ABSTRACT The upper Miocene to lower Pliocene Deschutes Formation of central Oregon is a sequence of interstratified volcanic and sedimentary rocks, as much as 700 m thick, largely derived from the adjacent Cascade Range. The formation is correlative with the early High Cascade eruptive episode that included voluminous pyroclastic eruptions and culminated in the development of an intra-arc graben in the central Oregon High Cascades. Facies associations and paleocurrent data define three depositional settings. 1) The eastward-sloping arc-adjacent alluvial plain was the depositional site by sheetfloods, debris flows, and hyperconcentrated flood flows. Their deposits from 10- to 70-m-thick sequences separated by erosion surfaces with up to 60 m of relief. Widespread superimposed paleosols overlie these facies and constitute the upper 10 to 50 m of the section. Sedimentation was episodic with pulses of rapid aggradation, corresponding to periods of explosive volcanism and abundant sediment supply, separated by periods of nondeposition when streams incised to reestablish grade as sediment loads diminished. 2) A gravel-bedload river flowed northward through the basin at the foot of the alluvial plain and is represented by channel-fill conglomerates and overbank sandstones and siltstones. 3) A thin sequence derived from older Tertiary highlands was deposited on the east side of the basin and was little affected by Cascade volcanism. Extensive development of thick, superimposed paleosols reflects the inactive nature of the eastern basin margin as a sediment source. Deschutes Formation deposition records the response of a fluvial system to large, volcanism-induced sediment loads. Popular facies models do not adequately allow for the influence of volcanism on fluvial systems because sediment is mobilized episodically and on a scale unparalleled in nonvolcanic settings.


The Hudson-Kreitman-Aguade (HKA) test is based on the prediction from the neutral theory that levels of polymorphism within a species and the divergence between two closely related species should be correlated. Population subdivision has been shown to alter both the amounts of polymorphism segregating within species and the rate of divergence between species, meaning that genomic regions with different population structures also differ in their divergence to polymorphism ratios. Population subdivision may hence hamper the utility of the HKA test for detecting deviations from the standard neutral model, especially for organelle genomes that often have different patterns of population structure compared with nuclear genes. In this paper, I show that population subdivision inflates the number of instances where the HKA test detects deviations from the neutral model. Using coalescent simulations I show that this bias is most apparent when population subdivision is strong and differs substantially between the loci included. However, if divergence time is large and population structure substantial even changes in the levels of polymorphism and divergence associated with differences in the effective population size between two loci is enough to substantially alter the number of significant outcomes of the HKA test. A dataset on cytoplasmic diversity in Sileine vulgaris and S. latifolia (Ingvarsson & Taylor, 2002) is also reanalysed. The previous study had shown a marked excess of intraspecific polymorphism in both species. However, when effects of population subdivision were removed, ad hoc, levels of intraspecific polymorphism were no longer significantly different from neutral expectations, suggesting that population subdivision contributed to the observed excess of intraspecific polymorphism seen in both species of Silene.


WiMAX which represents World Interoperability for Microwave Access is a major part of broadband wireless network having IEEE 802.16 standard provides innovative fixed as well as mobile platform for broadband internet access anywhere in anytime. This thesis provides the detail about the two main applications of WiMAX which are fixed WiMAX and Mobile WiMAX. Fixed WiMAX 802.16 delivers point to multipoint broadband wireless access to our homes and offices. Whereas Mobile WiMAX gives full mobility of cellular networks at higher broadband speeds than other broadband networks like Wi-Fi. Both applications of WiMAX are designed in a proper network planning which is helpful to offer better throughput broadband wireless connectivity at a much lower cost.


Particle filters are becoming increasingly important and useful for state estimation in nonlinear systems. Many filter versions have been suggested, and several results on convergence of filter properties have been reported. However, apparently a result on the convergence of the state estimate itself has been lacking. This contribution describes a general framework for particle filters for state estimation, as well as a robustified filter version. For this version a quite general convergence result is established. In particular, it is proved that the particle filter estimate convergences w.p.1 to the optimal estimate, as the number of particles tends to infinity.


