not testimonial statements, as the data were in essence "statements" by the machine rather than the operator of the instrument. Id. The Confrontation Clause implicates statements made by persons, not machines. Id.; see Blaylock v. State, 259 S.W.3d 202, 205-08 (Tex.App.-Texarkana 2008, pet. ref'd) (holding Confrontation Clause not violated by testimony of chemist that substance was cocaine when opinion based on data and notes of analysis performed by different chemist), cert. denied, ___ U.S. ___, 129 S.Ct. 2861, 174 L.Ed.2d 601 (2009). Accordingly, we hold Foster's opinion, based on data generated by scientific instruments operated by other scientists, did not violate the Confrontation Clause. Harm Analysis The trial court erred in allowing Foster to testify as to Graham's findings. We must determine whether the error was harmful, requiring reversal. Federal constitutional error is harmless and not reversible if it appears "beyond a reasonable doubt that the error complained of did not contribute to the verdict obtained." Chapman v. California, 386 U.S. 18, 24, 87 S.Ct. 824, 17 L.Ed.2d 705 (1967); Clay v. State, 240 S.W.3d 895, 904 (Tex.Crim.App. 2007). "Under Chapman, a federal constitutional error `did not contribute to the verdict obtained' if the verdict `would have been the same absent the error.'" Clay, 240 S.W.3d at 904 (quoting Neder v. United States, 527 U.S. 1, 15-18, 119 S.Ct. 1827, 144 L.Ed.2d 35 (1999)). The Chapman test is codified in rule 44.2(a) of the Texas Rules of Appellate Procedure. Clay, 240 S.W.3d at 904. To assess the likelihood that, absent the trial court's error in admitting the evidence, the jury's verdict would have been the same, we must examine the entire record. Id. Among the factors to consider are: (1) the importance of the evidence to the State's case; (2) whether the evidence was cumulative of other evidence; (3) the presence or absence of other evidence corroborating or contradicting the evidence on material points; and (4) the overall strength of the State's case. Id. We must also consider any other factor in the record that may shed light on the probable impact of the trial court's error on the minds of average jurors. Id. Applying the relevant factors, we conclude Hamilton was not harmed by the erroneous admission of Foster's testimony about Graham's findings. Based on the victim's identification of Hamilton as her attacker, the importance of the DNA evidence was moderate. Evidence of Graham's report was cumulative because Foster properly testified to his opinion that Hamilton was not excluded as the contributor of the DNA found on evidence samples obtained from the victim. No other evidence contradicted the evidence of Graham's analysis, and a great amount of evidence supported it the victim identified Hamilton as her attacker based on the hour she spent with him prior to the assault, the victim's credit cards were found in the pocket of Hamilton's jacket, Foster's testimony as to his independent opinion that Hamilton was not excluded as a donor of the DNA, and Foster's testimony that the odds of a "random probability match" was one in seven quadrillion. The State's case against Hamilton was strong without the evidence of Graham's analysis. Accordingly, we conclude beyond a reasonable doubt the erroneous evidence did not contribute to his conviction, and we overrule Hamilton's third issue. CONCLUSION Having overruled Hamilton's issues, we affirm the trial court's judgment. | Mid | [
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I've made a living here (theoretically of course) of posting various musings about how my sports fandom (most notably the Reds) affects every waking hour of my being. I've posted about schedules on the wall, planning life events around games, etc.... I've done this to the amusement of some and the shock and awe of others. So, I thought I'd give you an update..... My basketball team, the Cavs, finally played well into May. They gave me a great run, a wonderful distraction, and a glorious month of exciting playoff basketball. The future is bright, but there is always some sadness when the season ends. During the Cavs run in April and May, I promised my wife that I would not "add" the Reds to my docket until the Cavs season officially came to an end. That doesn't mean I haven't been following the Reds, it just means I've been doing it on the DL. I am not paying for MLB Extra Innings for the first time since 1998, but I did get XM, and I already have plans to watch several games on MLB.TV. Actually, since the season started, I've probably been what a "normal" fan should be-- I've watched when convinient, caught innings here and there on the radio, spent some time following the gamecasts and game threads, and stayed abreast on the daily comings and goings of my team. All along I figured the Cavs season would end and by that time the Reds would already be out of contention. I thought I could spend my summer simply relaxing by the pool and waiting for football season. I didn't think the Reds would give me any reason to care. Well, the Cacs season ended yesterday, and here the Reds sit alone atop the wild card standings. Of course, they've played poorly enough over the past couple of weeks to make it clear that they probably won't stay there very long, but they are there nontheless. And therefore, I am trapped. Seeing I am a year-round sports nut, my wife and I agreed to a "three games a week" rule. I am allowed to watch (or listen) to three games a week from start to finish no matter what. On the other days, I've got to pick my spots to check scores, etc... one good trick is to rush off to the computer every time my wife takes a shower, brushes her teeth, etc... but I digress.. My point here (not that there really is one) is that less than 24 hours following the end of the Cavs season, I am full on board with the Reds once again. I already have a schedule printed up on my fridge detailing each of my three games per week that I've chosen and how I will be following it (XM, MLBTV, or regular TV). It's a flat-out sickness I tell you. If the Reds were 15-30 right now, I'd know not to bother-- I'd know to just chill around Redszone and soak up a few baseball rays w/o investing my sanity into the mix. But no, they had to go out and play awesome for the first month, muddying any rational thoughts in my head. All I know is that it's May 22nd, but it feels like opening day to me :) We've been struggling lately and the back to back gut-wrenching losses in Detroit don't help. We've got the Brewers and D'backs....dare I say......this is a VERY IMPORTANT six game stretch. I'm Back Baby!! :) 05-22-2006, 04:21 PM redsrule2500 Re: Uh-Oh, my sanity now belongs to the Reds.. Reds > Cavs 05-22-2006, 04:52 PM Unassisted Re: Uh-Oh, my sanity now belongs to the Reds.. On the plus side of the ledger, between the two Ohio teams playing in Detroit yesterday, the Reds' loss was less ugly than the Cavs' loss. ;) The Cavs had a nice run. I was hoping they'd be the team to keep the Pistons from a repeat visit to the Finals. I don't like having to rely on Shaq and Pat Riley for that now. | Mid | [
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Drop Down Menus I have drop down menus that are linked to IF statements. These menus have five choices, each linked to a different IF statement. Once the drop down is used, the choice stays visible and the appropriate cell is filled by the IF statement. Is it possible to have a blank as a choice in these menus so that the appropriate cell stays blank? The IF statements that I had previously used were incorrect and were rewritten. The prior IF statements allowed me to <delete> a drop down menu category which caused the corresponding linked cell to become blank. I need this feature as all of the drop down menus within the column are not always used. While I was succesfull creating the drop down menu the first time using the old IF statements, this time I couldnt get it correct. I tried to create a blank choice in the down drop menu by using Data>Validation>List and then enter the categories followed by a comma, but that didn't work. When I try to <delete> a drop down category using the new IF statement which is =if(c11=tally!$g$35,Vlookup(BB11,Tally!$F35:$V47,5,0),..., I get "#N/A". It would seem to me that the reference for having a blank cell as an option in the down drop menu should be included in the IF statement but I don't know where. You can add a blank choice by entering the final comma and then adding a space. BTW...you can also use a List from a range of cells instead of entering the list in the Data Validation dialog box. That way you could change the list and not have to update the Data Validation list for each cell that uses it. Adding a blank cell anywhere in that list will put a blank cell in your drop down. Add this to your mindset as you are creating a workbook: If you find yourself doing the same thing over and over again in a number of cells, then Excel probably has a more efficient way of doing it. e.g. referencing a list in a single range of cells instead of typing that data over and over again in multiple locations. When VLOOKUP doesn't find what it is looking for, it returns a #NA error. So we either need to tell the VLOOKUP function what to do with a blank cell or have the formula deal with the blank cell before it even gets to the VLOOKUP portion. Add the bold portion to the front of your formula: =IF(BB11="",0,IF(C11=Tally!$G$35,VLOOKUP(BB11...etc Don't forget to add the extra parenthesis at the end of the formula to close off the new one you added at the front. The addition to the IF statements worked as needed. I then added the blank to the drop down menu without any difficulty; however, when I tried to use a range of cells from a different worksheet in the Data Validation dialog box, I was unsuccessful and got the error message "You may not use references to other worksheets or workbooks for Data Validation criteria." Is it a good practice, therefore, to include the necessary range of cells on the target spreadsheet in a location that will not be printed? The information on Computing.Net is the opinions of its users. Such opinions may not be accurate and they are to be used at your own risk. Computing.Net cannot verify the validity of the statements made on this site. Computing.Net and Purch hereby disclaim all responsibility and liability for the content of Computing.Net and its accuracy. | Mid | [
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490 So.2d 140 (1986) Daniel SULLIVAN, et al., Appellants/Cross-Appellees, v. NORTHWEST FLORIDA WATER MANAGEMENT DISTRICT, Appellee/Cross-Appellant, and Department of Environmental Regulation, Appellee. No. BI-352. District Court of Appeal of Florida, First District. June 10, 1986. Carroll L. McCauley and Alvin L. Peters, of Carroll L. McCauley, P.A., Panama City, for appellants/cross-appellees. Douglas L. Stowell and Gary J. Anton, of Mang & Stowell, P.A., Tallahassee for appellee/cross-appellant Northwest Florida Water Management Dist. Douglas M. Wyckoff, Asst. Gen. Counsel of State of Florida Dept. of Environmental Regulation, Tallahassee, for appellee Dept. of Environmental Regulation. FRANK, Associate Judge. The genesis of this proceeding begins with Chapter 84-380, Laws of Florida, a 1984 legislative act transferring control of the Dead Lakes Dam in Gulf County to the appellee/cross-appellant Northwest Florida Water Management District (Northwest Florida) "for the sole purpose of removal of such dam." In compliance with the legislature's directive, Northwest Florida applied to the appellee Department of Environmental Regulation (DER) for the necessary permits. DER thereupon declared its intent to issue the destruction permits to "return the lake to its natural regime of river levels, habitat types, biological resources and navigational access." Following the receipt of DER's notice of intent to issue a permit to *141 Northwest Florida for the destruction of the dam, the appellants, owners of property adjacent to or near the lake, unsuccessfully petitioned DER to conduct a hearing pursuant to section 120.57(1). They alleged in their petitions that removal of the dam would cause the loss of their access to navigable waters and would irreparably diminish the recreational and aesthetic value of their contiguous property. They also disputed DER's conclusion that removal of the dam would benefit fish, wildlife, and the natural habitat. Our disposition of this matter encompasses the issues presented on appeal and Northwest Florida's cross appeal attacking DER's rejection of the hearing officer's mootness finding; we reverse and remand. A hearing officer appointed to conduct a hearing summarily dismissed the appellants' petitions after considering their responses to an interrogatory propounded by Northwest Florida. In answer to a request that they detail how their substantial interests would be affected by the proposed agency action, the appellants stated that: All of the petitioners have already suffered loss of their access to navigable water since the gates of Dead Lakes dam were partially opened [in Spring, 1980]. All of the petitioners in varying degrees, now have no access to navigable water... . Petitioners are unable to fish, boat, or ski from their "waterfront" property without traversing several yards of mud. Since most of the petitioners purchased their property for weekend retreats or other recreational purposes, said property is no longer usable for the purpose intended by the property owners. Subsequently, Northwest Florida filed supplemental motions to dismiss contending before the hearing officer that affidavits filed by the appellants rendered their claims moot; he concluded the appellants had conceded that the alleged threatened harm from permitting the dam's removal had already occurred. A further ground for dismissal urged by Northwest Florida was that the appellants' claimed diminution of property value was not within a zone of interest protected by sections 253.123 and 403.087, Florida Statutes. The appellants replied that section 403.91, et seq., Florida Statutes, had replaced section 253.123 effective October 1, 1984, and section 403.918(2)(a)1 prescribes that an adverse effect on the property of others is relevant in determining whether a project is in the public interest. The appellants further challenged the mootness notion asserting that even though the lake's present water conditions were bad, they would become worse and irremediable upon removal of the dam. The hearing