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I'm seeking any sort of advice about what sort of planning jobs fit my skills. What sort of firms should I be looking at and how can I position myself so that I'm an attractive candidate?
Here's my background:
I have two undergraduate degrees: a BA in Economics and a BA in Urban Planning. I also have a Masters in Urban Planning from a well-regarded school. My academic work revolved largely around heritage planning.
I graduated three years ago but rather than going into planning I started a business writing software and building web sites. Most of what I build is written in Flash and I work for advertising firms writing touch-screen kiosk systems, Flash web sites, and various other things for large companies (Toyota, Bayer, Dupont, etc). I'm self-taught and I don't claim to be the best programmer out there, but I make sharp looking things with really simple interfaces that do neat stuff in the background. My graphic design skills are quite good.
I like what I'm doing and it pays pretty well, but I'm thinking I might like a regular pay check. I feel that there must be a way to combine the software and design side of my experience with my academic planning background to form a package that employers would want. Presumably planning firms of a certain size would find it useful to have a guy who could develop interactive Flash walk-through terminals or web sites for clients or the public, or put together web sites or whatever they may need who also has a strong understanding of planning.
Trouble is, I'm not quite sure where to start. It's very rare that I see job listings that come close to what I'm picturing. Is it because I'm wrong and firms don't need people like me, or is it that I'm not looking in the right place?
Any thoughts on how I might go from where I'm at to where I'd like to be would be really helpful and appreciated.


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Sell anything,anywhere,anytime!
12m Shipping containers converted into self storage units.
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Discussion in 'Heavy Equipment & Pavement' started by Dirtman2007, Nov 17, 2008.
That was a fun 523 pages viewed in a day (I mostly look at pictures), keep it up!
started a project today that was worth taking some pics of as I hardly ever build rock walls, but this site had so many to get rid of.
Wow, you did all that in one day? Cool!
Damn good job Chris!
I like the steps too. The wall along the steps is the toughest part I would say esp with those long ones.
You use any fabric behind the rocks? that helps as the years go by with erosion and keeping weeds from growing in the cracks. Edit: nvm I see the roll of fabric now.
Looks like 200-250 sq ft wall to me, I'm impressed.
You build it from the top?
yes I used fabric behind the rocks, I had to build it all from the top as the septic field is about 4' infront of the wall. my helper telling me where to nudge them to make it tight. funny how the back can look so perfect then the front look like crap! lol Im only half done with the steps and the wall, ive got about another 50' past the steps to go and then a few terraces to do on the sides of the house.
Almost finished everything today, little more grading and cleanup tomorrow
Very impressive Chris.
How's the ole backhoe treating you? I've got the opportunity to pick up one pretty cheap. Thought it would make a nice winter project.
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thanks. its been very handy on the farm for any project. just always nice to have something to lift things and move heavy stuff around. god it was such a pain before! Now that im done with my little pond it does not get used everyday but its paid for so it doesn't hurt if it sits. Ive got a few things that need to be tinkered with on it as far as maintenance but its been a solid investment for what I have in it. Handy machine not the best for any job but it worked with the budget I had.
Walls look great Chris. Only thing I don't like about the steps is I would have rather used single large pieces to make the "stair treads" instead of the occasions where you used multiple pieces. It seems there is less of a chance of it being a "tripper" with one large piece. I also understand though that you are restricted to using what you find in the ground and as a landscaper I am ordering from a distributor and can be a little more picky LOL. Anyway, nice work as always keep the pics coming!
You're making me wanna build some boulder walls. Between what you're posting and what Cornell posts.
thanks, yeah I used the rocks I had for the steps. it was hard to find 6-7' long flat rocks. they guy said he was going to mortar all the joints to make them smooth.


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- Please select a date to see the proper prices!
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Rooms, services 22 comfortably furnished rooms are offered by Jägerhof Bodenmais to guests looking for accommodation in Bodenmais. Parking is availably nearby for those arriving by car. If you love spending your leisure time actively it may be a good idea to check the table tennis and billiard opportunities nearby. The exact scope of services offered by Jägerhof Bodenmais (including those for an extra fee) is available on the information sheet below.
Payment For the reservation you may need to provide advance payment by credit card or credit card guarantee, depending on the exact date, room and price.
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Discussion in 'Football' started by KFitzy87, Sep 8, 2012.
WOOOO GO CYCLONES!!! Not pretty but a win is a win!
Alot of **** to work on, but will take the W.
Have to agree ugly game. But we came out on top and can't be disappointed with that
Never thought 9 points would be enough to get it done. But man the D was balls today.
Clone fans should enjoy. Even if Iowa would have pulled it off at end there would have been no joy. ISU should have been up by 20.
Why do I still feel like we lost that one? Amazing for the D. 4 tournovers and away. ISU is clearly the better team.
Dogs win again, amirite?
So ugly, so bad. But....
We tried to lose that game every way possible but great job out of the defense to bail us out.
What a f**king play by Jake Knott
Here's to being 2-0 when nobody else thought we would be. Take that, ****ers!
Red zone offense. Gotta improve.
Right on the money. We won the game but it still feels like we lost. There were several wtf were we thinking moments.
Exactly....our play calling needs help
Well, let's all open a cold one and open up a second browser window to watch the fun unfold at Hawkeye Nation. It'll be like watching pleasure boaters put their boats in on Labor Day!
I don't think it was play calling, I think it was execution. I'll bet my left nut that Jantz just made some bad reads on the run calls. I'm certain we went more conservative in the second half because CPR just wanted to run the clock down as much as possible.
reading HN thread titles is fun at the moment. But I agree, I only got to see the last quarter and I'm not sure how else we could have tried to give them the win.
Jake Knott trending on Twitter.
Listening to my 6 year old daughter screaming: "The Hawks went DOWNNNNNN!!!!!!"...Priceless!
Both defenses played outstanding, but we sure piddled a few down our legs. A lot to learn from this one for sure. Great win even if it was ugly.


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The Servile Trailer (1994)
27 January 1994 Drama 112 mins
Thommy, a Christian migrant labourer from Kerala is an obedient slave of his aggressive, tyrannical landlord Bhaskara Pattelar. Thommy obeys all the orders of his master, whether it is to make his own wife sexually available to his master or in killing Pattelar's kindly wife, Saroja. When Pattelar escapes to a jungle, due to his own deeds, Thommy escorts him like a pet. But when Pattelar is killed Thommy exults in freedom.
Watch the official The Servile 1994 trailer in HD below or find more The Servile videos on Vidimovie.


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Qualitative and quantitative measures of mitochondrial function were performed in rats selectively bred 15 generations for intrinsic aerobic high running capacity (HCR; n = 8) or low running capacity (LCR; n = 8). As estimated from a speed-ramped treadmill exercise test to exhaustion (15° slope; initial velocity of 10 m/min, increased 1 m/min every 2 min), HCR rats ran 10 times further (2,375 ± 80 m) compared with LCR rats (238 ± 12 m). Fiber bundles were obtained from the soleus and chemically permeabilized. Respiration was measured 1) in the absence of ADP, 2) in the presence of a submaximally stimulating concentration of ADP (0.1 mM ADP, with and without 20 mM creatine), and 3) in the presence of a maximally stimulating concentration of ADP (2 mM). Although non-ADP-stimulated and maximally ADP-stimulated rates of respiration were 13% higher in HCR compared with LCR, the difference was not statistically significant (P > 0.05). Despite a similar rate of respiration in the presence of 0.1 mM ADP, HCR rats demonstrated a higher rate of respiration in the presence of 0.1 mM ADP + 20 mM creatine (HCR 33% higher vs. LCR, P < 0.05). Thus mitochondria from HCR rats exhibit enhanced mitochondrial sensitivity to creatine (i.e., the ability of creatine to decrease the Km for ADP). We propose that increased respiratory sensitivity to ADP in the presence of creatine can effectively increase muscle sensitivity to ADP during exercise (when creatine is increased) and may be, in part, a contributing factor for the increased running capacity in HCR rats.
- skeletal muscle
- oxidative phosphorylation
- exercise
- high-capacity runners
- low-capacity runners
although cardiopulmonary factors are crucial in determining maximal oxygen consumption (V̇o2 max), local oxidative capacity is another key component to aerobic exercise performance. For a given rate of submaximal steady-state work, a greater local oxidative capacity (i.e., mitochondrial density) will require a lesser degree of activation per mitochondrion to achieve a given rate of oxygen uptake (10, 17). This, in turn, elicits smaller increases in controllers of respiration (e.g., ADP and Pi) at a given submaximal rate of work. Thus increased mitochondrial density that accompanies chronic endurance training will lead to favorable adaptations such as altered substrate utilization and decreased blood lactate accumulation in exercising skeletal muscle (10).
In addition to quantitative changes in local oxidative capacity, qualitative properties of mitochondrial function are altered with exercise training. These qualitative alterations include an increased maximal ATP production rate via fatty acids compared with other substrates (38), decreased sensitivity of the mitochondrion to ADP (ADP sensitivity) (31, 36), and an enhanced ability of creatine (Cr) to further increase the rate of submaximally ADP-stimulated respiration (18). However, it remains unclear whether these qualitative changes in mitochondrial function are directly in response to exercise per se or whether they are related to an inherent capacity of muscle metabolism during exercise.