Introduction: Nonopioid-based strategies for managing chronic noncancer pain are needed to help reduce overdose deaths. Although lab studies and population-level data suggest that cannabinoids could provide opioid-sparing effects, among medical cannabis participants they may also impact overdose risk by modifying other controlled substance use such as sedative hypnotics. However, no study has combined observational data at the individual level to empirically address interactions between the use of cannabinoids and prescribed controlled substances. Methods: Electronic health records, including prescription drug monitoring program data, from a large multisite medical cannabis program in New York State were abstracted for all participants with noncancer pain and recently prescribed noncannabinoid controlled substances who completed a new intake visit from April 15, 2018-April 14, 2019 and who remained actively in treatment for >180 days. Participants were partitioned into two samples: those with recent opioid use and those with active opioid use and co-use of sedative hypnotics. A patient-month level analysis assessed total average equivalent milligrams by class of drug (i.e., cannabinoid distinguishing tetrahydrocannabinol [THC] vs. cannabidiol [CBD], opioids, and sedative-hypnotics) received as a time-varying outcome measure across each 30-day "month" period postintake for at least 6 months for all participants. Results: Sample 1 of 285 opioid users were 61.1 years of age (±13.5), 57.5% female, and using an average of 49.7 (±98.5) morphine equivalents daily at intake. Unadjusted analyses found a modest decline in morphine equivalents to 43.9 mg (±94.1 mg) from 49.7 (±98.5) in month 1 (p=0.047) while receiving relatively low doses of THC (2.93 mg/day) and CBD (2.15 mg/day). Sample 2 of 95 opioid and sedative-hypnotic users were 60.9 years of age (±13.1), 63.2% female, and using an average of 86.6 (±136.2) morphine equivalents daily, and an average of 4.3 (±5.6) lorazepam equivalents. Unadjusted analyses did not find significant changes in either morphine equivalents (p=0.81) or lorazepam equivalents (p=0.980), and patients similarly received relatively low doses of THC (2.32 mg/day) and CBD (2.24 mg/day). Conclusions: Findings demonstrated minimal to no change in either opioids or sedative hypnotics over the 6 months of medical cannabis use but may be limited by low retention rates, external generalizability, and an inability to account for nonprescribed substance use.


"Reform" in the economics literature refers to changes in government policies or institutional rules because status-quo policies and institutions are not working well to achieve the goals of economic wellbeing and development. Further, reform refers to alternative policies and institutions that are available which would most likely perform better than the status quo. The main question examined in the "political economy of reform" literature has been why reforms are not undertaken when they are needed for the good of society. The succinct answer from the first generation of research is that conflict of interest between organized socio-political groups is responsible for some groups being able to stall reforms to extract greater private rents from status-quo policies. The next generation of research is tackling more fundamental and enduring questions: Why does conflict of interest persist? How are some interest groups able to exert influence against reforms if there are indeed large gains to be had for society? What institutions are needed to overcome the problem of credible commitment so that interest groups can be compensated or persuaded to support reforms?
 Game theory—or the analysis of strategic interactions among individuals and groups—is being used more extensively, going beyond the first generation of research which focused on the interaction between "winners" and "losers" from reforms. Widespread expectations, or norms, in society at large, not just within organized interest groups, about how others are behaving in the political sphere of making demands upon government; and, beliefs about the role of public policies, or preferences for public goods, shape these strategic interactions and hence reform outcomes. Examining where these norms and preferences for public goods come from, and how they evolve, are key to understanding why conflict of interest persists and how reformers can commit to finding common ground for socially beneficial reforms. Political markets and institutions, through which the leaders who wield power over public policy are selected and sanctioned, shape norms and preferences for public goods. Leaders who want to pursue reforms need to use the evidence in favor of reforms to build broad-based support in political markets. Contrary to the first generation view of reforms by stealth, the next generation of research suggests that public communication in political markets is needed to develop a shared understanding of policies for the public good.
 Concomitantly, the areas of reform have circled from market liberalization, which dominated the 20th century, back to strengthening governments to address problems of market failure and public goods in the 21st century. Reforms involve anti-corruption and public sector management in developing countries; improving health, education, and social protection to address persistent inequality in developed countries; and regulation to preserve competition and to price externalities (such as pollution and environmental depletion) in markets around the world. Understanding the functioning of politics is more important than ever before in determining whether governments are able to pursue reforms for public goods or fall prey to corruption and populism.