officer concluded that the appellants' alleged injury diminution of the aesthetic and economic value of their property was outside the zone of interest protected by sections 253.123 and 403.087, Florida Statutes. He found also that the appellants were then suffering the harm they sought to prevent and consequently their petition was moot. When the hearing officer's recommended order reached the secretary of DER, she rejected the mootness conclusion but declined to remand to the hearing officer for the reason that the appellants lacked standing: "it is clear from their response to the Department's interrogatories that the removal of the dam will not affect the petitioners' substantial interest because they do not presently have access to navigable waters." We find summary dismissal of the appellants' petitions improper on two grounds: DER incorrectly analyzed the question of whether the appellants had standing to contest issuance of the permit for destruction of the dam; and in so doing, it erroneously denied the appellants the benefit of an evidentiary hearing from which factual issues could be resolved. The secretary's final action rejected the appellants' claims of standing upon a finding that they had not suffered injury in fact; she, therefore, did not pass upon the hearing officer's view that the appellants' alleged injury was not within a zone of interest the proceeding was designed to *142 protect. Thus, the final agency order is not responsive to the question of which statute is to define the scope of those interests. It is our judgment that the repeal of section 253.123 and its replacement by section 403.91 broadened the standing test. This court, adopting the principles expressed in the Second District's opinion in Agrico Chemical Co. v. Department of Environmental Regulation, 406 So.2d 478 (Fla. 2d DCA 1981), has said that a petitioner enjoys standing to seek a section 120.57 hearing (1) if confronted with injury in fact of sufficient immediacy and (2) the injury is of the type or nature that the particular proceeding is designed to protect. North Ridge General Hospital, Inc. v. NME Hospitals, Inc., 478 So.2d 1138 (Fla. 1st DCA 1985). Essentially, however, DER found the appellants lacked standing because, given their current degree of impaired accessibility to navigable waters, they failed to allege a sufficient injury in fact. That result ignores the potential for and the quantum of further harm to the appellants which could flow from permanent removal of the dam. It is obvious that whether such exposure exists, and whether the appellants will actually suffer the alleged injury, cannot be resolved without a factfinding proceeding. Hence, under the authority of section 120.68(6), Florida Statutes, we remand for such a hearing. Garrido v. State Department of Health, 386 So.2d 811 (Fla. 1st DCA 1980); Kuster Enterprises, Inc. v. State Department of Transportation, 347 So.2d 1092 (Fla. 1st DCA 1977). On remand, the hearing officer, and ultimately DER, in the event an inquiry into the zone of interest is deemed necessary upon consideration of the appellants asserted injury in fact, are to assess the appellants' claims in the context of the appropriate statutory scheme. Accordingly, we reverse and remand for proceedings consistent with this opinion. BOOTH, C.J., and SMITH, J., concur. | Mid | [
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--- abstract: 'Force-constant and positional disorder have been introduced into diamond lattice models in an attempt to mimic the vibrational properties of a realistic amorphous silicon model. Neither type of disorder is sufficient on its own to mimic the realistic model. By comparing the spectral densities of these models, it is shown that a combination of both disorders is a better representation, but still not completely satisfactory. Topological disorder in these models was investigated by renumbering the atoms and examining the dynamical matrix graphically. The dynamical matrix of the realistic model is similar to that of a positionally-disordered lattice model, implying that the short-range order in both systems is similar.' address: 'Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK' author: - 'J. K. Christie[^1]' - 'S. N. Taraskin' - 'S. R. Elliott' title: 'Atomic vibrations in disordered systems: Comparison of disordered diamond lattices and a realistic amorphous silicon model' --- Introduction ============ The physics of atomic vibrations in perfect crystals is well understood [@Maradudin; @et; @al; @Dove]. In the presence of disorder (e.g. noncrystallinity), many extra phenomena are observed: for example, localization [@John; @et; @al], the boson peak (extra modes at low frequencies) [@Taraskin; @et; @al], and anomalies in the specific heat [@Feldman; @et; @al] and thermal conductivity [@Pohl; @et; @al]. The microscopic origin of these and other, similar, phenomena have been difficult to deduce. In particular, it would be helpful to know the contributions due to different types of disorder. In this paper, we consider the effects of three types of disorder: [*force-constant disorder*]{}, in which the strengths of the springs between the atoms are disordered, [*positional disorder*]{}, in which the atomic positions are disordered, and [*topological disorder*]{}, in which the network of bonds is disordered. We compare the behaviour of models with force-constant and positional disorders (separately and in combination) to those of a realistic atomic model. A further aim is to see if it is possible to mimic the behaviour of amorphous systems with an appropriately-disordered crystal. Force-constant and positional disorder ====================================== In this paper, we study 3D diamond-cubic crystal lattices, in which all atoms are connected by springs, and have the same mass. We assume that the displacements from equilibrium are small, and use the [*harmonic approximation*]{}. Hence, we can treat the system classically [@Maradudin; @et; @al], and describe the vibrations by a Hermitian dynamical matrix $\hat{\bf{D}}$. The problem can then be treated in the Hamiltonian formalism [@Elliott; @et; @al; @Ehrenreich; @and; @Schwarts; @Economou], with energy $\epsilon=\omega^{2}$, the squared vibrational frequency. We study the effect of disorder on the [*spectral density*]{}: $\hat{{\bf A}}(\epsilon)=\left\langle\delta(\epsilon-\hat{{\bf D}}) \right\rangle$, where $\left\langle\ldots\right\rangle$ represents configurational averaging. We can represent the spectral-density operator in the crystalline basis $|\bf{k},\beta\rangle$, where $\bf{k}$ is the wavevector of a plane wave, and $\beta$ is the polarization [@Taraskin; @and; @Elliott]. In this case, the spectral density $A_{\bf{k}\beta}(\epsilon)$ is: $$A_{\bf{k}\beta}(\epsilon)=\left\langle\sum_{d}|\left\langle d|\bf{k}, \beta\right\rangle|^{2}\delta(\epsilon-\epsilon_{d})\right\rangle,$$ where $|\left\langle d|\bf{k},\beta\right\rangle|^{2}$ are the weights of the (disordered) eigenstate $|d\rangle$ (with energy $\epsilon_{d}$) in the crystalline eigenstate $|\bf{k},\beta\rangle$. Large ($\sim 10^{5}$ atoms) diamond-cubic crystals have been simulated, with nearest-neighbour spring constant $\kappa_{1}$ and next-nearest-neighbour spring constant $\kappa_{2}$. A ratio of $\kappa_{1}/\kappa_{2}=8$ was chosen, as this gave a vibrational density of states (VDOS) most like that of a crystal with the more realistic modified Stillinger-Weber (mSW) potential [@SW; @mSW]. Force-constant disorder was added by randomly taking the spring constants from a uniform distribution of half width $\Delta$, centred on the crystalline spring-constant value. The width $\Delta$ is expressed as a fraction of the crystalline spring-constant value $\kappa$, and this fraction is the same for both spring constants. To avoid mechanical instabilities, widths were limited such that all force constants were positive, i.e. $\Delta\leq\kappa$. Positional disorder was introduced by randomly shifting all atoms by distances, chosen from Gaussian distributions centred on zero with half width $\sigma$, independently in the $x$-, $y$- and $z$-directions. Figure \[fig:1\] shows the dispersion relation for a positionally-disordered diamond lattice with $\sigma=0.1r_{1}$, where $r_{1}$ is the nearest-neighbour distance. At each value of $k$, the spectral density has been orientationally averaged, and the positions of the peaks are shown in the figure. The dispersion relation shows many of the expected features: three acoustic branches are observed, of which one is longitudinal, and two are transverse. Mixing between the polarisations is seen: the longitudinal spectral density picks up the peaks due to the transverse acoustic (TA) branches. The optic modes are less clearly defined; the peaks due to these modes were broadened considerably by even small amounts of disorder. Nevertheless, the presence of optic branches at high energy in both the transverse and longitudinal spectral densities is observed. {height="3.25in"} \[fig:1\] The effect of a low degree of positional disorder on the spectral density is qualitatively very similar to the effect of small force-constant disorder [@TLNE]; the peak shifts in position, and broadens. When compared to the spectral density of a realistic 4096-atom model of amorphous silicon, generated with a modified WWW procedure [@WWW; @Barkema; @and; @Mousseau] and relaxed under the mSW potential, it was observed that neither type of disorder was adequate on its own to reproduce the features of the amorphous model’s spectral density. A combination of these two types of disorder is better able to reproduce the spectral density, as seen in Figure \[fig:2\]. The disordered lattice models are able to mimic the main features of the amorphous model, with peak positions and shapes at least roughly correct, but they often have more peaks (particularly at high $k$) than the rather smoother amorphous spectral densities. This is due to the orientational averaging - each of these peaks comes from a different orientation of the $\bf{k}$-vector. The fact that these peaks are at different energies suggests that, despite the added disorder, the lattice models are still anisotropic, whereas the amorphous model is isotropic (since the multiple peaks are absent). This implies that a form of disorder needs to be considered that will render the lattice models less anisotropic. {width="4.0in"} \[fig:2\] Topological disorder ==================== Another type of disorder is topological disorder, in which the bond network is disordered such that the ring-size distribution is no longer crystalline. Topological disorder was examined by studying the dynamical matrix. If two atoms $i$ and $j$ interact, then the dynamical matrix elements representing that interaction will be non-zero. We make use of a simple atom renumbering scheme and show the dynamical matrix graphically, to compare the topological disorder present in the realistic model and in positionally-disordered models. Atoms were renumbered by first dividing the models into small cubes, such that the average occupation was one atom per small cube. The models are cubic, with side $L$. The origin was taken at one corner of the model (say $x,y,z=0$), and atoms were numbered by moving up through all the small cubes above it in the positive $z$-direction, numbering the atoms in order of the $z$-coordinate of their position. Once the $z=L$ face of the model was reached, the scheme returned to the $z=0$ face, and moved along one small cube distance in the $y$-direction. As before, atoms were numbered by moving up in the $z$-direction. This process was repeated until the $y=L$ face was reached, when the scheme returned to $y,z=0$ and shifted along one small cube in the $x$-direction, and then repeated the numbering above, until all atoms were numbered. The atom number now corresponds (in some way) to its position. -------------------------------------------- -------------------------------------------- -------------------------------------------- \(a) {width="1.5in"} \(b) {width="1.5in"} \(c) {width="1.5in"} -------------------------------------------- -------------------------------------------- -------------------------------------------- \[fig:3\] In this renumbering scheme, the dynamical matrix of a crystalline diamond lattice with nearest- and next-nearest neighbour interactions is shown in Fig. \[fig:3\]a. The effect of introducing positional disorder ($\sigma=0.6r_{1}$), into the diamond lattice, is shown in Fig. \[fig:3\]b. The realistic model of amorphous silicon, with the same renumbering scheme, is shown in Fig. \[fig:3\]c. Remarkably, the dynamical matrix for the realistic model (Fig. \[fig:3\]c) looks very similar to that of the positionally-disordered crystal (Fig. \[fig:3\]b). We interpret this as implying that the short-range structural order, responsible for the vibrational behaviour, in the topologically-disordered amorphous model is very close to that in a positionally-disordered crystal. Conclusion ========== Examining the spectral densities of diamond lattice models with added force-constant and positional disorders shows that these disorders are insufficient (either by themselves or in combination) to mimic completely the vibrational behaviour of a realistic model of amorphous silicon. Representing the neighbour list graphically shows that the short-range order, responsible for the vibrational behaviour, in a positionally-disordered diamond lattice is similar to that of a realistic model, and this is an avenue for further research. JKC is grateful to the Engineering and Physical Sciences Research Council for financial support. We thank G. T. Barkema for providing us with the atomic co-ordinates of the amorphous model used. [10]{} A. A. Maradudin, E. W. Montroll, G. Weiss and I. P. Ipatova, Theory of Lattice Dynamics in the Harmonic Approximation (Academic Press, New York, 1971). M. T. Dove, Introduction to Lattice Dynamics (Cambridge University Press, 1993). S. John, H. Sompolinsky and M. J. Stephens, Phys. Rev. B [**27**]{}, 5592 (1983). S. N. Taraskin, Y. L. Loh, G. Natarajan and S. R. Elliott, Phys. Rev. Lett. [**86**]{}, 1255 (2001). J. L. Feldman, P. B. Allen and S. R. Bickham, Phys. Rev. B [**59**]{}, 3351 (1999). R. O. Pohl, X. Liu and E. Thompson, Rev. Mod.Phys. [**74**]{}, 991 (2002). R. J. Elliott, J. A. Krumhansl and P. L. Leath, Rev. Mod. Phys. [**46**]{}, 465 (1974). H. Ehrenreich and L. Schwarts, Solid State Physics [**31**]{}, 149 (1976). E. N. Economou, Green’s Functions in Quantum Physics, (Springer, Berlin, 1983), 2nd edition. S. N. Taraskin and S. R. Elliott, J. Phys.: Condens. Matter [**14**]{}, 3143 (2002). F. H. Stillinger and T. A. Weber, Phys. Rev. B [**31**]{}, 5262 (1985). R. L. C. Vink, G. T. Barkema, N. Mousseau and W. F.van der Weg, J. Non-Cryst. Solids [**282**]{}, 248 (2001) S. N. Taraskin, J. J. Ludlam, G. Natarajan and S. R.Elliott, Philos. Mag. B [**82**]{}, 197 (2002). F. Wooten, K. Winer and D. Weaire, Phys. Rev. Lett. [**54**]{}, 1392 (1985). G. T. Barkema and N. Mousseau, Phys.Rev. B [**62**]{}, 4985 (2000). [^1]: Corresponding author: e-mail: [[email protected]]{} | Mid | [