We previously reported the development of rats artificially selected for low and high intrinsic aerobic running capacity (13). With the exception of a test to evaluate aerobic treadmill running capacity, the rats remain sedentary throughout their lifetime; accordingly, differences between lines reflect genetically determined differences in intrinsic exercise capacity. After 15 generations, maximal distance run during an incremental exercise test to exhaustion was 10-fold greater in high-capacity runners (HCR) compared with low-capacity runners (LCR). Therefore, rats selectively bred for high or low innate exercise capacity offer a unique method by which to further investigate the origin of the quantitative and qualitative differences in mitochondrial function observed after exercise training.
In the present study we measured quantitative and qualitative mitochondrial function in permeabilized fiber bundles from the soleus of generation 15 LCR and HCR rats. The use of permeabilized fibers allowed mitochondria to be assessed in their natural structural environment, making measurements of ADP sensitivity and respiratory stimulation by Cr possible (27). Specifically, we tested the hypothesis that the decrease in ADP sensitivity and increase in Cr sensitivity observed after endurance training are not directly related to exercise per se but rather to the oxidative and exercise capacity of the muscle.
Subject data.
The development of the LCR and HCR was described in detail previously (13). Briefly, artificial, divergent, selective breeding was used to create low and high lines for intrinsic (untrained) treadmill running capacity. The founder population was 80 male and 88 female genetically heterogeneous rats (N:NIH stock) obtained from a colony developed at the National Institutes of Health (7). Each rat in the founder population was of different parentage so that selection was not among brothers and sisters, which produced a broader initial genetic variance (8).
After six generations, maximal distance run to exhaustion was on average threefold higher in HCR than LCR. V̇o2 max of extreme examples of generation 7 females (7-fold difference in running capacity) was 12% higher in HCR than in LCR (9). The higher V̇o2 max of HCR was not due to differences in central factors but rather due to a greater ability to transport oxygen from the tissue capillaries to the cells (9) and by increased utilization of oxygen by skeletal muscle cells (11). This greater oxidative capacity paralleled greater capillary density, higher oxidative enzyme citrate synthase and β-hydroxyacyl-CoA dehydrogenase, and no difference in resting skeletal muscle [ATP] (brackets denote concentration) (11). Data collected at generations 10 and 11 show differences in a number of key mitochondrial proteins between the LCR and HCR rats and suggest that an impairment of mitochondrial function links low intrinsic aerobic capacity to risks for cardiovascular and metabolic disease (39). For this study, female rats were obtained from a colony housed at the Medical University of Ohio and shipped to the University of California, San Diego at 16 wk of age.
Assessment of running capacity.
The protocol for estimation of exercise capacity required 2 wk and was started when the rats were 10 wk old (13). The first week consisted of placing the rats on the treadmill (model Exer-4, Columbus Instruments, Columbus, OH) for increasing duration each day, until the animals were able to run 5 min at 10 m/min on a 15° slope. During the second week, each rat underwent a daily exercise trial on 5 consecutive days at a constant slope of 15° and an initial velocity of 10 m/min. Treadmill velocity was increased by 1 m/min every 2 min until the third time a rat could no longer keep pace with the speed of the treadmill. For each of the five trials, the total distance run (in m) was used as the estimate of exercise capacity. The single best daily run of five trials for each rat was considered the trial most closely associated with the heritable component of exercise capacity.
Eight LCR and eight HCR female rats representing the extremes of generation 15 were selected for the present study. Age was not different between groups (31.1 ± 0.7 wk LCR vs. 29.8 ± 0.5 wk HCR). The LCR rats weighed significantly more than HCR rats (251 ± 12 vs. 183 ± 7 g; P < 0.05).
Tissue preparation.
Both left and right soleus muscles were removed intact immediately after death by pentobarbital sodium (60 mg/kg iv). A transverse slice from the widest point of the middle belly portion of either the left or right soleus (randomized) was excised and frozen in precooled isopentane (−140°C) and stored at −80°C. Transverse 8-μm serial sections were cut on a cryotome (Cryostat) at −26°C and mounted on slides for histochemical analysis of fiber type.
The contralateral soleus was dissected longitudinally into three sections and was placed in an ice-cold medium consisting of (in mmol/l) 10 EGTA-Ca-EGTA buffer (free Ca2+ concentration, 100 nM), 20 imidazole, 3 KH2PO4, 0.5 dithiothreitol, 20 taurine, 5.3 ATP, 15 phosphocreatine (PCr), 9.5 MgCl2, and 53.5 MES, pH 7.00. Fiber bundles in each section were separated with sharp-ended needles, leaving only small areas of contact, and incubated in 1.5 ml of the above medium (4°C) containing 50 μg/ml of saponin for 30 min with mild stirring. To completely remove saponin and metabolites, the fibers were washed three times with mild stirring for 5 min in 1.2 ml of a cooled (4°C) washing and oxygraph medium consisting of (in mmol/l) 10 EGTA-Ca-EGTA buffer (free Ca2+ concentration, 100 nM), 3 KH2PO4, 27 HEPES, 20 imidazole, 0.5 dithiothreitol, 20 taurine, 4 MgCl2, 74 sucrose, 5 pyruvate, 2 malate, 100 MES, and 2 mg/ml BSA, pH 7.00. After washing, the fibers were stored in the washing and oxygraph solution on ice until measurements of respiration were performed.
Measurements of mitochondrial respiration.
Mitochondrial oxygen consumption measurements were performed in a water-jacketed chamber maintained at 25°C. Oxygen consumption was monitored with a fiber-optic system (Instech model 210 fiber-optic oxygen monitor, Plymouth Meeting, PA) and a digital data-acquisition system (Ocean Optics, Dunedin, FL). Unlike a Clarke electrode, the fiber-optic system does not consume oxygen and is based on the phosphorescence quenching principle in which the oxygen concentration affects the rate of phosphorescent decay of the coated electrode tip. A bifurcated optic cable transmits the excitation light to the chamber probe and returns the resulting phosphorescence signal to the photo detector. Measurements were performed in 640 μl of the above-described washing and oxygraph solution. In all fibers, respiration was measured in the absence of ADP (V̇0) and after the sequential addition of 0.1 mM ADP (V̇submax), 20 mM Cr (V̇creatine), and 1.5 mM ADP (V̇max). Immediately after respiratory measurements, the fiber bundles were removed, quick-frozen in liquid nitrogen, freeze-dried, and weighed. Wet weight was used as a reference for respiration and was obtained from the dry weight, by assuming 77% water content (2).
Fiber-type determination.
A modified procedure of Ogilvie and Feeback (19) was used to delineate the muscle fiber types. Sections were preincubated for 8 min in a medium containing 0.49% potassium acetate and 0.26% calcium chloride at pH 4.4 and then briefly rinsed in 0.1 M Tris buffer at pH 7.8. Sections were then incubated at room temperature for 30 min in a medium containing 0.4% glycine, 0.42% CaCl2, 0.38% NaCl, 0.19% sodium hydroxide, and 0.15% ATP at pH 9.4. Slides were rinsed with 1% CaCl2 and stained in 0.1% toluidine blue for 1 min, rinsed in distilled H2O, dehydrated in ethanol, cleared in Hemo-De, and mounted with Permount. Stained sections were viewed under a light microscope at ×25 magnification. The entire muscle cross section was digitally imaged (each rectangular image being 1.15 mm × 0.86 mm). Images were stitched together in Photoshop (Adobe Systems, San Jose, CA), and type I and II fibers were counted.
Data analysis.
All values are presented as means ± SE. Differences between means were tested for statistical significance with a Student's t-test with significance set at P < 0.05.
Exercise capacity.
At 11 wk of age, HCR rats (n = 8) ran 2,375 ± 80 m before exhaustion, compared with 238 ± 12 m for LCR rats (n = 8). Exercise time until exhaustion in HCR was 80.2 ± 1.6 vs. 17.9 ± 0.2 min for LCR.
Fiber type.
Because the intrinsic ADP and Cr sensitivity of mitochondrial respiration has been shown to be fiber-type dependent (16), one soleus muscle (randomized leg) was used to analyze fiber type (n = 6 HCR; n = 5 LCR). No differences between the two groups of rats were found, with the average percentage of type I fibers in the soleus being 87.2 ± 0.7%, similar to that found in other laboratories (5).
Mitochondrial function.
Permeabilized fiber bundles from HCR and LCR rats exhibited a high degree of respiratory coupling as indicated by a respiratory control ratio (the ratio of maximally ADP-stimulated respiration to noncoupled respiration) of 4.5 ± 0.3. Non-ADP-stimulated respiration (V̇0), submaximally ADP-stimulated respiration (V̇submax), and maximally ADP-stimulated respiration (V̇max) were 13–18% greater in HCR, but they were not statistically different at the 5% level (Fig. 1). Similarly, mitochondrial sensitivity to ADP [ADP sensitivity; (V̇submax − V̇0)/(V̇max − V̇0)] was not significantly different between groups (Table 1). Respiration in the presence of 0.1 mM ADP + 20 mM Cr (V̇creatine) was 33% higher (P < 0.01) in HCR compared with LCR (Fig. 1). Therefore, mitochondria from HCR rats demonstrated a significantly greater respiratory sensitivity to Cr [(V̇creatine − V̇0)/(V̇max − V̇0)] (Table 1).
The primary finding of this study is that despite similar oxidative capacity and training history of the soleus muscle, mitochondria from high-capacity runners demonstrated greater sensitivity for Cr-induced stimulation of submaximally ADP-stimulated respiration than low-capacity runners.