This paper summarizes the recent progress we have made for the computer vision technologies in physical therapy with the accessible and affordable devices. We first introduce the remote health coaching system we build with Microsoft Kinect. Since the motion data captured by Kinect is noisy, we investigate the data accuracy of Kinect with respect to the high accuracy motion capture system. We also propose an outlier data removal algorithm based on the data distribution. In order to generate the kinematic parameter from the noisy data captured by Kinect, we propose a kinematic filtering algorithm based on Unscented Kalman Filter and the kinematic model of human skeleton. The proposed algorithm can obtain smooth kinematic parameter with reduced noise compared to the kinematic parameter generated from the raw motion data from Kinect.


: The potential of atomic force microscopy (AFM) for the investigation of peculiarities of microorganisms genome structure is demonstrated. AFM images of phage lambda DNA linear molecules and supercoiled mica in buffer solution was imaged in air. New experimental method of DNA stretching based on using amino-modified mica with a decreased surface density of active amino-groups is proposed. Stretched molecules of phage lambda DNA were imaged by AFM.


Aim. To study the markers of renal graft dysfunction in patients with type 1 diabetes mellitus (T1DM) after kidney transplantation (KT) and simultaneous pancreas-kidney transplantation (SPKT). Subjects and methods. The investigation enrolled 20 patients after successful SPKT and 41 patients after KT (of them 21 received continuous subcutaneous insulin infusion with an insulin doser; 20 had multiple insulin injections). The periods after KT and SPKT at patient inclusion were 8 (7; 8) and 11 (8; 18) months, respectively. A control group comprised 15 patients with T1DM without diabetic nephropathy. The patients were matched for gender, age, and T1DM duration. At a 9-month follow-up, the main biomarkers of kidney graft dysfunction were identified using the standard kits: Cystatin C (Cys C; serum; urine), NGAL, KIM-1, Podocin, Nephrin, IL-18, MMP-9 (urine), TGF-β1, VEGF-A, and Osteopontin (OPN; serum). Fasting blood was taken; a morning urinary portion was examined. Results. The posttransplantation glomerular filtration rate (GFR) in the patients corresponded to Stage C2; albuminuria did to Category A1 chronic kidney disease. Despite successful SPKT in the group of patients with T1DM, as in that of patients after isolated KT, there was a statistically significant increase in the level of kidney dysfunction markers (Cys C, NGAL, Podocin, and OPN) versus the control group regardless of the compensation for glucose metabolism. compensation. It was found that the level of Cys C was high and correlated negatively with GFR (r=–0.36; p<0.05) and positively with the level of albuminuria (r=0.40; p<0.05). There was also a direct correlation of urinary podocin concentrations with blood creatinine levels (r=0.35; p<0.05) and that of NGAL with albuminuria (r=0.35; p<0.05) in recipients after transplantation. Conclusion. The high levels of biomarkers for kidney graft dysfunction in the examinees (including subjects after SPKT) reflect the persistence of graft microstructural injuries in clinically stable function.


Purpose – This study aims to introduce an application of web‐based data mining that integrates online data collection and data mining in selling strategies for online auctions. This study seeks to illustrate the process of spider online data collection from eBay and the application of the classification and regression tree (CART) in constructing effective selling strategies. Design/methodology/approach – After developing a prototype of web‐based data mining, the four steps of spider online data collection and CART data mining are shown. A business dataset from eBay is collected, and the application to derive effective selling strategies for online auctions is used. Findings – In the web‐based data‐mining application the spiders can effectively and efficiently collect online auction data from the internet, and the CART model provides sellers with effective selling strategies. By using expected auction prices with the classification and regression trees, sellers can integrate their two primary goals, i.e. auction success and anticipated prices, in their selling strategies for online auctions. Practical implications – This study provides sellers with a useful tool to construct effective selling strategies by taking advantage of web‐based data mining. These effective selling strategies will help improve their online auction performance. Originality/value – This study contributes to the literature by providing an innovative tool for collecting online data and for constructing effective selling strategies, which are important for the growth of electronic marketplaces.