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Q: The [jest] tag is used for two different projects There are currently about 80 questions labeled with jest. Of these, about 70% are questions about searchbox-io/Jest, an Elasticsearch Java Rest Client. The rest are about facebook/jest, a JavaScript Unit Testing framework. The tag wiki excerpt only talks about the Elasticsearch Java Rest Client. What is the best course of action to resolve this ambiguity? A: April 2019 update: Facebook's Jest became popular and is basically known by many as just Jest, while searchbox.io's Jest did not grow as fast. As a conscequence, there are now: 5474 jestjs questions 955 jest questions 69 jest java questions which means that: Around 14% of questions about jestjs are incorrectly tagged jest Around only 7% of jest are actually about searchbox.io's Jest! This is ugly, but there are a few things we can do: Edit jest to jestjs: 10s per edit + 5 users with rep > 2k = only half an hour to clean the whole mess. I've already started it using following edit summary: Corrected a frequent tag misuse: 'jest' (Java Elasticsearch client) replaced by 'jestjs' (JS testing framework) Emphasize the this-is-not-jestjs warning in the tag wiki excerpt of jest so as to prevent future mistakes. A proposition: DO NOT USE FOR THE JAVASCRIPT TESTING FRAMEWORK, USE [jestjs] INSTEAD. Jest is a Java HTTP Rest client for ElasticSearch.. This is not ideal as it would only address part of the mistakes, and tag disclaimers have been criticized. | Mid | [
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Klopp Hails ‘Fantastic Boy’ Shaqiri The path players take to reach their career pinnacle is frequently unpredictable. Some climb the ranks at their childhood club; others move along the pipeline from club to more illustrious club until they find their eventual summit; and others still experience myriad ups and downs, as their talent development fails to mirror their expected path. Xherdan Shaqiri definitely belongs in the latter category. When the Swiss prodigy made the move from Bayern to Inter to Stoke over the course of a mere six months, many raised an eyebrow at the career trajectory of the Powercube. When he failed to make much of an impact with the Potters in his first year, the assumption was that the once so bright starlet was about to quietly burn out in the English midlands. A relegation and associated £13m release clause later, though, Shaqiri found himself at Anfield, a-probably-but-not-officially replacement for Nabil Fekir, whose £50m transfer fell through on account of the Frenchman’s stupid, fragile knees. Questions about his weight and attitude were quickly brushed aside by the power of Jürgen Klopp’s approval, as well as an outstanding overhead kick to put Manchester United to the sword in pre-season. The 27-year old was given his debut in the opening match of the season, and to date, has appeared in 11 of the club’s 17 matches. Has Die Kraftwürfel lived up to expectations? “Yeah, or even more. What can I say?” Klopp told Liverpool’s official site. “He’s just a fantastic boy on top, that’s really good, and he knows that he has so much potential still to improve. “But of course he’s the guy for decisive moments, that’s how it is, and we have to make sure that it stays like this. Another really good performance and a fantastic goal on top, so it’s really cool.” Indeed, two goals and three assists in only 400-odd minutes is excellent return on a squad player bought cheaply from a Championship side. The fact that the former Basel wonderkid entertains with his energy on the ball, odd-fitting jackets, goblin faces, penchant for hanging onto Klopp hugs just a little longer than others, and overall thiccness is just a delightful bonus on top of the production. Whether Shaqiri can consistently force his way into the starting XI when Naby Keïta, Adam Lallana and James Milner are all fit and firing remains to be seen, but the early returns on Liverpool’s bargain gamble are looking overwhelmingly positive. | High | [
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Distribution of bound hydroxycinnamic acids and their glycosyl esters in barley (Hordeum vulgare L.) air-classified flour: comparative study between reversed phase-high performance chromatography-mass spectrometry (RP-HPLC/MS) and spectrophotometric analysis. The level of bound hydroxycinnamic acid was determined by spectrophotometry (as total hydroxycinnamic compounds and free-radical-scavenging activity) and reversed-phase high-performance chromatography (RP-HPLC) coupled to mass spectrometry (MS) in barley flours (whole meals and air-classified fractions: coarse fraction and fine fraction). Hydroxycinnamic acids and their derivatives were the main bound phenols in barley flours. A total of 12 different hydroxycinnamic acids were identified and quantified by HPLC/diode array detector (DAD)-MS within 90 min. Ferulic acid (as a simple and glycosylated derivative) was the main phenolic acid in barley flours, representing 89-93% of total hydroxycinnamic acids. The amount of total hydroxycinnamic acid in air-classified coarse fraction was 2 and 3 times higher than those of whole meal and the air-classified fine fraction, respectively. Similarly, the coarse fraction showed higher antioxidant activity (650.03 micromol of TEAC/100 g of flour) compared to whole meal and the fine fraction (388.78 and 320.27 micromol of TEAC/100 g of flour, respectively). | Mid | [
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# frozen_string_literal: true require_relative "../command" require_relative "../helpers/parse" module Byebug # # Implements the next functionality. # # Allows the user the continue execution until the next instruction in the # current frame. # class NextCommand < Command include Helpers::ParseHelper def self.regexp /^\s* n(?:ext)? (?:\s+(\S+))? \s*$/x end def self.description <<-DESCRIPTION n[ext][ nnn] #{short_description} DESCRIPTION end def self.short_description "Runs one or more lines of code" end def execute steps, err = parse_steps(@match[1], "Next") return errmsg(err) unless steps context.step_over(steps, context.frame.pos) processor.proceed! end end end | Mid | [
0.5492424242424241,
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Background ========== *Mariner-*like elements (*MLEs*) are class II transposons found in most eukaryotic genomes. These elements are discrete DNA fragments that are able to move around within eukaryotic genomes, and in some cases they make up a high proportion of these genomes. *MLEs*consist of a DNA fragment of 1200 to 2000 base pairs (bp) that contains a single transposase-encoding gene without an intron. This gene is flanked by two short inverted terminal repeats (ITRs) of 19 to 40 bp in length. The widespread occurrence of *MLEs*in animal genomes is considered to be attributable to the fact that their transposition does not require host factors since, *in vitro*, the transposase (Tpase) encoded by these elements is all that is required to catalyze all the transposition steps \[[@B1]\]. The requirements for *mariner*transposition seem to be very simple, involving just two ITRs separated by a DNA fragment, a Tpase source, and magnesium cations as cofactors \[[@B1]-[@B5]\]. However, several factors can impair the ability of *MLEs*to achieve their own transposition *in vivo*. Physical and biochemical conditions may interfere with the transposition efficiency. It has previously been demonstrated that *in vitro*the *Himar1*Tpase (HIMAR1) is about twice as efficient at 28°C as at 23 or 40°C \[[@B1]\]. In addition, data from *in vitro*and *in vivo*assays have shown that *MLE*nucleic acid components are also interfering factors. The quality of the ITR sequence is crucial for the transposition efficiency of *Mos1*\[[@B3],[@B6]\], and the untranslated regions (UTRs) located between the ITR and the Tpase ORF at both ends of the transposon act as transposition enhancers \[[@B7]\]. Inner regions of the transposon also modulate transposition efficiency *in vivo*, since transposition depends on the size of the DNA stuffer between the ITRs \[[@B4],[@B8]\], and also in some cases to the quality of this inner sequence \[[@B9]\]. So far, studies investigating factors that modulate *Mos1*transposition have been fragmentary \[[@B10]-[@B13]\]. *Mos1*is a potential tool in gene transfer and mutagenesis, and so we think that it is important to investigate these factors in more detail. In this study, we investigated the impact on the ability of *Mos1*to transpose of two factors: (1) the DNA configuration of the transposon donor, and (2) the properties of the stuffer. Our main findings concern four points. First, we show that the nucleic acid sequence of the DNA stuffer (in terms of GC content), and its length, can markedly impair transposition efficiency. Second, our study provides the first *in vitro*experimental demonstration that MITEs of *MLE*origin are able to transpose. We therefore propose a model for the physical constraint associated with the size of these small transposons. Third, our studies show that excessive temperature down-regulates *Mos1*transposition, yielding excision products that are unable to re-integrate. Finally, we have demonstrated that super-helicity of the transposon donor has a dramatic impact on transposition efficiency. Results ======= Impact of the stuffer size on *Mos1*transposition ------------------------------------------------- It had already been pointed out that increasing the stuffer size alters the transposition efficiency for *Himar1*\[[@B4]\] and *Mos1*\[[@B8]\]. We re-investigated this feature for *Mos1*using 3Tet3 transposons enlarged from the 3\' end of the tetracycline marker in bacterial transposition assays. Our findings confirmed that increasing the stuffer size did indeed dramatically decrease the transposition efficiency (Table [1](#T1){ref-type="table"}). The impact of decreasing stuffer size was also investigated using *Mos1*pseudo-transposons made with small marker genes encoding resistance to zeocin, blasticidin, and puromycin (375-bp, 423-bp and 662-bp respectively). Our findings show that 3Bla3, 3Zeo3 and 3Puro3 transposons were able to transpose efficiently (Table [1](#T1){ref-type="table"}). ###### Transposition frequencies of pseudo-Mos1 with various lengths **Pseudo-Mos1** **Transgene size (bp)** **Transposition frequencies** ----------------- ------------------------- ------------------------------- 3Zeo3 375 3.1 × 10^-4^ 3Bla3 423 0.9 × 10^-4^ 3Puro3 622 4 × 10^-4^ 3Kana3 1185 0.9 × 10^-4^ 3Tet3 1191 1 × 10^-4^ Enlarged 3Tet3 2500 1.2 × 10^-4^ 5000 5 × 10^-6^ 7000 3.6 × 10^-8^ 12500 \<10^-9^ Transposition of Minute transposon ---------------------------------- To transpose, the *Mos1*transposon has to be bent, bringing the ITR together \[[@B14]\]. DNA fragments that are longer than the bending persistence length (90-bp) are spontaneously bent, with little force. In contrast, significant bending of DNA fragments less than 90-bp in length requires considerable force \[[@B15]\]. These constraints should prevent the transposition of *MLE*with stuffer DNA less than 90-bp in length: this looks in contradiction with the presence of thousands of 80-bp *Hsmar1 MLE*interspersed within the human genome \[[@B16],[@B17]\]. Since no antibiotic marker less than 90-bp was available, we designed a novel transposition assay (Fig. [1a](#F1){ref-type="fig"}). This assay was monitored *in vitro*, ensuring that the bending of the DNA stuffer was not due to a host factor. We were able to recover surviving DH5α bacteria, indicating that the 122-bp *Mos1*transposon was indeed able to transpose within the *ccd*B+ gene. Sequencing the *ccd*B+ gene indicated that five of the twenty clones analyzed corresponded to real transpositions of the 122-bp *Mos1*transposon, as shown by the duplication of a TA dinucleotide at the integration site (Fig. [2b](#F2){ref-type="fig"}). The other clones are due to bacteria that naturally escape the toxin encoded by the *ccd*B+ gene, as indicated by the Manufacturer (see Materials and Methods). {#F1} {#F2} These findings were not consistent with what we know about the bending ability of small, double-stranded DNA fragments. Since there was no helping host factor in our *in vitro*assay, we searched for sources of flexibility that would allow the bending required for assembling the synaptic complex. The binding of a protein to DNA is often associated with a bend in the DNA. Bending of ITRs has been demonstrated for Tn*7*, Tn*5*and IS*903*bacterial transposons \[[@B18]-[@B20]\]. We therefore first investigated whether MOS1 bends its ITR. EMSA were performed using six 113 bp fragments containing the 28 bp 3\'ITR or 5\'ITR at various positions (Fig. [2a](#F2){ref-type="fig"}) and purified MBP-MOS1. The mobility differences between the MOS1-ITR complexes formed with the six different probes indicated that the MOS1 did bend the ITR. The possibility that these bends were due to single strand DNA cleavage at the outer or the inner extremity of the ITR was ruled out as all the experimental steps were carried out for 15 minutes at 4°C, conditions for which the cleavage activity of the Tpase is inhibited. Fig. [2b](#F2){ref-type="fig"} shows a representative data obtained with probes containing the 5\'ITR. Similar data were obtained with probes containing the 3\'ITR. The Rf of all the observed complexes was measured and plotted *versus*the position of the center of each probe (Fig. [2c](#F2){ref-type="fig"}). For each probe, two single end complexes (SEC1 and SEC2) were obtained, as expected \[[@B3]\]. The sinus curves calculated from our data allowed us to map the center of the MOS1-induced bend, located at the lowest point of the curve. This was at position 107 (± 3 bp) for SEC1, which located the bending core around the 21^st^nucleotide of both ITR (Fig. [2d](#F2){ref-type="fig"}). For SEC2, the lowest point of the curve was around position 104 (± 3 bp), which located the bending core around the 18^th^nucleotide for both ITRs (Fig. [2d](#F2){ref-type="fig"}). These values are the means (± SD) for at least five independent experiments. Zhou\'s equation \[[@B21]\] was used to determine bending angles of 89.7° (± 0.2) and 89.7° (± 1) for the SEC1 formed with the 3\' ITR- and the 5\' ITR-containing fragments respectively, and 89.2° (± 0.5) and 89.7° (± 1) for the SEC2 formed on the 3\' ITR- and the 5\' ITR-containing fragments respectively. In conclusion, our results indicated that both 3\'- and 5\'-ITR were bent at angles of about 90° as a result of MOS1 binding. Interestingly, these angles may facilitate the assembly of a transposition complex in a minute transposon, such as the-one investigated here, since the stuffer fragment needs only form an angle of less than 90° to bring the transposon ends together which is quite possible for a 66-bp DNA segment \[[@B15]\]. Another source of DNA flexibility, such as single strand DNA cleavage at the inner end of the ITR, was also investigated. The cleavages produced by MOS1 in SEC2 and PEC1 were therefore re-investigated, taking into account the inner part of the ITR (Fig. [3a](#F3){ref-type="fig"}). We have already published that the ITR is mainly cleaved at the 3\'-end of the transferred strand and at positions +2 and +3 on the non-transferred strand, although several other cleaved positions were detected in the flanking DNA on both strands (Fig. [3b](#F3){ref-type="fig"}, black marks) \[[@B22]\]. Analysis of the bottom part of the gel also reveals that a single strand DNA cleavage occurred on the transferred strand at position 27, which is located at the inner end of the ITR (Fig. [3a](#F3){ref-type="fig"}, gray mark). {#F3} Impact of stuffer sequence on *Mos1*transposition ------------------------------------------------- Two questions were addressed concerning the impact on transposition efficiency of the GC content of the transposon sequence, and of the number of TA dinucleotides in the transposon sequence. We first prepared nine pseudo-*Mos1*with GC contents ranging from 50.1 to 59.1%. The reference construct was the pBC-3Tet3, which has a GC content of 61.4%. In bacterial transposition assays, the transposition efficiency of the ten pseudo-transposons ranged over two orders of magnitude (Fig. [4a](#F4){ref-type="fig"}). The data were plotted, and the correlation between the two parameters (CG content *versus*transposition frequency) was tested using the Spearman correlation test with a significance threshold of 0.05 (XLSTAT2007). Nine of the 10 constructs plotted in this analysis were included in the ellipse (Fig. [4b](#F4){ref-type="fig"}), and the correlation between GC content and transposition frequency had a coefficient of about 0.8. This coefficient was significant enough to consider that there was a correlation between GC content and transposition frequency. However, the facts that one transposon construct fell outside the ellipse, and that two other transposon constructs with GC contents close to 56% differ by more than one order of magnitude indicates that GC content is not the only sequence parameter that affects the stuffer quality for transposition. {#F4} We then prepared two modified genes encoding for tetracycline resistance: the first was TA-rich (87 TA dinucleotides), and the second was TA-poor (14 TA dinucleotides), but this did not have any marked effect on the percentage of GC (58 and 62% respectively). These two genes were used as markers in transposition assays in bacteria. It was expected that reducing the TA density would result in increased transposition efficiency, simply because some suicide auto-integrations would be avoided. We observed no correlation between the TA numbers (or TA density), and the transposition frequency (Table [2](#T2){ref-type="table"}). This point was confirmed by the fact that a bleomycin resistance gene without the TA dinucleotide (3Zeo3 \[noTA\]) gave the same result in transposition assays in bacteria as the wild type bleomycin resistance gene (3Zeo3; Table [2](#T2){ref-type="table"}). ###### Transposition frequencies of pseudo-Mos1 having various TA numbers **Pseudo-*Mos1*** **TA density/100 bp (total TA number)** **Transposition frequencies** ------------------- ----------------------------------------- ------------------------------- 3Tet3 3.1 (37) 1 × 10^-4^ 3Tet3 \[TA-rich\] 7.5 (87) 0.25 × 10^-4^ 3Tet3 \[TA-poor\] 1.2 (14) 0.1 × 10^-4^ 3Zeo3 0.2 (1) 3.1 × 10^-4^ 3Zeo3 \[noTA\] 0 (0) 4 × 10^-4^ Impact of temperature on *Mos1*transposition efficiency ------------------------------------------------------- *In vitro*transposition assays were performed at four temperatures, 25, 28, 32 and 37°C (Fig. [5a](#F5){ref-type="fig"}). Our results are in agreement with those previously obtained for HIMAR1 \[[@B4]\], as we found an optimal temperature of about 28°C, with no significant differences found between 28°C and 30°C (not shown). Since we had previously shown that MOS1 binds to its ITR with similar efficiency regardless of temperature \[[@B22]\], we therefore checked whether a temperature effect was observed for *Mos1*excision or not. Time course excision assays were performed either at 30 or 37°C, using pBC-3Tet3 plasmid as the transposon donor, and purified MBP-MOS1. Changing the excision temperature led to two main differences (Fig. [5b](#F5){ref-type="fig"}). The first was that, at 37°C, a marked DNA degradation occurred, leading to the loss of about 50% of the DNA two hours into the reaction, whereas no DNA loss was observed after 24 hours at 30°C. The second difference was that, despite the DNA degradation, the pseudo-*Mos1*(3Tet3) accumulated at 37°C, whereas it was not detectable at 30°C. This is not very surprising because an accurately excised transposon tends to be reinserted rather than accumulating. Indeed, insertion products were seen in the assay performed at 30°C, but not in the assay performed at 37°C (Fig. [5b](#F5){ref-type="fig"}, bands pinpointed by asterisks). This was in total agreement with the fact that more efficient transposition was observed at 30°C than at 37°C. The DNA degradation and the 3Tet3 accumulation detected at 37°C might be due to a single phenomenon: at 37°C, MOS1 cleaves DNA not only at the end of the ITR but anywhere in the DNA. This loss of specificity may promote the production of excised 3Tet3 with extremities that are unable to integrate. ![**Impact of the temperature on *Mos1*transposition**. (a) Effect of the temperature (horizontal axis) on the transposition efficiency (vertical axis). *In vitro*assays were performed using two plasmids (pET-3Tet3 as the transposon donor, and pBC-SK+ as the target for integration) and purified MBP-MOS1. Two different shapes of pBC-3Tet3 were used: the super-helical form (gray bars) and that linearized with *Nco*I (empty bars). (b) Effect of temperature on the excision. Time course analyses were done using super coiled pBC-3Tet3 as pseudo-*Mos1*and purified MBP-MOS1. The assays were performed at 30°C (top panel) or 37°C (bottom panel) and the resulting products were loaded onto BET-stained agarose gel. Molecular weight markers are indicated in the left margin. The various products are depicted on the right and their positions on the gel are indicated. OC: open circle; Lin: linear; SC: super coiled; 3Tet3: excised transposon. On the top panel (30°C) the expected position of 3Tet3 is pointed out, but the corresponding product is not detected. Asterisks indicate the integration products, determined according to \[[@B38]\] and personal data.](1471-2199-9-106-5){#F5} Organization of excised pseudo-*Mos1*produced at 37°C ----------------------------------------------------- The organization of the pseudo-*Mos1*that accumulated at 37°C was analyzed using a variant of the pBC3Tet3, pBC-3Kana3, a transposon donor with a unique *Cla*I site in 3Kana3 (Fig. [6a](#F6){ref-type="fig"}). In Southern blot analyses, pBC-3Kana3 is detected both as open circle and linear molecules, whereas the excised 3Kana3 accumulates as a double-band of 1.3 kbp (Fig. [6a](#F6){ref-type="fig"}). Due to the sensibility of the technique, integration events are also detected. The detection of a double-band of about 1.3-kpb (Fig. [6a](#F6){ref-type="fig"}, lanes 1 to 4, bands located by gray and black diamonds) suggests that excision products could exist both in linear and circular configurations. Southern analysis of the DNA samples digested by *Cla*I was then monitored. Once cleaved by *Cla*I, the band with the highest apparent molecular weight in undigested DNA samples was shortened accordingly to the position of the restriction *Cla*I site (Fig. [6a](#F6){ref-type="fig"}, lanes 5 to 8, bands located by a gray diamond). This suggests that this band corresponds to a linear excision product. In contrast, the band of lower intensity in undigested DNA samples is unaffected or only slightly by *Cla*I digestion, thus suggesting that it corresponds to a circular excision product or that it had no *Cla*I site. {ref-type="table"}). Motifs highlighted in black with the sequence typed in white were used to design the primers KanaJunc1 and KanJunc2 (Table [3](#T3){ref-type="table"}). The start and stop codons of the kanamycin resistance gene are highlighted in dark gray and typed in white. The *Cla*I site is typed in black and boxed in gray. (c) Diagrammatic representation of the excision products obtained after incubation of pBC-3Kana3 with MOS1 at 37°C. Three forms of the excised transposon are drawn: linear (1) and circular (2) molecules containing a full-length transposon, and (3) circular molecules containing a truncated transposon, due to intra-molecular auto-integration after excision. ITR are represented by light gray arrows and promoters by 90°-angled arrows. KanaR: Kanamycin resistance gene. ChlR: CAT gene. (d) Sequences of the twelve excision products analyzed. The 3\'ITR is in bold uppercase letters. On the right, the pBC MCS is in lowercase letters. On the left, the dinucleotide of the auto-integration site is in gray-boxed uppercase letters. Numbers flanking the insertion sites correspond to the position of insertion in the 3Kana3 pseudo-*Mos1*. They are the same as in (b). The sequence in 5\' of the insertion site corresponds to the inner sequence for 3Kana3.](1471-2199-9-106-6){#F6} ###### Oligonucleotides used in the study ***Primer Name*** Nucleic acid sequence -------------------------------------------------------------------------- --------------------------------------------------- [End modification of the kanamycin resistance gene]{.ul} KanaSal1 5\'-AGCGTCGCATACAAGGGGTGTTATGAGCCAT-3\' KanaHind3 5\'-ACCCAAGCTTAATCGGGGGCTCCCTTTAGG-3\' [3Kana3 junction from the kanamycin resistance gene]{.ul} KanaJunc1 5\'-TCATCTGTATAACATCATTGGC-3\' KanaJunc2 5\'-CATGGTGATTTCTCACTTG-3\' *Stuffer fragments amplified from DpAV4 sequence referenced as AJ279812* 3primeXba1 5\'-GCTCTAGACGGACGTCCAATACATGATG-3\' 5primeXba1-F1 5\'-GCTCTAGACCGAAAAGATAGACAGTGTG-3\' 5primeXba1-F2 5\'-GCTCTAGAAACGTGACGCACATGGCTAT-3\' 5primeXba1-F3 5\'-GCTCTAGAAAACATCCTTCGCCCTGAAC-3\' 5primeXba1-F4 5\'-GCTCTAGAAGGATTGGTGGGATTTTCCG-3\' 5primeXba1-F5 5\'-GCTCTAGAACGGCAACTTTCGGAACTAC-3\' Test-orient-F 5\'-GCGAATTGGCCCCTAGATTT-3\' *Insertion site analyses in the ccdB gene* ccdBup 5\'-AGTCGTTCGGCTTCATCTGG-3\' ccdBdown 5\'-ATCAGGAAGGGATGGCTGAG-3\' *ITR cloning for circular permutation* 5\'ITRup 5\'-AGCTCGTTTACCAGGTGTACAAGTAGGGAATGTCGGTTCCC-3\' 5\'ITRdw 5\'-GGGAACCGACATTCCCTACTTGTACACCTGGTAAACGAGCT-3\' 3\'ITRup 5\'-AGCTCGTTTATCAGGTGTACAAGTATGAAATGTCGTTTCCC-3\' 3\'ITRdw 5\'-GGGAAACGACATTTCATACTTGTACACCTGATAAACGAGCT-3\' *Fragments for circular permutation* O1 5\'-GGGTTTTCCCAGTCACG-3\' O1R 5\'-AACGACATTTCATACTTGTA-3\' O2 5\'-ACGTTGTAAAACGACGGC-3\' O2R 5\'-CTAGAGCGGCCGCGG-3\' O3 5\'-CCAGTGAGCGCGCGTA-3\' O3R 5\'-CGGGGGATCCACTAGTT-3\' O4 5\'-TACGACTCACTATAGGGC-3\' O4R 5\'-ATCGAATTCCTGCAGCCC-3\' O5 5\'-CGAATTGGAGCTCGTTTAT-3 O5R 5\'-GTATCGATAAGCTTGATATC-3\' O6 5\'-ATCAGGTGTACAAGTATGAA-3\' O6R 5\'-TTCCCTCGAGGTCGACG-3\' The excision products were therefore purified by agarose gel elution from untreated DNA samples. They were submitted to PCR using primers anchored in an inverse orientation in the sequence of the kanamycin resistance gene, KanaJunc1 and KanaJunc2 (Table [3](#T3){ref-type="table"} and Fig. [6b](#F6){ref-type="fig"}), in order to amplify ITR junctions looking like those isolated from *Bombyx mori*cells transformed by *Mos1*-based vectors \[[@B24]\]. The amplification of a fragment of about 950-bp is expected if the circular forms correspond to the circularization of an excised full-length transposon (Fig. [6c](#F6){ref-type="fig"}). Fragments ranging from 600 to 800-bp were obtained and cloned. Twelve were sequenced: they all contained the *Cla*I site, and a single ITR, inserted into or close to the kanamycin resistance gene (Fig. [6d](#F6){ref-type="fig"}). This fact, combined with the fact that they were shorter than expected, indicates that these fragments resulted from intra-molecular integration events. Among the twelve fragments analyzed here, four came from auto-integration events occurring in a dinucleotide that was not a TA but TT (sequence n°4), TC (sequence n°6), TG (sequence n°8) or CA (sequence n°11) dinucleotides. In conclusion, our data are consistent with the fact that some of *Mos1*excision products formed at 37°C are not able to perform integration into a target DNA. This is due to the formation of (1) linear products with inefficient extremities and (2) circular products resulting from intra-molecular auto-integration. Taken together, these events account for the decreased transposition efficiency observed at 37°C. Impact of the transposon donor configuration on *Mos1*transposition ------------------------------------------------------------------- *In vitro*transpositions were performed using a linear plasmid donor of transposon (Fig. [5a](#F5){ref-type="fig"}, empty boxes) and compared to those obtained using a super coiled transposon donor (Fig. [5a](#F5){ref-type="fig"}, gray bars). Linearization of the transposon source dramatically reduced the transposition efficiency (more than 1000-folds) at 28°C, and hindered transposition at other temperatures. Excision efficiencies of a super-helical donor were then compared to those obtained with the same donor linearized by *Nco*I. When the super-helical pBC-3Tet3 was used as the substrate, products were digested by *Nco*I at the end of the experiment, making it possible to carry out direct comparisons. Excision assays have