Mitochondrial oxidative capacity.
HCR rats exhibited 13% higher mean rates of both non-ADP-stimulated and maximally ADP-stimulated respiration that was not statistically significant. Although not a strict measure of mitochondrial density, comparisons of V̇0 per unit muscle mass at similar respiratory coupling ratios are indicative of mitochondrial density (4). Given that much larger changes in V̇0 have been reported after only 6 wk of training in human (35%) (36) and 4 wk of training in rat (55%) (4), the present data suggest there is little difference in mitochondrial density between groups and imply that factors other than large inherent differences in mitochondrial density were responsible for the enhanced exercise capacity of the HCR group.
ADP sensitivity.
It has previously been demonstrated that the sensitivity of the mitochondrion to ADP is fiber-type dependent and negatively correlated to training status (16, 30–32, 36). A lower ADP sensitivity in this context is not in regard to the whole muscle (which is dependent largely on mitochondrial density, and therefore, likely increased after training) but rather the sensitivity of the individual mitochondrion to ADP. Although seemingly contradictory to improved performance, it has been hypothesized that a decrease in mitochondrial sensitivity to ADP could be an adaptation to maintain normal resting [ADP] and rates of respiration despite the increased mitochondrial density that accompanies endurance training. However, the higher maximal oxidative capacity (mitochondrial density) of muscle, together with an exercise-induced increase in mitochondrial ADP sensitivity (via changes in PCr/Cr; see below), ensures that endurance trained muscle exhibits improved oxidative function during exercise (36, 37).
In the present study, ADP sensitivity averaged 0.15 ± 0.03, similar to that found in previous studies (35), and was nearly identical between groups (Table 1). As discussed above, measurements of V̇0 and respiratory control ratio imply a similar mitochondrial density between groups, supporting the hypothesis that ADP sensitivity is decreased in response to increased oxidative capacity. However, given that the training stimulus was minimal and identical between groups, it cannot be ruled out that some other exercise-related factor is responsible for setting the ADP sensitivity of the mitochondrion.
Cr sensitivity.
Mitochondria in slow-twitch mammalian muscle exhibit a decreased outer mitochondrial membrane permeability for ADP, leading to a Km for ADP that is over an order of magnitude higher than fast-twitch muscle (i.e., decreased ADP sensitivity) (16). However, PCr and Cr appear to easily pass over the outer mitochondrial membrane even in slow-twitch muscle. Therefore, in addition to providing a temporal energetic buffer, a secondary role for creatine kinase (CK) in slow-twitch muscle has been proposed on the basis of the localization of distinct isoforms of CK at the myofibril and/or sarcoplasmic reticulum (MM-CK) and the outside of the inner mitochondrial membrane (mi-CK) near the adenine nucleotide translocase (ANT). It is believed that functional coupling of these CK isoforms with ATPases and ANT results in the preferential formation of ATP at the myofibrils (14, 15, 20, 28) and ADP at the mitochondrion (12, 21, 23–26). According to the Cr shuttle hypothesis, it is thought that PCr and Cr, and not adenine nucleotides, are primarily shuttled between these two compartments (3, 12, 22, 23, 34). Therefore, alterations in cytosolic PCr-to-Cr ratio (PCr/Cr) will control, through interaction with mi-CK, the mitochondrial intermembrane concentration of adenine nucleotides in slow-twitch fibers.
During exercise the PCr/Cr is lowered, favoring the formation of ADP in the intermembrane space of the mitochondrion. It has previously been demonstrated in situ that changes in the [PCr] and [Cr] from those occurring at rest to those during high-intensity exercise can double the rate of mitochondrial respiration in the presence of an identical submaximal cytosolic [ADP] (37). Thus, during exercise, mitochondria become more sensitive to a given cytosolic [ADP] by the decrease in PCr/Cr that accompanies increased rates of work. In the present study, an increased ability of Cr to further stimulate respiration in the presence of a submaximally stimulating [ADP] was demonstrated in innate HCR rats, suggesting that ability of PCr/Cr to regulate mitochondrial respiration is enhanced. Therefore, it would be predicted that the mitochondria in HCR rats become progressively more sensitive to ADP than LCR rats as exercise intensity increases, minimizing the necessary cytosolic increases in [ADP] and [Pi]. Although mitochondrial density is an important factor in altering whole muscle sensitivity to ADP after endurance training, an increased sensitivity to PCr/Cr will have a similar effect by increasing the sensitivity of each mitochondrion to ADP during exercise. It can be speculated that part of the enhanced exercise performance demonstrated by HCR rats, despite similar local oxidative capacity, is the effect of this mechanism. Indeed, mi-CK has been demonstrated to increase after endurance training (1) and chronic stimulation (29). Furthermore, increased respiratory sensitivity to Cr has previously been reported as an adaptation to chronic training both in untrained (together with an increase in mitochondrial density) (36) and highly trained humans (with no change in mitochondrial density) (18, 36). These studies, together with the present data, suggest that mitochondrial sensitivity to Cr can play a fundamental role in determining exercise performance independent of alterations in local oxidative power.
The mechanism by which mitochondria from HCR muscle enhance sensitivity to Cr is unknown. However, the present data suggest that HCR rats exhibit an increased functional coupling of mi-CK to ANT. It has previously been shown that when mi-CK is dissociated from the inner membrane it exhibits roughly one-third of the activity of the structurally bound form (6, 24). Additionally, under conditions in which CK will dissociate from the membrane (increased Pi), Cr stimulated respiration has been shown to be reduced in permeabilized fibers from both cardiac (33) and skeletal (35) muscle. Therefore, in addition to the possibility of increased mi-CK content, it is possible that HCR rats maintain a higher degree of functional coupling between CK and ANT than LCR rats.
In conclusion, these results demonstrate that rats bred for high intrinsic running capacity exhibit an enhanced respiratory sensitivity to Cr. An increased sensitivity to Cr indicates a greater reliance on the PCr/Cr shuttle in propagating the signal for energetic demand to the mitochondria. This presumably results in an increased sensitivity of the mitochondrion, and thus whole muscle, to ADP during exercise despite similar fiber type, maximal oxidative power, and mitochondrial density and may contribute to the performance differences between HCR and LCR.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 the American Physiological Society


text:
The Employment Tribunal has rejected an age discrimination claim by lawyer Leslie Seldon against his former firm Clarkson Wright & Jakes (CWJ), bringing to an end five-year legal battle that reached the Supreme Court.
Seldon first instructed BP Collins partner Jo Davis to launch a case against CWJ in March 2007 after it enacted its partnership agreement and forced him to retire at the age of 65. He argued that the firm could not justify the retirement and therefore discriminated against him (7 July 2010).
The case then went to the Court of Appeal (CoA) (29 July 2010) and the Supreme Court (25 April 2012), with the courts debating upon what grounds a firm can justify retiring a partner.
From the CoA stage Seldon's case has been funded by the Equalities & Human Rights Commission, with Cloisters' Robin Allen QC instructed for the Supreme Court hearing. Allen led 36 Bedford Row's Richard O'Dair, who represented Seldon at the latest tribunal hearing having been instructed by the EHRC.
The Supreme Court ruled that Seldon's firm did have some valid reasons for having a mandatory retirement age for partners. However, it referred the case back to the Employment Tribunal to consider whether forcing partners to leave after their 65th birthday was appropriate and necessary.
In this latest bout, the tribunal considered the remitted issues concerning whether a mandatory retirement age of 65 in the partnership deed of was justified direct age discrimination.
It held that the retirement age was justified at the time that Seldon retired in 2006 because of the need to reflect the expectations of the partners and associates, ensure succession and fulfil the needs of the partnership. It also found that the consent of the partners to the clause was particularly relevant, as was the fact that at the time of retirement the Default Retirement Age for employees was 65.
"While the position might have been different if the relevant date had been after the abolition of the default retirement age and after the planned changes in the state pension age the tribunal is satisfied that the mandatory retirement ago is appropriate and reasonably necessary," the tribunal ruled.
For the claimant Seldon
36 Bedford Row's Richard O'Dair instructed by the EHRC
For the defendant CWJ
Blackstone Chambers' Tom Croxford and Emily Neill


text:
Jan. 30, 1989. #meshach taylor poses during an interview in Los Angeles, Calif. Taylor's agent says the actor, who appeared in the hit sitcoms "Designing Women" and "Dave's World" died of cancer on Saturday, June 28, 2014, at his home in Los Angeles. He was 67.The Associated Press
Meshach Taylor, who played a lovable ex-convict surrounded by boisterous Southern belles on the sitcom "Designing Women" and appeared in numerous other TV and film roles, died of cancer at age 67, his agent said Sunday.
Taylor got an Emmy nod for his portrayal of Anthony Bouvier on "Designing Women" from 1986 to 1993. Then he costarred for four seasons on another successful comedy, "Dave's World," as the best friend of a newspaper humor columnist played by the series' star, Harry Anderson.
Other series included the cult favorite "Buffalo Bill" and the popular Nickelodeon comedy "Ned's Declassified School Survival Guide."
Taylor's movie roles included a flamboyant window dresser in the 1987 comedy-romance "Mannequin" as well as "Damien: Omen II."