In this study, a review and discussion has been made on the research work of heat transfer in manifolds previously done. Since it is difficult to determine the heat transfer coefficients in different areas of a suction or discharge chamber by using conventional methods, the mass transfer analogy -sublimation of naphthalene has been used to develop the heat transfer correlations for the four areas in a suction chamber. The mass transfer experiments were carried out on a model under the stable flow conditions with air as the medium. The correctness of the correlations has been verified through the measurement of U.e average heat transfer coefficient in the chamber. The maximum deviation of heat transfer coefficients measured from the correlations is within ±10%. project supported by the Science Fund of the Chinese Academy of Sci~nces 175 INTRODUCTION Since the 1970s, some work have been done to determine the manifold heat transfer coefficients in refrigerating compressors. J. M. Hughes (1) and Dang Jinquan (2) respectively presented the following heat transfer correlations for the valve passage, the suction chamber and the discharge chamber that they have used in their heat transfer experiments~ Hughes: Valve Passage o.i>3 0.6 Nu "" 1.48Re Pr


Global production of biofuels has been expanding with the enduring concerns on climate change and energy security. The U.S. Congress has established a renewable fuel standard 2 (RFS2) rule that mandates annual combined production of 36 billion gallons (bg) biofuels by 2022 (USEPA, 2010). Large scale production of biofuels results in far-reaching intended and unintended consequences on the economy and environment. In this study, a computable general equilibrium model (CGE) - Applied Dynamic Analysis of Global Economy -- ADAGE-Biofuel is developed to examine the global implications of the U.S. RFS2 policy. This model is built upon a dynamic version of ADAGE model (Ross, 2009) by introducing eight crop categories, one livestock and one forestry sectors, seven first generation biofuels, three second generation biofuels and five land categories and explicitly model land-use changes. We find out that despite of continued increase in land productivity and energy efficiency, increase in population and economic growth leads to a global-wide increase in agriculture production, rise in price of food, agriculture, biofuel and energy and land conversion from the other four land types to cropland from 2010 to 2025 when RFS2 is not implemented and biofuel consumption remain at the base year (2010) level in all the regions until 2025 (BAU scenario). The implementation of RFS2 policy would require 36.3 million ha (mha) of land for switchgrass production by 2025, where 34.8 mha from existing cropland, 0.9 mha from pasture, and 0.6 mha from managed forest land. Compared with the BAU scenario, price is projected to increase by around 5~7% for eight crops, 1.6% for livestock and 1.6% for forestry as a result of reducing production. Globally, due to reduction in agriculture exports from U.S. as a result of the RFS2 policy, all other regions would allocate slightly more land for crop and food production, leading to gentle loss of natural grassland and natural forestland, especially in Africa, which would lose 0.5 million ha of natural grassland for crop and livestock production. The RFS2 policy would bring environmental benefits too. The accumulated carbon saving from 2010 to 2025 would be arround 392 mmt c globally with 207 mmt c from fossile fuel and 185 mmt from land. Among it, U.S. alone would contribute 300 mmt c with 208 mmt c from fossile fuel and 92 mmt c from land.


Diversity represents an important aspect of genetic programming, being directly correlated with search performance. When considered at the genotype level, diversity often requires expensive tree distance measures which have a negative impact on the algorithm's runtime performance. In this work we introduce a fast, hash-based tree distance measure to massively speed-up the calculation of population diversity during the algorithmic run. We combine this measure with the standard GA and the NSGA-II genetic algorithms to steer the search towards higher diversity. We validate the approach on a collection of benchmark problems for symbolic regression where our method consistently outperforms the standard GA as well as NSGA-II configurations with different secondary objectives.