been first analyzed by tracing the dead-end products of the reaction, *i.e*. bands α and δ(Fig. [7a](#F7){ref-type="fig"}). Our data therefore show no major difference between the two reactions. Analyses of the time taken to obtain 50% of α and δ fragments (T1/2) indicated that it was about 6 and 8 hours for the super-coiled and linear donors, respectively (Fig. [7b](#F7){ref-type="fig"} and [7c](#F7){ref-type="fig"}, black arrows). Furthermore, the curves differ in shape, the production of α + δ (for the first points of time, *i.e*. the initial reaction speed) being faster with the circular substrate. This suggested differences between the two excision reactions. {#F7} This difference was studied measuring the patterns of appearance of the β and γ fragments that are not dead-end products of the reaction. Indeed, when *Mos1*excision occurs within the synaptic complex, β and γ are not expected to accumulate, because cleavage is believed to occur in a concerted fashion at both ITRs. Much more β and γ accumulated when the donor was linear, rising to a peak before decreasing, as the result of cleaving the second ITR (Fig. [7d](#F7){ref-type="fig"}). In contrast, little β and γ accumulated when the substrate was super coiled, reaching a maximum of 10-fmoles. These data supported the idea that the concerted cleavage at both ITRs is reduced or abolished when the substrate is linear, a phenomenon that may account for an overall decrease in the transposition efficiency. Finally, transposition assays presented in Fig. [5a](#F5){ref-type="fig"} corresponded to 30 minutes reactions. At this time, excision and re-integration of the transposon from the circular substrate had already occurred (Fig. [7b](#F7){ref-type="fig"}, lane 0.5) whereas this had not occurred for the linear substrate (Fig. [7c](#F7){ref-type="fig"}, lane 0.5). Data in this section indicates that the excision is probably one of the limiting factors that accounts for the drastic decrease in transposition efficiency when the donor is linear. At least two non-mutually exclusive explanations can be proposed: (1) excision from a linear donor is slower and (2) excision from a linear donor takes place independently at both ITRs (non-concerted excision). Discussion ========== In addition to requiring ITR and the Tpase, previous studies have demonstrated that the transposition of *MLE*or *TLE*requires critical parameters that interfere with transposition efficiency. These parameters include (1) Tpase concentrations, demonstrated *in vitro*for HIMAR1 \[[@B4]\] and MOS1 \[[@B7]\] and *in vivo*for MOS1 \[[@B25]\], (2) temperature \[[@B4]\], (3) size of the stuffer, demonstrated *in vitro*for *Tc1*\[[@B26]\], (4) sequence of the stuffer, demonstrated *in vivo*for MOS1 \[[@B9]\], (5) structural configuration of the target DNA, demonstrated *in vitro*for *Tc1*\[[@B27]\]. In this study, we have used an *in vitro*approach to address several parameters affecting *Mos1*transposition. Parameters for optimal *mariner*transposition --------------------------------------------- Our results highlight the importance of the stuffer sequence since they show that the GC content is an important factor, even if it is probably not the only parameter that affects the stuffer performance for transposition. *In silicio*analyses <http://hydra.icgeb.trieste.it/~kristian/dna/> failed to establish a correlation between DNA curvature and/or flexibility and transposition efficiency. Our results also confirm the impact of stuffer length on transposition efficiency, as already shown \[[@B4],[@B8],[@B28]\]. Length dependence of *Mos1*transposition might rely on auto-integration after excision. This is supported by the fact that large sophisticated transposons such as the phage *Mu*or Tn*7*have specific mechanisms that prevent the transposon from inserting into itself \[[@B29],[@B30]\]. In contrast, simple elements such as *mariners*lack this function. A third parameter that controls *Mos1*transposition rate is the temperature. Interestingly, elevated temperature (37°C) promotes auto-integration events. Auto-integration does not absolutely require a TA dinucleotide. This fact, associated with the fact that the percentage of TA dinucleotides does not influence *Mos1*transposition efficiency, rules out the possibility of designing large transgenes containing no (or only a few) TA to limit the length-dependence of *Mos1*transposition. Mariner excision: making a molecule that produces efficient integration ----------------------------------------------------------------------- Data presented here highlight an important, although not new, idea: transposition efficiency is in great part controlled by the quality of the excision product. This is in contradiction with published data \[[@B1],[@B17],[@B22],[@B23]\] that support the idea that cleavages at *MLEs*ends are far from accurate (Fig. [8](#F8){ref-type="fig"}). However, all these data were collected *in vitro*, using linear, double-stranded oligonucleotides. On the other hand, *MLE in vivo*excision footprints are often less variable, and closely match what the model predicts, *i.e*. hydrolysis at the 3\' end of the element, and 5\' break two or three nucleotides within the transposon \[[@B17],[@B24],[@B31]\]. This suggests that experimental conditions can bias the description of excision product ends. ![**Published data on *mariner*double stranded cleavages**. Data about cleavages *in vitro*. (T) is the transferred strand, and (NT) the nontransferred strand. Upper-case letters indicate the terminal DNA sequence at the right end of *Mos1*, and of both ends of *Himar1*, and *Hsmar1*respectively. Lower-case letters indicate the flanking DNA. The TA dinucleotide flanking the element is in bold. Numbers indicate base pair positions relative to the transposon-donor junction. Crosses correspond to the cleaved positions mentioned in \[[@B22]\]; Circles correspond to the cleaved positions mentioned in \[[@B23]\]; Stars correspond to the cleaved positions mentioned in \[[@B1]\] and \[[@B17]\] for *Himar1*and *Hsmar1*respectively.](1471-2199-9-106-8){#F8} Our data allow proposing that there is a relationship between the super-helicity of the donor DNA, and the production of efficient excision products, through the assembly of the synaptic complexes. Indeed, *Mos1*excision from a super-coiled donor yields transposition that is 1000-fold more efficient than that resulting from a linear donor plasmid (10^-3^and 5 × 10^-7^respectively). These findings are fully consistent with super-helicity acting as a regulatory factor of *mariner*transposition *in vitro*, and probably *in vivo*. From this standpoint, *mariner*looks like many other transposons. For instance, Mu transposition requires DNA super coiling in the donor DNA \[[@B24]\] whereas Tn*10*needs either DNA super coiling in the DNA substrate, or IHF acting as a \"super coiling relief factor\" \[[@B32]\]. Super coiling is probably not required for the chemical steps of the transposition, but might be a limiting factor for the assembly of *mariner*transposition complexes. Although *mariner*transposition has been shown to take place *in vitro*, we cannot rule out the possibility that host factors may assist the transposase during *in vivo*transposition. MITE transposition ------------------ MITEs are small, repetitive, DNA elements ranging in size from approximately 80 to 500 bp that are interspersed within eukaryotic genomes. Their sequence is palindromic, AT-rich, and has no coding capacity. For their mobility, they generally use a source of Tpase *in trans*, originating from a related complete transposon copy \[[@B33]\]. Our data indicate that the size of MITEs of *MLE*origin does not limit their ability to transpose. For the smallest ones, found in the human genome (80-bp) or in that of the ant *Messor bouvieri*(130-bp, \[[@B34]\]), the binding of MOS1 causes major ITRs bending, thus bringing the two ends of the transposon close to each other. In addition, the inner ITR cleavage by MOS1 could also allows the ITR bending. Similar cleavage was found on the non-transferred strand of the *Hsmar1*ITR cleaved by HSMAR1. No host factor is therefore required to bend the DNA and assemble the synaptic complex (Fig. [9](#F9){ref-type="fig"}). {#F9} This model provides a very satisfying explanation of the mobility of the *MLE*MITEs, because it explains how a minute *Mos1*can assemble a functional synaptic complex similar to that of the full-length *MLE*. Moreover, it is supported by *in vitro*transposition data. However, it does not explain why most of the MITEs, including those derived from *MLE*, display a palindromic organization throughout their sequence. In contrast to what was previously proposed \[[@B35]\], our data suggest that complete palindromy is not a requirement for MITE mobility, and that it could therefore result from other constraints. Conclusion ========== Non-viral vectors are presently invading the world of gene transfer and mutagenesis. Among the tools that are currently under evaluation, the transposon *Mos1*raises a growing interest. In fact, it is perceived as a small versatile and quasi-universal means of transforming a variety of cells, except mammal ones \[[@B13]\]. However, as for any new tool, it is necessary to control every parameter driving its transposition, and, in a first place, the factors that might limit its efficiency and specificity for DNA transfer. In the present work, we have investigated several parameters, particularly those related to the structure of the transposon. In this respect, we have demonstrated that the DNA sequence (in term of GC content) as well as the length of the inner part of the transposon have a crucial effect on the transposition efficiency. Our results provide, for the first time, an experimental *in vitro*demonstration that MITEs of *MLE*origin that are as small as 80--120 bp are able to transpose. Hence, we propose a model that bypasses the physical constraints associated to the transposition of such small transposons. We have also demonstrated that the super-helicity of the transposon impacts considerably on the efficiency of transposition. Finally, we have found that *mariner*transposition is dependent on the temperature. The fact that higher temperature disfavors re-integration of the excision products might be related to the transposase enzymatic properties. Methods ======= DNA manipulation ---------------- A double-stranded 3\'ITR oligonucleotide with *Bam*HI extremities was cloned at the *Bam*HI site of pBS II SK+ (Stratagene), to produce pBS-3\'ITR. This plasmid was subjected to *Eco*RI/*Xba*I cleavage, yielding the ITR70 fragment (*i.e*. a fragment 70 bp in length) that was then agarose-purified. After precipitation, the DNA concentration was estimated on BET-stained agarose gel. Analysis of the cleavages occurring in SEC2 and PEC1 was performed using ITR70 labeled on one strand. To obtain single-strand labeling of the non-transferred strand (giving ITR70α), the ITR70 fragment was filled-in at the *Eco*RI site using the DNA polymerase Klenow fragment and dATP α-^32^P without dCGT. To obtain single-strand labeling on the transferred strand (giving ITR70γ) the pBS-3\'ITR was digested by *Xba*I and dephosphorylated using CIP (Promega) before *Eco*RI digestion. After purification, the *Xba*I/*Eco*RI fragment was labeled at the dephosphorylated end using the T4 polynucleotide kinase (Promega) and ATP γ-^32^P. Polymerase chain reaction ------------------------- The sequences and properties of the oligonucleotides used for the PCR amplification involved in plasmid constructs are shown in Table [3](#T3){ref-type="table"}. PCR amplifications of fragments smaller than 2 kbp were performed on 1 ng DNA. PCR reactions were done in 10 mM Tris-HCl, pH 9, 1.5 mM MgCl~2~, 50 mM KCl, and 0.1% Triton X100, 150 mM of each dNTP, and 0.1 mM of each oligonucleotide in a 50 μl reaction volume containing 1 unit of Taq DNA Polymerase (Promega). Each PCR was carried out in a programmable temperature controller (Eppendorf) for 30 cycles. The cycle was as follows: denaturing at 94°C for 1 min, annealing at 55°C for 30 sec, and extension at 72°C for 1 min. At the end of the 30^th^cycle, the heat-denaturing step was omitted, and extension was allowed to proceed at 72°C for 7 min. Fragments larger than 2 kbp were amplified using the Expand™ Long Template PCR System, under the conditions specified by the supplier (Roche Molecular Biochemicals). Briefly, reactions were done on 10 ng of gDNA in 1× buffer 1 or 2, 350 μM of each dNTP, 0.05 nM of each oligonucleotide in a 50-μl reaction volume, with 3.5 units of Taq/Tgo DNA polymerase mixture. Each PCR was carried out for 30 cycles comprising denaturing at 94°C for 30 sec, annealing at 61°C for 1 min, and extension at 68°C for 10 min. At the end of the 30^th^cycle, the heat denaturing step was omitted, and extension was allowed to proceed at 68°C for 15 min. Proteins -------- The pMAL-c2-MOS1 encoding the wild type MOS1 (amino acids 1 to 345) was used as previously described, and the Tpase was produced and purified as a fusion protein linked to maltose-binding protein (MBP) \[[@B2]\]. MBP-MOS1 was used instead of MOS1, because although it has the same specific activity it is much more stable during purification, biochemical assays and *in-vitro*transposition assays. Henceforth in the text, the terms \"transposase\", \"Tpase\" and \"Tpase molecule\" all refer to a single subunit of MOS1. The amount of MOS1 present after purification was determined on SDS-PAGE. Various amount of the samples for analysis were loaded onto the gel, and co-migrated with a range of dilutions of BSA. After staining with colloidal Coomassie dye, the gels were scanned, and the final concentrations were determined using the Molecular Analyst software (Biorad, \[[@B36]\]). Plasmids for transposition assays --------------------------------- ### Tpase source A strong, IPTG-dependent MOS1 expression vector was constructed in the pKK-233 plasmid (Clontech) to obtain pKK-MOS1 \[[@B3]\]. This plasmid was used for transposition assays in bacteria. ### Transposon donor A pseudo *Mos1*donor plasmid was constructed with two 3\'ITRs flanking the promoterless tetracycline resistance gene of pBR322 (Tet), as previously described \[[@B3]\], and designated pBC-3Tet3. Several variants of pBC-3Tet3 were prepared: pET-3Tet3 was made by cloning 3Tet3 transposon, between the *Sac*I-*Bss*HII sites of the pET26b(+) (Novagen). pBC3Kana3, which contains a promoterless gene encoding the kanamycin resistance instead of the tetracycline