Curated from www.foxnews.com
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text:
20 Old-School Alan Jackson Live Shots [PICTURES]
Country Music Hall of Fame-er Alan Jackson has been performing live since starting a band after high school — though, these days, he's performing on much bigger stages. Jackson signed his first record deal in June of 1989, and while his debut single failed to chart, his first album, Here in the Real World, spawned four Top 5 singles — including the No. 1 "I'd Love You All Over Again" — and launched Jackson into life as a country star.
As any major artist does, Jackson has spent plenty of time out on the road and performing at festivals and awards show. These days, he still routinely tours, but it's cool to see what he looked like onstage in those early years. During the 1990s and early 2000s, Jackson played New York City's famed Beacon Theatre and CBGB; stopped by The Tonight Show With Jay Leno frequently; and was asked to perform during a number of awards shows.
Flip through the photo gallery above to see 20 old-school photos of Jackson onstage. Fans can visit his official website to find out where he's headed on tour next.
Test Your Alan Jackson Knowledge!


text:
Brittany Callaghan thinks she's dreaming when a blond, nearly seven-feet-tall Nordic god shows up on her doorstep in her tiny California town. He claims to be a barbarian warrior in need of her help.Though a stunning, statuesque beauty herself, intelligent and independent Brittany has struggled hard to earn respect in a man's world. She is taken aback when Dalden, a spectacular Viking who is a long way from home, needs her help - and is willing to pay for it. He's had Brittany's blood running red-hot since she first saw him, and warrior or not, she agrees to help him.As bold and brash as she is beautiful, Brittany isn't going to be subservient to any man, even one who is everything she ever wanted in a lover, and whose very touch sets her senses afire. Dalden is a warrior to the depths of his soul - proud, powerful and brave - a man who will fight fearlessly and relentlessly for what he wants. And now, what he wants most of all is Brittany....More
"Add a smart-mouthed computer, the burgeoning passion between the oh-so-different protagonists, and Heart of a Warrior offers a wild romp that only Lindsey could write. Fasten your seat belts and relish the ride!" (Amazon.com review)
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Not the beginning of the trio
- Anneliese
Enjoyable as a book, but not when narrated...
I have read and own every Johanna Lindsey book published, and a few on audible as well. I expected to enjoy this much more than I actually did. Laurel Merlington has done "okay" jobs on other Lindsey novels but when narrating the parts of the male main character her voice takes on an almost robot"ish" tone. Also, even though this is fantasy/romance many of the words in the book seem mispronounced, and I have caught a few that are in fact mispronounced (example: Challen, Tedra's lifemate is supposed to be pronounced as Challenge without the G. If you put as much emphasis on detail as I do this will annoy you too much to enjoy having someone else narrate for you. I was unable to enjoy this purchase, and find I am unable to complete the listening experience.
The narrator.
Male main character had a robot"ish" voice that ruined the reading for me, and some words were, and seemed to be mispronounced.
I was unable to finish the experience.
Is a refund possible?
- Michelle


text:
"Brilliant Paramedic"
About: South Western Ambulance Service NHS Foundation Trust South Western Ambulance Service NHS Foundation Trust Exeter EX2 7HY
Posted by Lauym3 (as ),
The following feedback was received by South Western Ambulance Service NHS Foundation Trust via an online Have Your Say survey:
My brother had a heart attack and stroke on Saturday. I would like to thank the Paramedic that first turned up, he was brilliant. I would like to personally thank the young man who first came to our call for help, also would like to thank the rest of the crews that also attended, but my personal thanks for the help that he gave to me at that time.
Response from Laura Martin, Patient Engagement Administrator, Governance, South Western Ambulance Service 3 years ago
South Western Ambulance Service NHS Foundation Trust is very grateful to those who take the time to contact us. All feedback helps us improve the services we offer to our patients and their families.
Unfortunately, we have been unable to identify the members of staff involved in this incident. If you recognise this feeback, and are able to provide the address to which the ambulance attended, please do contact me at firstname.lastname@example.com.
- {{helpful}} {{helpful == 1 ? "person thinks" : "people think"}} this response is helpful
- Was this response helpful? Yes
Thank you for your feedback.
See more responses from Laura Martin


text:
Background. Cystic Fibrosis patients with nonsense mutation in the CFTR gene generally make virtually no CFTR protein and thus often have a more severe form of CF. Recently, Ataluren (formerly PTC124) was suggested to induce the read-through of premature termination codons (PTCs) mainly the UGA codon. However, despite promising results there is not a general consensus of Ataluren efficacy and mechanism of action.
Hypothesis and objectives. The design of new small molecules (PTC124 related) together with the understanding of their mechanism of action could lead to new pharmacologic approaches for the cure of CF caused by nonsense mutations in the CFTR gene. This project was aimed to evaluate the activity of some PTC124 analogues identified by a virtual screening, by different orthogonal assays with vectors containing PTCs in reporter genes and in CF bronchial epithelial cells.
Background. Most physiological assays used for CF diagnosis and as a biomarker in clinical trials measure CFTR-dependent chloride but not bicarbonate transport. Recent studies however reveal that defective bicarbonate rather than chloride transport is the primary cause of impaired mucociliary clearance in the airways and luminal obstruction in the GI tract in CF.
Hypothesis and objectives. Our major aims were (i) development of new protocols to measure bicarbonate transport in rectal biopsies and intestinal organoids from healthy controls and CF patients; (ii) ex vivo testing of CFTR correctors and potentiators for their ability to restore bicarbonate secretion in these models; (iii) validating the concept that CFTR functional variants associated with pancreatitis and sinusitis but not CF have a specific bicarbonate permeation defect.
Background. Since the CFTR gene was cloned in 1989, several strategies for correction of CF lung disease have been explored. Among these, cell-based approaches are under investigation. Endogenous lung stem and progenitor cells have been studied although their contribution in the amelioration of chronic lung diseases is still debated. Stem cell-based approaches to treat CF have not achieved the efficiencies of delivery and engraftment needed for therapy. The reasons rely in the low cell engraftment in the lungs after systemic administration, in the small percentage of differentiated cells in airway epithelia and in the even less percentage of CFTR expression.
Hypothesis and objectives. During our recent works on a class of mouse progenitor cell derived from vessel, named mesoangioblasts4 (mMABs), we observed that mMABs, when systemically transplanted in healthy mice distribute throughout lung, trachea and intestinal epithelium for up to 2 months.The major aim of this study was the evaluation overtime of the engraftment of adult mMABs transplanted in CF mice, in terms of percentage of engraftment and persistence in time. As a parallel purpose, mMABs have been studied in terms of their ability to differentiate in epithelial cells and to express functional CFTR in transplanted CF mice, thus resulting in a general amelioration of the pathology. The whole study aimed to develop a cell therapy approach for patients affected by CF.
Background. CFTR F508 deletion (F508del) is the by far commonest mutation causative of Cystic Fibrosis (CF). F508delCFTR undergoes premature degradation subverting proteostasis regulation and generating fragments which have the potential to up-regulate the protein kinase CK2 that, in turn, can favour CFTR fragmentation and reduce CFTR stability.
Hypothesis & Objectives. The project provide the rationale and proof-of-concept for the design of an original and novel therapeutic strategy that restores CFTR channel function by targeting the specific context in which the mutant CFTR channel fails to traffic to the cell surface. It focuses on the derailed CF proteostatic environment that is driven by the mutant channel, instead of on CFTR protein itself. Our strategy induces a self-sustained positive loop that ameliorates the CF phenotype by inhibiting protein cross linking that blocks autophagy and dampening overactive CK2. The workflow is summarized in the following tasks: 1) Identification and functional characterization of endogenous CK2 targets whose phosphorylation is altered by F508delCFTR; 2) In vivo confirmation of the CK2/CFTR functional link; 3) Analysis of known kinase modulators as a new class of molecules useful to rescue/stabilize F508del-CFTR; 4) In vivo validation of CK2/protein kinases modulators as reagents able to rescue CF phenotypes.
Background. CF is caused by mutations that abolish the function of CFTR, a protein that is needed to transport chloride and bicarbonate across cell membrane in the epithelial cells. The most frequent mutation, F508del requires a specific pharmacological treatment. Such defects can be addressed with small molecules, known as correctors and potentiators. In previous studies, we identified a class of compounds called aminoarylthiazoles (AATs) that potentially correct the CF basic defect.
Hypothesis and objectives. The main objective of our project is to identify new AATs which could be efficiently able to correct the CFTR protein defect caused by F508del. By using an integrated approach (bioinformatics, chemical synthesis, and functional assays) we will aim at developing drug- like compounds with improved activity on mutant CFTR.
Background.The possibility of monitoring the inflammatory response in a IL-8 transgenic WT and CFTR knockout (CF), non invasive, animal model has been demonstrated in a previous project conducted by us [1, 2].
Hypothesis and objectives In the past project we shown that the antibiotic azithromycin causes a significant decrease of the lung inflammation in that is capable of inhibiting the synthesis of bacterial virulence factors. Azithromycin is extensively used in cystic fibrosis as an anti-inflammatory molecule but several cases of azithromycin resistance have been reported [1-2], especially in patients using the drug for long times. It seems then important to identify other therapeutic agents to be used in nonresponding patients.
Background. Pseudomonas aeruginosa is the most predominant lung pathogen in patients with cystic fibrosis (CF). It is quite difficult to eradicate because of its acquired resistance to most available antibiotics and ability to form sessile communities or biofilms, in a protective extracellular matrix. Cationic antimicrobial peptides (AMPs) hold promise as future anti-infective agents.