The authors of this article discuss the effects of shame and stigma on female caregivers of people living with AIDS in southern Thailand. They conducted a longitudinal ethnographic case study over 8 months and collected data using interviews, observations, field notes, and journaling. The authors performed qualitative content analysis and narrative analysis. Public judgment was created in a moral climate, framed by Buddhist precepts of correct and honorable behavior, with different levels of tolerance and stigmatization between men and women. Women caregivers engaged in concealing practices, deception, and withdrawal from social relationships to manage the effects of shame and stigma.


Although the habits of cigarette smoking and associated coffee drinking are generally ceased during pregnancy, they are often reinitiated after delivery when the breastfeeding period starts. This is a case report of a 32-year-old lactating smoker mother who consumed caffeinated drinks and who agreed to donate breast milk after smoking one cigarette (containing 0.6 mg of nicotine) and drinking one cup of espresso (containing 80 mg of caffeine) for an investigation of the excretion of nicotine, its major metabolite cotinine and caffeine into the breast milk and subsequent transfer to the infant. Nicotine and its metabolite cotinine peaked in the breast milk at 0.5 h after the cigarette smoking, and caffeine peaked 2 h after drinking coffee. Moreover, the nicotine disappeared from the milk by 3 h, the caffeine required 24 h and the cotinine required 72 h. The relative infant doses of caffeine, nicotine and cotinine were found to be 8.9, 12.8 and 77.6%, respectively. In the light of these results obtained after the mother smoked only one cigarette and consumed one cup of espresso, if a lactating mother cannot refrain from smoking cigarettes, she should extend the time between the last smoked cigarette and breastfeeding to at least 3 h when the nicotine has been completely eliminated from the milk. Similarly, nursing mothers should also drink coffee sparingly and immediately after nursing and avoid coffee or caffeinated beverages for at least 4 h prior to breastfeeding to minimize the infant's exposure to caffeine.


The ubiquity of smartphones in our lives has generated a booming market for mobile cell phone applications. This rapid expansion has created an increasing need for the development of functional prototypes for these applications that mimic, as accurately as possible, the behavior of the final product, in order to be able to perform usability tests. This poses a problem, as the general lack of technical skills of the usability experts, who usually design these prototypes, conflicts with the need of writing code to produce prototypes that have complex functionalities. On top of this, the usually used tools to perform this kind of tasks often possess, themselves, major usability flaws. Our proposed solution for this problem is twofold. On the one hand, we will develop a tool that allows HCI experts to visually develop complex prototypes with advanced back end functionality that minimizes the need of writing code. On the other hand, we will try to make this tool as usable as possible, by performing a four-stage study of the most popular approaches to several design environment problems that allows us to create a new design methodology for these kinds of cases. To sum up, we propose to create a tool that enables HCI specialists with minimal technical skills to quickly, efficiently and cheaply develop high quality functional mobile prototypes.


Software defined networking (SDN) can be beneficial in mobile ad hoc networks (MANETs) to increase flexibility, provide programmability and simplify management. The high dynamics in mobile networks, however, raise new reliability challenges to the conventional centralized control plane of SDN. To increase reliability, methods such as placing multiple controllers in the network have been considered that add redundancy in the control plane in a brute force manner. However, these methods cannot by themselves fundamentally solve the reliability problem. To address this issue, this paper complements the controller placement methods with a new architecture that has a hybrid structure splitting the routing decision logic between the controllers and the data plane nodes. Specifically, the controllers can break the routing path into segments, similar to the segment routing technique, and broadcast the list of segment labels to the data plane nodes. The latter are able to make the actual forwarding decisions for each segment in a distributed manner, e.g., by running an existing MANET protocol like OLSR. Experiments on a testbed built from commercial mobile devices with integrated SDN functionality highlight the feasibility and benefits of the proposed architecture.


Background/Objectives: This paper focuses on the intelligent extraction of ideal force by utilizing different MPPT techniques and its dispatch from a grid tied hybrid generation system containing a synchronous generator based wind generator and a Photo-Voltaic generator. Methods/Statistical Analysis: Although maximum power point tracking techniques such as Fuzzy Controller and OPPT technique such as PSO algorithm is implemented for PV generator, power extracted from PV system is a fuzzy capacity of the dc joins voltage, its rate of progress and the inverter active current component. This is to reduce high frequency oscillations in the dispatched power obtained from PV generator. Such an extraction of the optimum power is considered as a novelty of this paper. Findings: The performance of this is also verified under different fault conditions which are occurred at place of grid system. And the harmonics caused by this system is reduced by using active power filter. Application/Improvements: The effectiveness of the novel power extraction strategy proposed along with the fuzzy PD+I control of converters results in and brings about an upgraded power dispatch and a reduction in the oscillations of the currents.