gene. Three plasmids, lacking the promoter of one of the genes encoding antibiotic resistance, were designated pBC-3Bla3, pBC-3Zeo3 and pBC-3Puro3. They contained the blasticidin resistance gene of pORF39-Bsr (InvivoGen), the bleomycin resistance gene of pORF39-Sh-ble (InvivoGen) and the puromycin resistance gene of pORF39-Pac (InvivoGen) respectively. A pCR-Script Amp plasmid containing a minute pseudo-*Mos1*transposon of 122-bp, named ITR3pA3 \[see Additional file [1](#S1){ref-type="supplementary-material"}\], was also prepared. To assay DNA stuffers larger than 1.2-kbp, four fragments of about 1.3-, 3.8-, 6.3- and 11.3-kbp were amplified by PCR from a 12255-bp segment contained in the Ascovirus DpAV4a (Acc N°AJ279813). Each fragment was inserted at the *Xba*I site of the pBC-3Tet3 located just after the stop codon of the tetracycline resistance gene. These constructs contained DNA stuffers of 2.5-, 5-, 7.5- and 12.5-kbp respectively. To determine the impact of the sequence quality of the DNA stuffer, nine variants of pBC-3Tet3 were constructed by inserting into each of them amplified (primers in Table [3](#T3){ref-type="table"}) 1.1 kbp fragments with differing GC contents that corresponded to untranscribed sequences in bacteria \[see Additional file [1](#S1){ref-type="supplementary-material"}\]. These constructs were designated pBC-3Tet3-F1, -F6, -F46, -F108, -F116, -F193, F240, F289, and F523 respectively. Three other variants were constructed. The first, corresponding to the bleomycin resistance gene without the TA dinucleotide (pBC-3Zeo3 \[noTA\]), was synthesized using the Quick Change^®^Site-Directed Mutagenesis Kit (Stratagene), using the pBC-3Zeo3 as the template, and contained an Y75F substitution in the bleomycin resistance gene, that did not alter the activity of the protein. The other two contained tetracycline resistance genes with either a high dinucleotide TA content (87 TA), or a low dinucleotide TA content (14 TA) that differ from that of the wild type version of the tetracycline resistance gene (37 TA), but without any change in the encoded protein sequence. These two tetracycline genes were synthesized (ATG bio Synthetics) and subcloned in the pBC-3-3, to yield two constructs designated pBC-3Tet3 \[TArich\] and pBC-3Tet3 \[TApoor\] respectively. After sequencing, the three resulting plasmids were used in bacterial transposition assays. Transposition assays in bacteria -------------------------------- JM109 competent cells were freshly co-transformed with pKK-MOS1 and one of the pseudo-*Mos1*donors, and plated on LB-agar containing ampicillin (100 μg/ml) and chloramphenicol (150 μg/ml). Donor plasmids with a pBC backbone were also used as integration targets, since the CAT gene acts as a strong integration hot spot for *Mos1*\[[@B3]\]. Four to six colonies containing both plasmids were grown overnight at 37°C in 2.5 ml LB medium containing ampicillin and chloramphenicol. 2.5 ml of fresh LB medium containing ampicillin and chloramphenicol was inoculated with 250 μl of the overnight culture. The cells were grown for 1 h at 37°C, and transposition was induced with 1 mM IPTG. The cells were grown for 5 h at 32°C (except in experiments investigating the impact of temperature), and transpositions were detected by plating the cells on LB medium containing tetracycline (20 μg/ml), kanamycin (100 μg/ml), blasticidin (100 μg/ml), zeocin (25 μg/ml) or puromycin (250 μg/ml), depending on the donor used in the assay. Cells were titrated by plating an appropriate dilution of the cultured cells on LB medium. The transposition frequency was calculated as the number of antibiotic-resistant cells divided by the total number of cells \[[@B3]\]. This ratio corresponds to a number of events per cell. In tests with very low transposition frequencies, the cells were grown for 20 h (instead of 5 h) at 32°C, and then transferred to 25 ml fresh antibiotic-free LB medium. The cells were then grown for another 6 hours at 32°C before detecting the transposition events as described above. *In vitro*transposition assays ------------------------------ The procedure was based on that described in \[[@B1]\]. Three assays were performed. The first involved homo-plasmid transposition: 20 μl-reactions were carried out in 10 mM Tris-HCl \[pH9\], 50 mM NaCl, 0.5 mM DTT, 20 mM MgCl~2~, 0.5 mM EDTA, 100 ng BSA, 80 nM MBP-MOS1 to which 600 ng of pBC-3Tet3 had been added for 30 min at 30°C. The second involved hetero-plasmid transposition, and was carried out under similar conditions using 300 ng of pET-3Tet3 as the transposon donor (linear or super coiled), and 300 ng of pBC-SK+ (Stratagene) as the integration target. Linear donors were prepared from pET-3Tet3 digested by *Nco*I. Reactions were stopped by adding 10 μl of stop solution (0.4% SDS, 0.4 μg/ml proteinase K) and incubated for 30 min at 37°C. Reactions were then phenol-chloroform extracted, and nucleic acids were ethanol precipitated using 1 μg/μl of yeast tRNA as carrier. The precipitated reaction products were resuspended in 10 μl of sterile water. 2 μl of reaction products, supplemented with 0.01 ng of pBS SK+, were used to transform 45 μl of competent *Escherichia coli*by electroporation (2 mm cuvette, 5 ms, 1.5 kV in a MicroPulser™ Bio-Rad). Cells were grown at 37°C for 1 hour and aliquots were plated on LB-ampicillin (to monitor the transformation efficiency), LB-tetracycline and LB-chloramphenicol (to monitor transposition rates = clone number on LB-tetracycline/clone number on LB- chloramphenicol). The third assay was also a hetero-plasmid transposition assay (with similar incubation conditions as before), but used 300 ng of ITR3pA3 as the minute *Mos1*donor, and 300 ng of pDONR221-CmR^-^as a target for integration. This 3599-bp plasmid contained the ccdB gene that encoded a toxin lethal for the DH5α strain *of E. coli*, making it possible to select integration events. It was made from pDONR221 (Invitrogen) by removing the *Bam*HI-*Eco*RV fragment, containing the *cat*gene and located between positions 1833 and 3000, in order to avoid integration interference. As indicated by the manufacturer, using pDONR221 yields a background of about 10^-4^naturally resistant DH5α. Insertion sites of the pseudo *Mos1*were amplified by PCR, using primer ccdBup and ccdBdown (Table [3](#T3){ref-type="table"}), cloned in pGEM-T Easy (Promega), and sequenced by MWG biotech (Germany). Excision assays --------------- Excision assays were performed in the same conditions than *in vitro*transposition assays. Reactions were performed using 600 ng of a single transposon donor (pBC-3Tet3 or pBC-3Kana3), either super coiled or linear and at different temperatures, as indicated in the text. At the end of the reaction, products were directly loaded on 0.8% BET-agarose in 1× TBE buffer. Southern blots, and hybridizations were performed according to standard procedures \[[@B37]\]. After electrophoresis, samples were blotted on nylon membranes ((NylonN^+^, ICN products) and hybridized with a *Cla*I-*Hin*dIII fragment purified from pBC-3Kana3 and containing the promoterless gene encoding kanamycin resistance. This probe was randomly labeled with \[α ^32^P\]dATP (3000 Ci/mmole; ICN products) and purified using a Qiagen Kit. Hybridizations were allowed to proceed in 0.5 M Na~2~HPO~4~-NaH~2~PO~4~plus 7% SDS at 65°C for 16--18 h at 65°C. After probing, filters were washed once with 2 × SSC (1 × SSC = 0.15 M NaCl, 0.015 M sodium citrate)/0.1% SDS for 30 min at 65°C, and twice with 0.1 × SSC/0.1%SDS for 30 min at 65°C and then placed against X-ray film. Circular permutation assays --------------------------- Double-stranded oligonucleotides containing the 5\' and 3\' ITR (Table [3](#T3){ref-type="table"}, 5\'ITRup+5\'ITRdw and 3\'ITRup+3\'ITRdw) were cloned in the *Sma*I restriction site of pBS II SK+ (Stratagene), giving the p5\' and p3\' constructs. Six 113-bp fragments containing the 3\'ITR or 5\'ITR at various positions were amplified by PCR from p3\' or p5\' and six pairs of oligonucleotides (Table [3](#T3){ref-type="table"}) as primers: O1+O1R; O2+O2R; O3+O3R; O4+O4R; O5+O5R; O6+O6R. Each fragment was purified from agarose gel, and ^32^P-end-labeled using a T4 polynucleotide kinase. Binding reactions were carried out in 50 mM NaCl, 0.5 mM DTT, 10 mM Tris pH9, 5% glycerol, 5 mM MgCl~2~and 100 ng of BSA. Each 20-μl reaction contained 0.2 pmol of labeled probes, and 400 nM purified Tpase \[[@B22]\]. The mixtures were incubated at 4°C, for 15 minutes, and then samples were loaded onto a 6% non-denaturing polyacrylamide (30:0.93) gel in 0.25 × TBE. The gel was run at 4°C and 200 V for 2 hours, dried and exposed to film overnight. At 4°C, two main complexes are expected, as described elsewhere \[[@B3],[@B22]\]: SEC1 and SEC2, single-end complexes 1 and 2. The relative mobility of each fragment (Rf) was defined as the migration distances of the bound complexes divided by the migration distance of free DNA. The Rf of each probe was plotted as a function of the position of the center in each probe to map the center of protein-induced bending. The apparent bend angle, α, was computed using the following equation \[[@B21]\]: $$\frac{\mu_{\text{i}}}{\mu_{\text{j}}} = \frac{\left\lbrack {1 - (2\chi_{\text{i}}/\text{L})(1 - \cos\alpha) + 2{(\chi_{\text{i}}/\text{L})}^{2}(1 - \cos\alpha)} \right\rbrack^{0.5}}{\left\lbrack {1 - (2\chi_{\text{i}}/\text{L})(1 - \cos\alpha) + 2{(\chi_{\text{i}}/\text{L})}^{2}(1 - \cos\alpha)} \right\rbrack^{0.5}}$$ In which μ~i~and μ~j~are the Rf values of the complexes with proteins bound to a centrally positioned ITR and a peripherally positioned ITR respectively, χ~i~/L and χ~j~/L are the fractional distances (*i.e*., the distance between the position of the bending center and the left end of the fragment divided by the length of the probe) of the same probes, and α is the angle of the bend. Statistical analyses -------------------- All the data used for graphic representation corresponded to mean values obtained from 5--9 experiments. The differences between samples were analyzed using a non-parametric Wilcoxon/Kruskal-Wallis test with a significance threshold of at least 0.05 after checking the normality of each sample with a Shapiro-Wilk test to a significance threshold of 0.05. Abbreviations ============= ITR: inverted terminal repeat; SEC: single end complexes; PEC: paired ends complexes. EMSA: electrophoretic mobility shift assay. Tpase: transposase. Authors\' contributions ======================= The study was conceived and designed by CAG and YB. Transposition assays in bacteria (length dependence and GC content) were carried out by LS and GJ. BB carried out *in vitro*transposition and excision assays. FRB and YB studied minute *Mos1*transposition. Circular permutation assays were carried out by CAG. The authors, in respect with their own contribution, analyzed the data. CAG and YB wrote the manuscript with input from FRB. All authors have read and approved the final manuscript. Supplementary Material ====================== ###### Additional File 1 **Sequences of DNA stuffer used in the study.** this file provides all the transgene sequences used in the study. ###### Click here for file Acknowledgements ================ This work was sustained by the University of François Rabelais of Tours and funded by grants from the European Commission (Project SyntheGeneDelivery, N°018716), the C.N.R.S., the Ministère de l\'Education Nationale, de la Recherche et de la Technologie, the Association Française contre la Myopathie, and the Groupement de Recherche CNRS 2157. The English text has been revised by Dr M. Ghosh. | Mid | [
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Molecular diagnostics for head and neck pathology. Molecular diagnostic techniques are quickly finding a role in the detection and diagnosis of tumors, and in predicting their behavior. They may also prove useful in developing new therapeutic approaches to head and neck cancer. The surgeon working in the craniomaxillofacial region should have an understanding of these technologies, their availability in various settings, and how they affect various aspects of treatment, particularly in the detection and treatment of malignancies. This article offers an overview of recent advances in molecular diagnostic techniques, with their implications for diagnosis and management of head and neck tumors. | High | [
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Q: Bugging message "You can only post once every 20 minutes" I am frequently being confronted by this message in Stackoverflow "You can only post once every 20 minutes.". You can find from my profile that I am just asking genuine questions regarding whatever I hit roadblocks in my code and also acknowledge the comments/answers on their receipt. What is causing this embargo to be frequently being slammed on my contributions to the website? A: You are not supposed to ask every question that comes to mind even if it is a good one. Do your homework. After your research you can ask a question. And that should take more than 20 minutes. | Low | [
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Thazhekkad, Irinjalakkuda Thazhekkad is a village in Thrissur district in the state of Kerala, India. Demographics India census, Thazhekkad had a population of 13387 with 6412 males and 6975 females. Thazhekkad is covering a vide area comparing to its nearby villages. Religion Hinduism, Christianity and Islam are the prominent religions in this area. 60% of the population are Hindus, 35% Christians and remaining 5% Islamic believers. St. Sebastian's church located in the village is a well known pilgrimage place for people regardless of caste or religious beliefs and social backgrounds. The deity St.Sebastian at the church is called as "Muthappan" by the residents. Followers of all religions lead harmonious and peaceful lives. Just opposite to St.Sebastian's Church, there is a temple of Lord Siva called as Thazhekkad Maha Siva Kshethram and there have not been any communal disturbances till date. This is well recognized as the best example for the communal harmony existing in the village. Economy The economy of the village is based mainly on agriculture. Agricultural crops grown include paddy, coconut, arecanut, banana, spice crops like pepper, nutmeg, and fruit trees. Thazhekkad has skilled youth who have gone to foreign lands, Middle East,Europe etc.; in search of better employment opportunities. The other significant source of income to the locality is remittances from NRIs. Transportation Road is the main mode of transportation for Thazhekad residents. The nearest railway station is Irinjalakuda, situated at Kallettumkara. The places/junctions connecting Thazhekkad to nearby towns and city include Kallettumkara, Kombinjamakkal, Thommana and Aloor and, these junctions and railway station are located at around 2-4 kilometers away from the village. Fast and easy to and fro commuting is an issue that the villagers face. Public transportation system, the most commonly used mode of transport by the public, is in its nascent stage over here. But gradually, many have overcome this issue to an extent by starting to use their own vehicles (bicycles, motor cycles and cars). Geography The landscape of this locale is attractive and naturally endowed. Evergreen paddy fields surrounded with water bodies like small canals and ponds with clear waters and aquatic richness add a perfect countryside picture to every body's heart. People from other parts of the district pay visits to Thazhekkad to enjoy holiday outings and there are a couple of interesting visitor's spots like Atbhutha Kulam (meaning 'wonder-pond'), fishing spots in paddy fields. References Category:Villages in Thrissur district | Mid | [