Hypothesis and objectives. Our objective was to develop a short-sized AMP from frog skin, Esc(1-21) and/or its diastereomer containing two D-amino acids, for treatment of P. aeruginosa lung infections. To this aim: (i) an in-vitro analysis of the anti-pseudomonal, anti-inflammatory, wound healing properties of the two peptides, and (ii) preclinical testing to establish both the peptides' safety profiles and therapeutic dosages were performed.
Background. In the airways, the CFTR genetic defect leads to dysregulation of inflammatory and iron homeostasis that precedes bacterial infection that, in turn, worsens host damage. Lactoferrin (Lf), an iron-chelating glycoprotein of the innate immunity present in airway secretions and secreted by neutrophils in infection/inflammation sites, in addition to the well-known antibacterial activity exerts a key role in inflammatory and iron homeostasis.
Hypothesis and objectives. We suppose that aerosolized bLf can exert a key role on inflammatory and iron dysregulation and reduce infection in pre-clinical CF mouse models of lung infection. Moreover, since Lf is a natural molecule, it shows no side effects and toxicity. In this study we employed bovine milk derived Lf (bLf) as it has been yet used in several clinical trials. Since in CF airways human and bacterial proteases may alter Lf integrity reducing its activity, we hypothesize that nano-delivery of bLf can protect the molecule against proteolysis. The objectives are: 1- to evaluate anti-inflammatory and antibacterial activities of bLf administered by aerosol in mouse models of chronic lung infection; 2- to prepare bLf-loaded nanoparticles (bLf-NANOs) to be aerosolized.
Background. We have shown that the interaction between Burkholderia cenocepacia and lung epithelial cells is mediated by redox sensitive enzymes of the protein disulphide isomerase (PDI) family, in particular by ERp57. In fact, either thiol reactive agents (DTT, GSH, and DTNB) or ERp57 inhibitors are able to drastically reduce the adhesion and the invasion of B. cenocepacia into epithelial cells and to attenuate the pro-inflammatory response elicited by bacteria. These observations suggest that defects in GSH export in the airway surface liquid, observed in cystic fibrosis (CF) patients, may favour B. cenocepacia infection.
Hypothesis and objectives. ERp57 inhibitors, in particular epigallocatechin-3-gallate (EGCG), the most abundant green tea catechin, could be useful in therapies aimed at controlling Burkholderia lung infection in CF patients. To this aim we have evaluated: 1) the effect of EGCG on Burkholderia infection in different cell types; 2) the effect of EGCG on Burkholderia intracellular replication; 3) the efficacy of EGCG in infected mice.
Background. The comprehension of molecular mechanisms underlying CF airways infection by Pseudomonas aeruginosa is instrumental to the design of clinical protocols to prevent and contrast it. Emerging candidates as molecular regulators of infection and virulence in P. aeruginosa are small RNAs (sRNAs), which in other bacterial pathogens have been shown to play key roles in modulating cellular processes linked to pathogenesis.
Hypothesis and objectives. From this perspective, the main aim of this project was the evaluation of the impact on P. aeruginosa virulence and infection of three new sRNAs recently identified in our lab and named ErsA, ReaL and PesA.
Background. Cystic fibrosis (CF) is characterized by chronic airway infections involving a complex and dynamic microbial lung community. Though several studies have investigated the taxonomic composition of the airway microbiota, little is still known about the overall functional capabilities of the resident microbial populations and their relation to patient's lung disease status.
Hypothesis and objectives. Previous studies found changes in CF airway microbiota associated with a severe decline in lung function. The overall goal of this project – which follows the FFC#10/2014 project – is to deeply investigate the airway microbiome of stable (S) and substantial decliners patients (SD) and single patients' dynamics over a 15-month period, to discover the functional traits harbored by microbial communities and new microbiome-based biomarkers, which may be predictive of decline in lung function.
Background. Inhalation treatments with glutathione (GSH) have gained interest among CF patients. GSH is a primary antioxidant whose levels are significantly decreased in lungs during inflammatory processes. However the results attained so far remain disappointing. One of the possible reasons may lie in the fact that CF lungs often present with increased levels of gammaglutamyltransferase (GGT), an enzyme secreted by inflammatory cells, capable of degrading GSH.
Hypothesis and objectives. The hypothesis to be verified was whether the different levels of airways GGT in CF patients might modulate the effects of GSH-based therapies. It is of importance to clarify whether GSH inhalation therapies are truly beneficial, useless or even – in selected conditions – potentially dangerous.
Background. Pseudomonas aeruginosa is the most dominant pathogen associated with adverse clinical outcomes in patients with cystic fibrosis (CF). Anti-pseudomonal β-lactams are the mainstay of therapy for the treatment of chronic P. aeruginosa lung infections CF patients. Unfortunately, this pathogen becomes increasingly resistant to available antibiotics and the global dissemination of multidrug resistant P. aeruginosa strains with acquired carbapenemase genes is a public health concern.
Hypothesis and objectives. One important mechanism of resistance to β-lactams is the production of one or more β-lactamase(s), belonging to either the active serine enzymes or the metallo-β-lactamases (MBLs), which efficiently inactivate these antibiotics. Acquired MBLs are important resistance factors in P. aeruginosa, conferring resistance to most β-lactams, including the last-resort carbapenems. Considering the increasing prevalence of MBL-producing strains in CF patients (as high as >50% in some settings), our goal is to perform the preclinical investigation and optimization of MBLs inhibitors to be used in combination with currently-available β-lactam antibiotics
Background. The chronic airway infection by Pseudomonas aeruginosa (P. aeruginosa) in Cystic Fibrosis (CF) is a pathological manifestation associated with an excessive inflammatory response. The NOD-like receptors (NLRs) are intracellular pattern-recognition receptors that recognize pathogen-associated molecular patterns activating pro-inflammatory response through the assembly of large caspase-1-activating complex, called inflammasome. Recent data suggest that the mitochondria integrate distinct pro-inflammatory signals and relay this information to a key molecular complex related to inflammation, the inflammasome. It has been demonstrated that mitochondria are the main source of inflammasome-activating radical species and as such may constitute the signal-integrating organelle for inflammasome recruitment and activation in P. aeruginosa-driven inflammation in CF. Moreover, in the previous project we have demonstrated that mislocalized CFTR is associated with an increase in intracellular Ca2+ content and that it favored the mitochondrial Ca2+ uptake, predisposing the organelle to a major stress responsivity.
Hypothesis and objectives. The overall goal of this project is to broaden our knowledge on role of mitochondria to decode and integrate the pro-inflammatory signals generated during P. aeruginosa infection in CF. We have performed experiments aimed at obtaining a deeper insight into the complex mechanism that controls the mitochondrial homeostasis, in particular the Ca2+ signal, and the inflammasome activation induced by pathogen in CF
Background. Host defence peptides (HDPs) are short cationic molecules produced by the immune systems of most multicellular organisms. They exhibit a wide range of biological activities from direct killing of invading pathogens to modulation of immunity. Chronic infection with P. aeruginosa is the main proven perpetrator of lung function decline and ultimate mortality in CF patients. HDPs, acting as anti-inflammatory molecules, could be able to block LPS pro-inflammatory activity attenuating inflammation and so limiting damage to host tissues. New potential HDPs have been identified by an in silico method and their biochemical and pharmacological features are under investigation.
Hypothesis and objectives. It has been demonstrated that many human proteins, with functions not necessarily related to host defense, are reservoirs of active host defense peptides. The aim of this study was to characterize structural propensity, antimicrobial activity, LPS neutralizing and anti-inflammatory properties of new human HDPs identified by a bioinformatic procedure that we have developed.
Background. Cystic fibrosis (CF) is a frequent and lethal genetic disease caused by mutations associated with the CF transmembrane regulator (CFTR), a chloride channel located in the apical membrane of epithelial cells lining the ducts. In nearly 70% of the CF patients, the mutation involved is a deletion of phenylalanine at position 508 of the protein (DF-CFTR). The mutant protein cannot fold properly leading to its intracellular retention and degradation. Pharmacological screening approaches have identified small molecule "correctors" (which promote a modest level of DF-CFTR arrival at the plasma membrane), some of which are in clinical trials. Unfortunately, their mode of action is not known.
Hypothesis and objectives. We proposed to develop a rational basis for the pharmacological correction of DF-CFTR defects, by characterizing the mechanism of action of correctors, to identify molecular components and pathways involved in the correction and then targeting them by efficient ways.
Background and rationale. CFTR is an anionic channel expressed in epithelia whose mutations cause cystic fibrosis, but its structure is still unknown.
Hypothesis and objectives. We explored a set of structural parameters of the wild type and mutated (F508del) CFTR by physical methods.
Essential methods. WT and F508del CFTR were over-expressed in yeast, solubilised in the detergent LPG-14 and purified. The detergent-CFTR complexes were studied by SAXS techniques using a solvent of variable density.
Background. Aberrant splicing represents a common disease-causing mechanism in CF and exon skipping is one of the most frequent defect. We recently reported that modified U1 core spliceosomal components (named ExSpe U1) , when specifically engineered to bind in the intron downstream the 5'ss rescues splicing of defective exons. This therapeutic activity can be observed in CFTR exon 13 and 5, where the modified U1s efficiently correct different splicing defects present either at the 5'ss or at the exonic splicing regulatory elements.