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The sensitivity of folding free energy landscapes of trpzips to mutations in the hydrophobic core. The sensitivity of the stability of folded states and free energy landscapes to the differences in the hydrophobic content of the core residues has been studied for the set of 16-residue trpzips, namely, Trpzip4, Trpzip5 and Trpzip6. The combination of principal component analysis and different secondary structure order metrics as reaction coordinates has been used to characterize and identify all the underlying attractive basins corresponding to the folded and the unfolded states for each trpzip at 300 K. Our results reveal that even a single mutation in the hydrophobic core perturbs the stability of the folded peptide and the conformational preferences for the partially folded and unfolded states significantly, leading to concomitant alterations in the free energy landscape of trpzips. Trpzip4 is observed to have the most rugged and variegated free energy landscape with occurrence of four metastable unfolded states in addition to the folded native state. In contrast, Trpzip5 and Trpzip6 are characterized by two such metastable states. The order metrics pertaining to the rigidity of the turn residues and the distances between the side chains of the hydrophobic core residues have been found to be most revealing to understand the degree of discrimination among the folded states of different peptides in addition to the unfolded states. Our results suggest that both turn propensity and hydrophobic interactions influence the thermodynamics of the folding pathways of trpzips. The implications of the sequence dependent response of amino acids, effect of aromatic stacking interactions and packing of protein's interior for shaping the free energy landscape of the peptides have been highlighted. | High | [
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Open Box - CP Pistons D16A6 9:1CR - SC7056 Open Box - CP Pistons D16A6 9:1CR - SC7056 500.00 We purchased these D16A6 CP forged pistons for our D16Y8 turbo build but decided to go with lower compression pistons instead. Never used or installed and come with the original set of rings that CP shipped with these pistons. See picture for detailed specs. | Low | [
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SACRAMENTO -- Gov. Jerry Brown won widespread praise Thursday for proposing a budget that beefs up education spending, averts more cuts to the social safety net and sets California on a fiscally stable course that until recently seemed like an impossible dream. Two years ago, in the midst of a stubbornly rotten economy and in the first year of his term, Brown was grappling with a projected $26.6 billion deficit over an 18-month period. A year later, it was $16 billion. And even until Thursday morning, the Legislative Analyst's Office was forecasting a $1.9 billion budget hole. But suddenly, Brown could crow about a balanced budget with projected future surpluses, thanks largely to previous grueling program cuts and voters who in November approved his $5.6 billion annual tax-hike measure, Proposition 30. "This is new; this is a breakthrough," Brown said at a news conference in which he unveiled his spending plan. "But it doesn't mean we're in the clear." As part of his $97.7 billion budget for the next fiscal year, which begins in July, Brown continued to take the path of paying down past debts over restoring previous cuts, as many of his Democratic allies are demanding. Brown calls for paying $4.2 billion down on the "wall of debt" built by previous governors -- "paying for the expenses of the past instead of meeting current needs" -- and establishing a $1 billion rainy-day fund. That green-eye-shade approach has instilled many in the Capitol with confidence, including leaders of the normally critical GOP opposition. Indeed, the apparent shift in tides has many talking about a revived Golden State. Advertisement "Just a few months ago, we were talking about dramatic cuts to education, ending school early," said Thad Kousser, a political science professor at UC San Diego. "But voters voted themselves a balanced budget and, barring a double-dip recession, the governor now gets to use the budget as a tool to reshape government and state policies rather than 'how to stop the bleeding.'" Though the Legislative Analyst's Office projected a $1.9 billion deficit through 2013, Brown's budget is balanced by counting $600 million from new revenues from Proposition 39 (a measure passed in November that closed corporate loopholes), $560 million from the closure of redevelopment agencies and slightly higher revenues from other tax programs. One major aspect of his budget is a policy initiative aimed at overhauling the K-12 school financing system. Brown is calling on legislators to scrap an antiquated formula that has created wide disparities in revenue among similar school districts -- and replace it with a formula awarding more to schools serving low-income students and those struggling to learn English. Brown also would give districts more latitude in spending decisions. K-12 schools would get $1.89 billion more than last year -- a 4 percent increase over last year. In addition, the state would pay back $1.8 billion that it owes schools from previous years. But Brown's biggest thrust in his budget rollout was to play the role of fiscal scold. The Democratic governor repeatedly warned legislators in his own party to cool it on their spending demands. "Fiscal discipline is not the enemy of democratic governance but rather its fundamental predicate," he said. "It's very hard to say no. That's basically going to be my job." A balanced budget, he said, "allows us to take care of people over time instead of a momentary rash of excitement -- and then we pay with a hangover." The governor will be in a strong position to say no, said David Latterman, a political science professor at the University of San Francisco. "Brown can pretty much pick and choose whatever he wants to do -- he's got all the political capital he needs from the voters," Latterman said. "He'll check some of the more shocking ideas that might come from the left, and voters expect him to do that." Republicans, who have fallen so low in their numbers at the Capitol that they won't likely have much impact on policy decisions in coming years, approved of Brown's fiscal message. "Assembly Republicans agree with the governor that a 'live within our means' budget is the most fiscally responsible course for our state this year," said Assembly GOP Leader Connie Conway, R-Visalia. "Now is not the time to enact massive spending increases that will reverse the progress we've made in reducing the deficit." Business groups gave Brown credit for, as Jim Wunderman, president and CEO of the Bay Area Council said, "restoring a measure of fiscal stability to California's budget." Brown's plan to continue to pay down debt and build a $1 billion reserve were good first steps, said John Kabateck, executive director of California's National Federation of Independent Businesses. But businesses remain skeptical that all the Proposition 30 money will go to schools. Though they generally embraced Brown's budget, allies from the left urged the governor to keep in mind that many people are still hurting from previous cuts in state support. Brown's budget "lacks a vision for the future about how we will help the millions of Californians who are unemployed or living in poverty despite working," said Vanessa Aramayo, director of California Partnership, a coalition of community organizations that helped turn out the vote of low-propensity voters for Proposition 30. Art Pulaski, secretary-treasurer of the California Labor Federation, called on the governor to "repair the gaping holes in our safety net" by eliminating or reforming corporate tax breaks that are not creating jobs. Brown is proposing restoring some social service cuts. His $19.5 billion budget for the Department of Social Services is an increase of $577.4 million from last year's budget. Senate President Pro Tem Darrell Steinberg, D-Sacramento, vowed to use the Democrats' newly gained two-thirds majority to eliminate certain corporate tax breaks. He also said he wants to restore programs that have been eliminated or diminished by past cuts, such as child care and adult dental care. Whichever path the Legislature takes before they counter with their own budget in the spring, Brown has proven himself to be a leader with the right touch, said Max Neiman, senior resident scholar at the Institute of Governmental Studies at UC Berkeley. "I've always been struck by how prudent and careful he's been, particularly in the last couple decades," Neiman said. "But we're real fortunate to have him in these times. He's the governor for these times." Staff writers Josh Richman and Sharon Noguchi contributed to this report. Contact Steven Harmon at 916-441-2101. Follow him at Twitter.com/ssharmon. Read the Political Blotter at IBAbuzz.com/politics. | Mid | [
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BIAS & the Quality of Data To separate good information from bad stick to the ABCs of forensic investigators: Assume nothing; Believe, no one; and Check everything. For people issues there is also a D: Dollars are usually a signpost to the root of an issue Evidence - called here data - as discussed in Bias Aware Thinking, is made up of an assortment of objects, information, testimony, indeed any sort of clue that supports or challenges a claim, theory, or argument. Data, of course, can be fraudulent, erroneous, incomplete, or the whole truth of the matter. Guidance to determine the quality of this data can often be found by an awareness of bias. When a self-interested group has made use of some data and the findings appear to be self-serving then the conclusions would generally be examined for bias. It is usual in those cases that supportive aspects of the matter were considered and other facts were either ignored or downplayed. But when one agrees with a certain conclusion the existence of biases in the data supporting it will rarely be questioned. As data quality is a major piece in solving The Bias Puzzle the merit of all data should established as far as possible or practical. This is no easy matter as the quality data can be misinterpreted when being used. So the unconditional rule is to examine data skeptically, whether one agrees with its conclusions or not. Perhaps the best way to evaluate the quality of data is to solicit input from diverse sources; especially from those whose brains function differently from one's own (see Step #10 in Bias Management). That is why most legal systems have juries of more than one person and information is presented by a prosecution and a defense each with (in many jurisdictions) their own experts. An analogy of how data can be biased is shown in sliding tile puzzle graphics below. There are eight facts represented by numbers 1 to 8; but the logical arrangement, or conclusion, from those facts can be different - only one of which would represent a truth. The bias would be in the determination of the appropriate arrangement - "sequential line-by-line" or "circular". both arrangements of the tiles seem logical but only one can represent the truth | High | [