Hypothesis. The molecular mechanism of ExSpeu1 -mediated splicing enhancement and effect in vivo are largely unknown.
Background. Pseudomonas aeruginosa colonization, prominent inflammation with massive expression of the neutrophil chemokine IL-8 and luminal infiltrates of neutrophils are hallmarks of chronic lung disease in Cystic Fibrosis (CF) patients. The nociceptive Transient Receptor Potential Ankyrin 1 (TRPA1) calcium channels have been recently found involved in non-neurogenic inflammation.
Hypothesis and objectives. TRPA1 channels could be involved in the pro-inflammatory signaling pathways activated in CF airway epithelial cells infected by P. aeruginosa. The principal objective is to verify whether TRPA1 channels could be relevant molecular targets for innovative anti-inflammatory therapies in CF patients.
Background and rationale. Pseudomonas aeruginosa is the most common pathogen found in the lung of cystic fibrosis patients (CF). The quality of life of CF patients largely depends on the success or failure of antibiotic treatment. Now, the alarming diffusion of isolates of P. aeruginosa multi-resistant to the antibiotics currently in use makes urgently need to develop new antibacterial therapies.
Hypothesis and objectives. Phage therapy, the use of the natural enemies of bacteria, is garnering renewed interest as bacterial resistance to antibiotics becomes widespread. This therapy, used for decades in Eastern Europe, can be considered as a therapeutic alternative or a complementary treatment to antibiotics in curing lung infections in CF patients.
Background. In cystic fibrosis (CF) patients, Pseudomonas aeruginosa-induced pneumonia requires frequent antibiotic treatment. Low sensitivity to many antibiotics by P. aeruginosa has prompted the search for novel drugs aimed at the specific inhibition of pathogenesis-related processes. Antimetabolite drugs, such as the pyrimidine analogue flucytosine (FC), are effective inhibitors of biofilm formation and of virulence factors' production, and show promising activity against P. aeruginosa infections in animal models. However, their utilization in therapy is hindered by possible toxicity, occurrence of resistance, and by lack of precise information of their mechanism of action.
Hypothesis and objectives. The main hypothesis behind this work was that antimetabolite drugs other than FC could share its properties and affect P. aeruginosa virulence and persistence in the host. In addition, we wanted to establish the specific mode of action of FC, as a starting point towards the development of new drugs sharing the same mechanism of action and showing lower risks of long term toxicity.
Background. Endogenous resolution mechanisms that promote return to homeostasis are defective in cystic fibrosis (CF) leaving inflammation unrestrained with consequent loss of respiratory function, disability, and premature death of patients. Resolvin (Rv) D1 is and endogenous pro-resolution mediator that has entered clinical trials for the treatment of inflammatory diseases. Therefore, its therapeutic potential in CF is of wide interest.
Hypothesis and Objectives. Overarching hypotheses tested in this project are that RvD1 represents a potent therapeutic candidate for limiting lung inflammation and enhancing resolution of P. aeruginosa infection in CF. Main objectives are to determine, in preclinical models of CF, if RvD1 a) dampens lung inflammation and damage, b) promotes resolution and clearance of bacterial infection
Background. In patients with Cystic Fibrosis (CF), the progressive decline of pulmonary function is due to a vicious cycle of airways infection and inflammation. Inflammation can be more damaging than the insult itself if uncontrolled, excessive, or prolonged. Although there is debate over whether inflammation in the CF lung is primary (i.e., caused by CFTR mutations) or secondary to chronic infection, inflammation remains the single most significant contributor to disease progression, and its control is crucial for improving patient outcomes. Building upon the results from our past projects–indicating how the application of a systems biology approach and new findings from the laboratory may translate into the development of new therapeutics and rationales for their use–we have proposed a preclinical evaluation study of anakinra, a recombinant, non-glycosylated version of human IL-1 receptor I antagonist (IL-1Ra) in CF. Since 2001, anakinra has proved to be efficacious in a broad spectrum of auto-inflammatory diseases with a remarkable record of safety.
Hypothesis and Objectives. 1. The relative contribution of different inflammasomes to fungal and bacterial infections and inflammation in CF mice. 2.The evaluation of the efficacy of anakinra in experimental and preclinical models of CF. 3. The definition of the molecular mechanisms underlying anakinra activity. 4. The screening of CF patients for IL-1Ra deficiency and the definition of anakinra-responsive signatures through microarray gene expression profiling.
Background. The remarkable heterogeneity among CF patients in the time of onset as well as in the severity of P. aeruginosa lung disease raised the question whether other genetic loci in addition to the CFTR can contribute to the clinical variation. Recently, Collaborative Cross (CC) mouse population has been generated as an innovative and powerful source to model the diversity of the human population.
Hypothesis and objectives. By using the CC lines as a novel and high genetically diverse mouse resource population, this project aims to identify genetic factors that may influence the severity of P. aeruginosa respiratory infections in CF.
Background. Despite the involvement of endothelial cells (EC) in cystic fibrosis (CF) pathogenesis is suggested by (1)the emerging evidence of the risk for cardiovascular events in CF patients as well as by (2) our work showing endothelial dysfunction and its correlation with lung disease in CF patients, EC have not been extensively studied in CF.
Hypothesis and objectives. We hypothesized that the elucidation of CFTR signaling in EC may provide clues for innovative pharmacology for CF. Main objectives of this study were to: 1. Uncover mechanisms of CF endothelial dysfunction as molecular targets for novel therapeutics. 2. Elucidate the clinical relevance of circulating endothelial cells (CEC) and endothelial microvesicles (EMV) in CF.
Background and Rationale. The underlying cause of cystic fibrosis (CF) is a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-stimulated chloride channel. The consequent CFTR dysfunction primarily affects the respiratory system, where the reduced activity of the channel results in obstruction of small airways and, together with airway inflammation and infections, eventually leads to respiratory failure. A number of CFTR correctors and potentiators have been developed, but their ability to rescue the basic defect of CF is still unsatisfactory.
Hypothesis and Objectives. We previously showed that phosphoinositide 3-kinase γ (PI3K γ) acts as a scaffold protein and negatively regulates cAMP. Here, we hypothesized that targeting PI3K γ scaffold activity enhances cAMP in airway smooth muscle, immune and epithelial cells, leading to concomitant (i) bronchodilation, (ii) anti-inflammatory effects and (iii) CFTR potentiation.
Background. Several studies indicate that sphingolipids (SL) play a regulatory role in airway inflammation, the most critical aspect of CF lung disease. Recently, Ceramide (Cer) derived from glycosphingolipids (GSL) has gained more interest since inhibition of the glucocerebrosidase GBA2 and its down-regulation by siRNA, are associated with a significant reduction of IL-8 after P.aeruginosa (PAO) infection, as well as a reduction of the intrinsic inflammatory state in CF human epithelial bronchial cells (CFhEBC).
Hypothesis and Objectives. In our work hypothesis, the aberrant inflammatory response to PAO in CFhEBC starts from alterations in the lipid composition of specific plasma membrane (PM) macromolecular complex by the action of the GSL-hydrolases associated with the cell surface, including GBA2. To figure out the possible molecular mechanism we investigated the effect of PAO infection on specialized membrane area called lipids rafts. Moreover, with the aim to develop a new anti-inflammatory treatment we developed new lipid based-nanoparticles for the delivery of siRNA targeting GBA2.
Background. A clinical guideline (LG) is a document with the aim of guiding decisions and criteria regarding diagnosis, management, and treatment in specific areas of healthcare; also in the Cystic Fibrosis (CF) world, scientific societies and organizations publish LG to give recommendations; since guidelines may have both methodological problems and conflict of interest our strategy is needed to choose which guidelines should be implemented.
Aims. Evaluate the reliability of every single guideline produced within the CF; identify the accurate documents and to implement its knowledge among the healthcare profession; produce a reasoned synopsis of the existing recommendations.
Background. Cystic fibrosis (CF) represents the most common lethal autosomal recessive disorder in the white population, mainly affecting the lungs. It affects the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, which encodes a protein expressed on the apical membrane of airway epithelial cells, where it acts as a cAMP-dependent chloride channel and regulator of other channels, including the epithelial Na+ channel (ENaC). Airway colonization of the airways and lung infections are a hallmark of this disease, in particular with Pseudomonas aeruginosa (PA) that affects '70% of CF patients and is associated with poor clinical outcomes. However, the mechanisms underlying the persistence of pathogens in CF airways, remain largely unclear. Secretory-immunoglobulin A (S-IgA) is a major line of mucosal defense, through so-called immune exclusion of inhaled / ingested antigens and pathogens. Following synthesis of polymeric (mainly dimeric) IgA by subepithelial mucosal plasma cells, IgA is transported across the epithelium by a transcellular routing mediated by the polymeric immunoglobulin receptor (pIgR).
Hypothesis and objectives. This project aims to investigate whether the production of secretory IgA (S-IgA) is impaired in the CF lung, through which mechanisms, and whether this defect contributes to the pathogenesis of CF by impairing immunoprotection against respiratory pathogens such as PA.
Background. M. abscessus (MA) is a species frequently isolated from cystic fibrosis (CF) patients. Three Subspecies (subsp.) of MA exist and their identification is crucial for epidemiology and optimal patient's management. Although the environment is considered the source of MA infections, its transmission between CF patients has been hypothesized.