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A new West Point study released by the U.S. Military Academy's Combating Terrorism Center is linking opposition to abortion and other "fundamental" positions to terrorism, and pro-life leaders say it's just a way to paint them in a negative way. The study, "Challenges from the Sidelines: Understanding America's Violent Far-Right," says the major far right threats are from, "a racist/white supremacy movement, an anti-federalist movement and a fundamentalist movement." Author Arie Perliger cites "anti-abortionists" as an active threat for terrorist activity. "The anti-abortionists have been extremely productive during the last two decades, amassing 227 attacks, many of them perpetrated without the responsible perpetrators identified or caught," Perliger wrote. "And while, in both cases, the 1990s were more violent than the last decade, in the case of anti-abortion, the trend is much more extreme, as 90 percent of attacks were perpetrated before 2001." American Life League President Judie Brown believes this is a smear tactic. TRENDING: Wildfires to get worse thanks to Clinton policies, says fire expert who predicted uptick in blazes "I can see exactly what is going on with reference to the pro-life movement. The use of two words expose the bias and hatred for what we stand for as a movement. Those words are 'attacks' and 'violence'," Brown said. "When it comes to pro-life activism, the definition of violence is retooled to include screaming, sitting in or blockading, and in the situation when someone who is clearly mentally imbalanced does something actually violent at or near an abortion mill, the act is immediately attributed to a pro-lifer even when there is no evidence that the perpetrator was ever involved with the mainstream pro-life effort," Brown said. "All of us have issued statements condemning violence because abortion is the ultimate act of violence and in response we are called to imitate Christ, not the abortionists. So the paragraph is designed to paint pro-lifers in a way that scares others, whether or not the depiction even remotely reflects the facts, which of course it does not," Brown said. The report comes from a center at the institution where men and women are trained to be Army officers. While the center's reports often address threats from al-Qaida and other extremists, the latest work addresses the cross-section of America that authors perceive as the "far right." It alleges "anti-federalists" are those who have strong beliefs about the government, "believing it to be corrupt and tyrannical," and those Americans who support individual freedoms and self government. It claims that those who adopt a liberal philosophy are "future oriented" while conservatives are linked to the violence of the "far right" and live in the past. "Liberal worldviews are future- or progressive-oriented, conservative perspectives are more past-oriented, and in general, are interested in preserving the status quo," wrote the authors. "The far right represents a more extreme version of conservatism, as its political vision is usually justified by the aspiration to restore or preserve values and practices that are part of the idealized historical heritage of the nation…" Another suspect group in Perliger's study are people who support the sovereignty of the United States. And he concludes the anti-government movement is a recent phenomenon. "Violence derived from the modern anti-federalist movement appeared in full force only in the early to mid-1990s and is interested in undermining the influence, legitimacy and effective sovereignty of the federal government and its proxy organizations," Perliger wrote. "The anti- federalist rationale is multifaceted, and includes the beliefs that the American political system and its proxies were hijacked by external forces interested in promoting a New World Order in which the United States will be absorbed into the United Nations or another version of global government," Perliger wrote. "They also espouse strong convictions regarding the federal government, believing it to be corrupt and tyrannical, with a natural tendency to intrude on individuals' civil and constitutional rights. Finally, they support civil activism, individual freedoms, and self-government. Extremists in the anti-federalist movement direct most [of] their violence against the federal government and its proxies in law enforcement," Perliger wrote. Herb Titus, a constitutional law professor, former dean of the Regent University School of Law and distinguished fellow with the Inter-American Institute for Philosophy, Government, and Social Thought, says it's an attempt to link conservative thought with violence. "Professor Perliger has adopted the strategy of many left-wing members of the professoriate, concentrating on the behavior of a few in order to discredit many who hold similar views but who do not engage in any form of violence," Titus said. "His theory is that of the iceberg, that which as seen may be small, but it hides what is a much larger threat just below the surface. Obviously, the professor disagrees with those who favor small government, cutting back of federal government encroachments upon the powers of the state and to discredit this movement focuses on a few gun-toting militia," Titus said. Titus turns his attention to who he believes is the source of the study. "Like so many in the Obama administration, Perliger does not want to engage in any dialogue on the issues, but just discredit an entire political movement by ad hominem charged words," Titus said. "Perliger is not a serious scholar, but a propagandist for the existing regime." Perliger turned his attention to Christian fundamentalism and asserts a connection between all three of his sub-groups. "Unlike the movements discussed previously, the fundamentalist movement's militant and violent nature was relatively late to develop. For many years the… fundamentalist movement did not produce violent sub-groups, but rather functioned as a source of intellectual inspiration and a moral justification for the violent activities and operations of ideologically related movements," Perliger wrote. "Hence, it is not surprising that many of the prominent ideologues of the white supremacist and anti-federalist movements intensively cooperated with – and at times saw themselves as part of – the fundamentalist movement. This dynamic allowed the penetration of non-identity ideas into the movement, and in many ways facilitated the narrowing of the gaps between the fundamentalist movement and other streams of the American far right," Perliger wrote. Former Army intelligence officer and NATO intelligence specialist Tim Tooman says the juxtaposition of all three groups in one paragraph is intentional and notes the frequent use of the words for Christianity. "Christian and derivatives [are] used 75 times in the document, although often carefully qualified as in Christian Identity Group. Perliger's writing is OK, but could be misinterpreted by the quick reader," Tooman said. "There is no problem with U.S. Christianity supporting domestic terrorism. Personally I think some in the mainstream media would like there to be as it would make a great headline – and distract from actual terrorism support from some Islamic groups," Tooman said. Tooman says the paper is directed at solving a non-existent problem. "This seems to be a well researched research paper on a non-issue as far as the military is concerned. There are of course issues discussed within it relevant to local and national law enforcement agencies. So, it's 148 pages of beating a dead horse that never really had any life in the beginning," Tooman said. Tooman also takes issue with Perliger's frequent use of the two-word phrase, "far right." "I find the overuse of the term 'far right' objectionable – 410 times in a 148-page document. Pages 13-18 purport to define the far right, but fall short," Tooman said. Former FBI counterterrorism officer and terrorism analyst and consultant John Guandolo says the study is another example of the continuing ideological shift of the national security apparatus away from the real terrorism threat to the United States – Islamic terrorism. "That shift has already been made. The Department of Homeland Security has codified it in their internal language. Veterans and Christians are the threat. Muslims are all peaceful and there is nothing more to see here," Guandolo said. He cited John Brennan, the nominee to be the next CIA director, and his vocal defense of Islam. In a speech delivered Aug. 9, 2009, to the Center for Strategic and International Studies that is archived on the White House website, Brennan said using "a legitimate term, 'jihad' – meaning to purify oneself or to wage a holy struggle for a moral goal" – to describe terrorists "risks reinforcing the idea that the United States is somehow at war with Islam itself." As WND reported, Brennan advised in the speech that U.S. foreign policy should encourage greater assimilation of the Hezbollah terrorist organization into the Lebanese government. In a July 2008 article in The Annals, a publication of the American Academy of Political and Social Sciences, Brennan argued it "would not be foolhardy, however, for the United States to tolerate, and even to encourage, greater assimilation of Hezbollah into Lebanon's political system, a process that is subject to Iranian influence." Terrorism analyst and Jihad Watch publisher Robert Spencer says the public should be aware of what the military and intelligence communities are saying to one another. Spencer says the West Point-released study is another obvious example of the government's four-year campaign to downplay the threat of Islamic terrorism. "This is of a piece with the 2009 DHS report that identified right-wing extremists as a terror threat. It is another attempt to deflect attention away from the Islamic jihadists," Spencer said. WND reported that the April 2009 report, "Right-wing Extremism: Current Economic and Political Climate Fueling Resurgence in Radicalization and Recruitment," openly says Christians are the main threat to the United States. Islam and terrorism analyst and Atlas Shrugs publisher Pamela Geller says this is another insult towards those who love their country. "This is another appalling attempt to demonize loyal Americans and whitewash the Islamic threat," Geller said. "West Point probably is working on orders from higher ups. Or else it has bought into the dominant PC culture." The Combating Terrorism Center at West Point has not responded to WND's requests for an interview. | Mid | [
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Stephen Williams MP praises Bristol ECLO Bristol West MP, Stephen Williams met with Bristol Eye Hospital ECLO, Laura Kirby, on Friday 16 May to find out more about her role providing practical advice and emotional support to people who are have been recently diagnosed with sight loss. Laura explained: “The impact of sight loss is different for every patient. Some feel a loss of identity, others fear they will lose their independence. Part of my role is to discuss with patients what their fears are and to try to find ways those can be overcome.” Laura added: “Often patients just want someone to talk to. I have the time that unfortunately clinical staff don’t have during appointments, and can talk them through all sorts of difficulties. Patients can call me at any time, even if it is months after the diagnosis.” As well as a tour of the Eye Hospital, Mr Williams attended a focus group where he met consultants, nurses, patients and support workers, who explained the impact of having an ECLO. Mr Williams said: “Losing your sight affects every aspect of your life, so the role of the ECLO is very much appreciated by the patients, to be that first port of call for the information and guidance people will need.” Over two thirds of eye clinics in the South West do not offer any dedicated support to people who are losing their sight. This needs to change. | Mid | [
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Nippa Station is an above-ground metro station located in Kōhoku-ku, Yokohama, Kanagawa Prefecture, Japan operated by the Yokohama Municipal Subway’s Blue Line (Line 3). It is 31.8 kilometers from the terminus of the Blue Line at Shōnandai Station. History Nippa Station was opened on March 18, 1993. Platform screen doors were installed in April 2007. Lines Yokohama Municipal Subway Blue Line Station layout Nippa Station has two elevated island platforms serving four tracks. The ground-level station building is located underneath the tracks and platforms. The inner Tracks 2 and 3 are used for services originating at Nippa Station Platforms Adjacent stations References Harris, Ken and Clarke, Jackie. Jane's World Railways 2008-2009. Jane's Information Group (2008). External links Nippa Station (Blue Line) Category:Railway stations in Kanagawa Prefecture Category:Railway stations opened in 1993 Category:Blue Line (Yokohama) | Low | [
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The Ontario government has proposed a Great Lakes Protection Act, strategy, and support for local actions. Already, several groups have commented on the news. “Protecting the Great Lakes is not just a ‘nice’ thing to do; it’s absolutely necessary for our social, economic and environmental well being,” said Don Pearson, general manager of Conservation Ontario, the organization that represents Ontario’s 36 conservation authorities. “Despite efforts to date, which are often the result of coordinated support from a wide variety of sources including municipal, provincial and federal governments, there are still significant challenges to address. These include invasive species, beach closures resulting from contaminated runoff, algae blooms affecting drinking water and public health, and climate change impacts. This announcement is evidence that the Ontario government cares about the Great Lakes and we’re pleased to see that,” said Pearson. “There are many organizations in Ontario who are working hard to implement important stewardship and monitoring programs that address local watershed challenges and how they impact conditions in the downstream Great Lakes,” Pearson added. “It’s good to see that support for this work will continue.” On May 9, the Canadian Environmental Law Association (CELA) produced a statement of expectations (pdf here) for a Great Lakes Protection Act, in collaboration with Ecojustice, Ducks Unlimited, Environmental Defence, Great Lakes United, and the Sierra Club of Canada. In a release, Ecojustice’s Rick Smith said that he feels the collective advice to the government has been heard. “We are looking forward to seeing all party support for an important Act to restore the Great Lakes, a huge economic engine, and the drinking water of 37 million people,” he said. “The government’s proposed bottom-up approach to identifying problems and solutions based on local input and involvement is efficient and inclusive,” said CELA’s Theresa McClenaghan. “I am also pleased to see that this act follows the Environmental Commissioner of Ontario’s advice to bring multiple ministries together to address cross-cutting issues.” According to The Canadian Press, the act would establish a Great Lakes Guardians Council, chaired by Environment Minister Jim Bradley and including other ministers, municipal representatives, First Nations members, people from the agriculture sector and scientists. Bradley says the council would identify provincial Great Lakes improvement priorities and direct resources. The act would also establish a Great Lakes Community Action Fund, which would provide $1.5 million in the first year to community groups for projects that would benefit the lakes. | High | [
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Tarantino Marathon: 3-True Romance The second film in my second marathon of 2017 is not actually directed by Q.T, but was written by him and directed by the late great, Tony Scott. True Romance feels like a Tarantino joint with his witty banter, grindhouse violence, and countless pop culture references. Q.T sharpens his writing chops with the script for True Romance. Many of his classic tropes can be seen in his script. Overall this is one of the best of his career and should be enjoyed by all! One of my all time favorite scenes stars Christopher Walken and Dennis Hopper that will leave you wondering what the hell you just heard. 5/5 | High | [
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