Objectives. We aimed to investigate a large collection of MA isolates obtained from CF patients to increase present knowledge about the prevalence of the 3 subsp., their antimicrobial susceptibility, the presence of MA genotypes characterized by increased virulence and responsible for severe clinical manifestations, the transmissibility between patients of the infection.
Background. The sweat test (ST) remains the main test for Cystic fibrosis (CF) diagnosis and it is now also used to evaluate the function of the CFTR protein in basal conditions and under the influence of CFTR modulators. However it is not yet well-defined the biological variability of the test, both among different individuals (inter-individual) and within the same individual at different times and under different conditions (intra-individual).
Hypothesis and objectives. The project aims to study intra-individual sweat chloride (Cl) biological variability both in subjects with CF and in healthy people and to assess its possible correlation to different variables (diet, seasons, menstrual cycle).
Background. MTOR-inhibitors (mTOR-I), Everolimus (EVE) and Sirolimus, immunosuppressants broadly used in transplantation, may determine severe adverse events including pulmonary fibrosis.
Hypothesis and objectives. The pathogenic mechanism of mTOR-I-associated pulmonary toxicity is still unclear, but epithelial to mesenchymal transition (EMT) of bronchial/pulmonary cells may have a role.


text:
Light, fun, average Joe, technical, baritone
Voice Description
I have a natural baritone voice, British accented, very slight south east lilt.
Warm, slow and deep for narrations/radio advertisements/commercials.
Sexy (so I'm told) for romantic commercials/recordings etc
Technical for documentaries, presentations
Clear and measured diction for book and story reading
Qualified Mechanical Engineer - deliver technical terms convincingly
Voice Genders and "Ages" I Can Perform
• Young Adult Male
• Middle Age Male
• Senior Male
Language(s) of Which I Am a Native Speaker:
• English - British
I Offer my Services for these Recording Purposes
• Commercials
• Promos
• IVR, voicemail, phone systems, and on-hold messages
• Training, business presentations, sales, and web sites
• Audiobooks
• Videogames
• Documentaries
• TV shows and movies
• Movie and game trailers
• Podcasts
• Cartoon/Animation
Jobs I Am Willing to Take (Union-wise)
• Non-Union Jobs
• Jobs for ACTRA (Canada) signatories
• Jobs for British Equity signatories
• Jobs for Union des Artistes (Canada) signatories
• Jobs for SAG-AFTRA (US) signatories
My Union Affiliations and Memberships
My Recording and Delivery Capabilities
• I will go to any designated studio in my area
• I can record and then deliver the audio files via Email
• I can record and then upload the audio files via FTP
• I can record and then deliver the files by regular mail
Pre-, Post- and Production Services I Offer
• I offer copywriting services
• I offer translation services
• I can deliver edited and finished voice tracks
• I have a music library and can add music to any project
My Home Base
Izmir, Turkey
Accents, Impersonations, Characters and Dialects
British english dialects - London and South East, Cambridge English, Scottish (but only for fun), Irish (for fun). Overdone American accents - New York, Boston, Texas, etc
My Voice Experience
My first foray into the voice over profession was for a language school, where I was working as a teacher of the English language.
Following that, I completed a great many voice-overs for commercial marketing and advertising DVD's for international companies, including:
Norm Civata, Eldor Corp. Baraks Ambalaj, BMC Military Vehicles, BMC (New Image Launch), Orion Fair (Agricultural exhibition in Izmir).
I have provided the voices for a series of 12 English proficiency reading/listening books for Atlas Publishing in Istanbul, Turkey for use in various university courses in that country.
I still provide voice-overs for new company promotional videos, mostly locally-based, at a rate of 1-4 per month.
Find me on Youtube! https://www.youtube.com/watch?v=HAbnBssL0CI
My Training
I am a graduate mechanical engineer of 30+ years experience, now living and working in Izmir, Turkey.
In my past, I have also been a ballet dancer and recording artist (for my sins!)
At the age of 14, I hosted a radio program on hospital radio three days a week and ran my own mobile disco (when that sort of thing was popular).
My Studio Equipment
I do not have my own personal recording studio, but have access to a professional studio at a prominent and well respected university which specialises in media and broadcasting disciplines, as well as two or three professional studios where I currently record voice-overs for current projects.
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Unknown - Click here to ask Chris Brennan
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Chris Brennan does not appear to be an active participant of the Voice123 marketplace at this time. Chris Brennan was last active on Voice123 more than 365 days ago, OR may not be receiving our email messages.


text:
Implementing Two-Factor Authentication for Dummies
What is Two-Factor Authentication and why you should be interested
It is no surprise that security is a hot topic when building a modern web application. As the CEO of Ashley Madison could probably tell you, having your account stolen is not only annoying, it can be downright embarrassing. Having only a password is no longer the secure option it used to be. Users are vulnerable to social engineering or simple carelessness if they leave passwords on sticky notes (usually attached to their monitors). A password can also be revealed through the use of brute-force techniques by hackers. Therefore it's no longer a question of should Two-Factor Authentication be implemented in your web application, but rather when.


text:
August 2010
31 Aug 2010. North to Okongwe. The two lionesses recovered well from the darting and by late morning they settled in a mopane thicket a few kilometres to the east. Two nights ago, the Hoanib Floodplain male (Xpl-56) returned to Okongwe. It was decided to locate and follow him with the hopes that he may lead us to the missing lions of the Hoanib Pride.
30 Aug 2010. Find Hoanib Pride. After 18 days of searching, members of the Hoanib Pride that were present during the poising incident last month were located today east of the Obias junction in the Hoanib River. Disappointingly there were only two lionesses present (Xpl-57 & 58). Both were darted. The radio collar of Xpl-57 was replaced and Xpl-58's collar was lengthened. It is unclear if the remainder of the pride are still alive.
29 Aug 2010. Xpl-10. The additional lions in the Hoaruseb could not be located and the search for the Hoanib Pride continued down to the Mudorib and Amp's Poort area. Xpl-10 and the two sub-adult lionesses of the Floodplain Pride were located in the granite ridges south-west of Amp's Poort, and a brown hyaena was observed scavenging on the remains of an oryx carcass.
28 Aug 2010. Tawny & Morada. The two Hoaruseb lionesses (Xpl-37 & 38, better known as Morada & Tawny), were located in the Hoasruseb River, about 5 km from the sea. There is a strong possibility that the lions that were observed east of Leyland's Drift during the past two weeks were not Tawny & Morada, but Hoanib lions. This will be investigated during the next few days. Both Hoaruseb lionesses were immobilised this evening. A GPS collar was fitted to Morada (Xpl-37) and the VHF collar of Tawny (Xpl-38) was replaced. The Holder family and Wilderness Staff, based at Khumib Camp, assisted with the dartings.
27 Aug 2010. Presentation. After Xpl-73 recovered from the anaesthetics, the search for the rest of the Hoanib Pride was extended to the Hoaruseb River. At the request of Wilderness Safaris, a talk on the Desert Lion Project was presented to the Holder family and other guests at the Skeleton Coast.
26 Aug 2010. Dart Hoanib lioness. After sitting in the vehicle the entire day the Hoanib lions slipped away during the late afternoon. They crossed several mountain ridges and disappeared. By total chance, they were located again at 23h00 and were observed in the moonlight. The group consisted of 4 lionesses, none of whom were present during the recent poisoning in the Ganamub River. A lioness was darted and fitted with a GPS radio collar. The whereabouts and welfare of the rest of the Hoanib Pride is unknown and of concern.
25 Aug 2010. Breakthrough. At 02h10 this morning a sub-group of the Hoanib Pride was located in a narrow valley about 15 km north-east of Okongwe Spring, after a 15-day search. Their tracks were first picked-up at midnight and then the signals of at least two radio-colarred lionesses were heard. Due to the difficult terrain it was impossible to get close enough to the lions to observe them. They will be approached carefully during the day and efforts will be made to observe them tonight. It is important to determine which of the marked lions are still alive, following the poisoning incident in late July 2010.
24 Aug 2010. Okongwe. The Land Cruiser proved once again to be an outstanding off-road vehicle. The search for the Hoanib lions was extended into the northern section of the Okongwe area. There are no roads in this area and routes were planned through the mountains using satellite photos. These were displayed on the PowerBook Mac computer and linked to a GPS using the MacGPS Pro programme. A recently abandoned Himba village was discovered in one of the northern valleys. The rising of the full moon at 19h56 was quite spectacular.
23 Aug 2010. Fresh spoor. By late morning a second set of fresh lion tracks were found near Okongwe. After careful assessment the lion was again identified as a member of the Hoanib Floodplain Pride (Xpl-56). The blue squares (middle photo) indicate where the tracks were observed and the red dots show the movements of Xpl-56 as recorded by his satellite GPS collar. It is suspected that Xpl-56 moved into the Okongwe area, which is far outside his current home range, because he may have been attracted by the vocalisations of other lions. An effort is currently being made to follow the route that he travelled with the hopes that this may lead to finding the Hoanib lions.
21/22 Aug 2010. Xpl-10. The mystery of the spoor of a single lioness around the water-hole at the Hoanib/Mudorib junction was solved. The tracks were followed and to great surprise Xpl-10, the Hoanib Floodplain lioness, was located. It appears that she might have given birth to a litter of cubs nearby.
20 Aug 2010. Central Hoanib. After collecting medical supplies at Palmwag, the entire Hoanib River and some of the tributaries were searched again. There was still no sign of the main Hoanib Pride.
19 Aug 2010. Eastern Hoanib. The Hoanib-lion-search continued as the entire Hoanib River, from Amp's Poort to Sesfontein and south to the Obeb River, was covered. The spoor of 2 lions (a sub-adult male and female) was picked-up at the Obias River, but no sign of the main Hoanib Pride has yet been found.
18 Aug 2010. SA male lion. The southern and western part of the Okongwe area were searched for the missing Hoanib lions. At 22h30 the sub-adult male lion (Xpl-56) of the Hoanib Floodplain Pride was located East of Sima Hill. He was still on his own, and thus supporting the hypothesis (of 12 Aug 2010) that the lionesses have abandoned him. Searching for the Hoanib lions was extended to the Tsuxub River and the Amp's Poort area without picking up any fresh spoor or radio-signals.
17 Aug 2010. North to Okongwe. Many fruitless hours were spent looking and waiting for the lioness at the Hoanib/Mudorib junction. At 23h00 the search for the Hoanib Pride was continued to the Obias River and then north into the Okongwe mountains. By sundown today every possible track had been driven and most of the dry water courses were scanned for fresh spoor. No evidence of the Hoanib lions could be found.
16 Aug 2010. Mudorib River. The fresh spoor of a lioness was spotted near the water-hole at the Hoanib/Mudorib junction. Closer investigation revealed more tracks of a lioness (possibly the same individual) frequenting the area. The water-hole and the surrounding areas are being monitored closely.
|Several elephant breeding herds are using the water-hole
|Augur Buzzard
15 Aug 2010. Hoanib search.
During the past five days a total distance of 471 kilometres have been driven along all the major tributaries of the Hoanib River, between Dubis and Amp's Poort (see map - right). No radio-telemetry signals or fresh signs of the main Hoanib Pride ("Bianca and 5 other radio-collared lionesses) have yet been found. The map displays a track-log (red lines) of the search pattern.
14 Aug 2010. Angry bees. The search for the Hoanib lionesses continue. The entire Hoanib River, as well as the Ganamub, Obias, Okongwe, and several other smaller tributaries have been covered thus far. Whilst trying to connect to the BGAN satellite IP modem this afternoon, a swarm of rather aggressive honey bees descended on the Cruiser. There was a frantic effort to get away from the bees, but an escape was only managed after being stung three times.
13 Aug 2010. Hoanib lions. With the aid that the increasing moonlight will provide during the following ten days, a big effort is made to locate Xpl-47 ("Bianca") and the rest of the Hoanib Pride. It is important to determine what the status of the group is following the poisoning of Xpl-64 and a sub-adult male (see 30 July 2010). The GPS collar of Xpl-47 must be removed, the data downloaded, and a new battery fitted. The strong south-westerly winds of the past week uprooted an Acacia tree near the Tsuxub River. The tracks of two lionesses were followed along a wash to the south of the Hoanib. One lion was spotted on a mountain slope, but it soon dissapeared. A female dusky sunbird made for an entertaining afternoon, while waiting for the lions to reappear.
12 Aug 2010. Xpl-56. The Land Cruiser gave a few more problems during the day, but they were managed. The sub-adult male (Xpl-56) of the Hoanib Floodplain pride was observed for the latter part of the day. He had been separated from the lionesses and was calling for them at regular intervals. This may be the initiation of him being ousted for the group.
11 Aug 2010. Amp's Poort. Removing the computer chip was a lengthy affair, but the opportunity was used to redesign and upgrade the electrical lay-out of the Cruiser. This included the solar power and all the 220 Volt access points for the computers and satellite communication. New images from the camera trap in the Hoanib Floodplain were downloaded. The camera was cleaned and new batteries were installed. Shortly after sunset the Hoanib Floodplain lions were located on the north-bank of the Hoanib River a few kilometres east of Amp's Poort.
10 Aug 2010. Second breakdown. The electrical problem of yesterday was repaired and the journey to Mowe Bay and the Hoanib River (via the Floodplain) was continued. Early this morning, whilst negotiating the soft sand and dunes leading up to the Hoanib Floodplain, the vehicle experienced more electrical problems. The problem became worse and the Cruiser was finally stopped amid thick succulent vegetation on the western edge of the Floodplain (see photo - bottom left). JB Auto Repairs (the "Land Cruiser Whisperer") in Cape Town was contacted via satellite phone. Johann identified the problem to be be a computer "chip" that was installed in the vehicle before it was purchased by the Land Cruiser Club of SA. Most of the day was spent removing the computer "chip" and reconnecting the correct wiring.
9 Aug 2010. Breakdown. An electrical problem with the Land Cruiser developed this morning (10h00) about 50 km south of Mowe Bay. Sand-storms and strong winds (gusting up to 60 km/h) complicated working on the vehicle. After five gruelling hours the problem was isolated and repairs are being made.
8 Aug 2010. Lower Uniab. During the return trip to the Hoanib, the tracks of several lions were spotted in the lower Uniab River. Some time was spent trying to locate the lions. During the 1980s, and even up to the early 1990's, lions regularly visited the Uniab Mouth. It is the first time that lions have moved this far west along the Uniab River for almost 15 years.
7 Aug 2010. News Page. This website is aimed at making information from the Desert Lion Conservation project available to everybody. Apart from providing data and results from the study, regular updates are present in the News Section with photographic images of day-to-day happenings. A concerted effort is made to only present the facts, and not to draw conclusions or make value judgements.The information and photos have been used and/or referenced extensively by third parties, in support of particular viewpoints or opinions. Despite the efforts to only present the facts, the interpretation of the information is subject to the particular viewpoints of viewers, and that has resulted in criticism towards Desert Lion Conservation. An example can be seen in a recent letter to a Namibian newspaper (see LINK). This brought into question the value of continuing with the regular updates in the News Section. But, it was decided to continue for as long as the information contributes to the long-term conservation of lions, as explained under Vision and Projects.
6 Aug 2010. Tire Sponsorship. The Land Cruiser was collected from Steckel's Toyota after a major service and repairs. The second sponsorship of 6 BFG Mud Terrain tires by Michelin Tyre Company, SA, was received (see Sponsors). Adolf Huester helped with the arrangements and paid the import fees. The tires were fitted by Swakop Fitment Centre and Wimpy Els is thanked for assisting. Special certificates of acknowledgement were designed and printed for each of the 22 people that worked on the rescue operation of the Humpback whale on 21 July 2010. A letter of appreciation was written to the Police Commissioner of the Kunene Region for the efforts by the eight Police officers.
5 Aug 2010. Land Cruiser. Searching for the Hoanib Pride will require a serious effort. It was decided to return to Swakopmund to collect the Land Cruiser. The Isuzu, borrowed from KCS, served the Project well. Russell & Tina Vinjevold are thanked for making it available.
4 Aug 2010. Water in the Hoanib. The third day of studying the ageing tracks and signs at the Ganamub did not reveal new information on the death of the two lions. Despite extensive radio tracking the remainder of the group (four radio-collared lionesses, including Xpl-47 "Bianca") could not be located during the past three days. Another sub-group of the Hoanib Pride (Xpl-70 & 71, recently marked in the Okongwe area, 11-14 July 2010) were located every day in the Hoanib River. The two artificial water installations in the Hoanib River (at the Ganamub & Mudorib river junctions) have been repaired by MET and many animals are starting to utilise the water-points.
3 Aug 2010. Lions killed giraffe. It has been a difficult task to reconstruct the sequence of events from tracks that were more than a week old, but the investigation has thus far revealed that lions from the Hoanib Pride killed livestock at a village 30 km further north in the Ganamub River. Members from the village and Sesfontein Conservancy pursued the lions and found them feeding on a fresh giraffe kill about 1.2 km north of the Hoanib River. The vehicle loaded the giraffe carcass (photos: left & middle), but left a piece of meat behind that was laced with poison. Two lions were found dead at the scene and it is likely that they died from the poison. Skin and hair samples will be analysed. The lions were also pursued by vehicle and on foot, and there is a possibility that shots may have been fired at the lions. Further efforts will be made to determine if any of the remaining lions were either shot or wounded. A Cape fox was found dead at the scene (photo: right) and may also have been poisoned.
2 Aug 2010. Lion carcasses burnt. By the time the location of the dead lions, courtesy of the Isuzu from Kunene Conservancy Safaris, was reached, the lion carcasses had already been burnt by MET (due to the suspicion that poison was used). Unfortunately some of the evidence was destroyed in the process. The staff from Hoanib Camp, Wilderness Safaris (Emsie Verwey, Frank Kasaona, & Moses Awiseb), assisted with the investigation that has led to new information. More work is needed and updates will follow.
1 Aug 2010. Samanab. En route to the Hoanib River to investigate the possible poisoning of Xpl-64, the Obab lions, including "Nina" (Xpl-49) & Xpl-45, were located amongst the dunes in the lower Samanab River. Two adult cheetahs were spotted just before dark south of the Hunkap River.


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Choir Camp auditions tonight
The general information and audition night for the third annual Summer Youth Choir Camp is today at 7 p.m. in the Del Norte High School music room.
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Representatives of galleries and other businesses that would like
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Activities at Harbor Gallery
Crescent Harbor Gallery's artist of the month for June is Kathy
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Art in Public Places exhibit
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Art Scene items should be sent to the Del Norte Association for
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