Background: HIV protease inhibitors have been shown to worsen glucose and lipid metabolism. Recent studies have suggested that protease inhibitors can impair insulin secretion in HIV-infected patients. We studied the effects of the protease inhibitor combination lopinavir and ritonavir on insulin secretion, insulin sensitivity, and lipid metabolism in HIV-negative persons. Methods: A combination dose of lopinavir 400 mg and ritonavir 100 mg was given twice daily to eight HIV-seronegative men for 4 weeks. Fasting glucose, insulin, lipid, and lipoprotein profiles; oral glucose tolerance; insulin secretion and insulin-mediated glucose disposal by hyperglycemic clamp; and body composition by dual energy X-ray absorptiometry were determined before and after lopinavir/ritonavir administration. Results: There was no change in first-phase insulin secretion (2.82 ± 0.30 versus 2.71 ± 0.31 nmol/l; P = 0.60), as well as fasting insulin and glucose levels, oral glucose tolerance, or insulin-mediated glucose disposal after 4 weeks administration of lopinavir/ritonavir. However, there were significant increases in fasting triglycerides (1.02 ± 0.13 versus 2.20 ± 0.31 mmol/l; P = 0.001), total cholesterol (4.42 ± 0.30 versus 5.70 ± 0.60 mmol/l; P = 0.007), and apo B-100 levels (0.86 ± 0.07 versus 1.07 ± 0.11 g/l; P = 0.0009). High-density lipoprotein cholesterol decreased (0.99 ± 0.11 versus 0.82 ± 0.10 mmol/l; P = 0.005). There were no changes in body composition, weight, or body fat. Conclusion: Although administration of lopinavir/ritonavir to healthy, HIV-seronegative volunteers for 4 weeks resulted in increased triglyceride and decreased high-density lipoprotein cholesterol levels, there was no change in first-phase insulin secretion during the hyperglycemic clamp. The reported effects of protease inhibitor on insulin secretion in HIV-infected individuals may be due to changes in HIV-related factors and not a direct drug effect.


Many real-world networks contain highly connected nodes called hubs. Hubs are often crucial for network function and spreading dynamics. However, classical models of how hubs originate during network development unrealistically assume that new nodes attain information about the connectivity (for example the degree) of existing nodes. Here, we introduce hub formation through nonlinear growth where the number of nodes generated at each stage increases over time and new nodes form connections independent of target node features. Our model reproduces variation in number of connections, hub occurrence time, and rich-club organization of networks ranging from protein–protein, neuronal and fibre tract brain networks to airline networks. Moreover, nonlinear growth gives a more generic representation of these networks compared with previous preferential attachment or duplication–divergence models. Overall, hub creation through nonlinear network expansion can serve as a benchmark model for studying the development of many real-world networks.


SIR,-Professor Richard Scott and Dr. P. D. Robertson (15 June, p. 643) describe the organization and methodology of a multiple screening programme in general practice. They make the valid point that within the context of our health care organization the logical place for screening is in, or in conjunction with, general practice. They pose the question as to what is the short-term or long-term effect of screening on the health of the patient. It must be regretted, however, that this question is not given more prominence, nor will the design of their study allow any answer to be obtained. Numerous examples of screening programmes have been reviewed by Wilson and Jungner.1 All of these, as well as Scott and Robertson, show that they can find a substandal amount of morbidity. There is no evidence, however, in any of these publications that in terms of subsequent morbidity and mortality the individual shown to have one or more of the conditions screened for has benefited. For many of the conditions for which screening is performed there is still little evidence that methods of treatment used improve prognosis. At this stage of our knowledge it is of great importance to assess the value of screening examinations by properly controlled trials. Any general practitioner who wishes to embark on a screening programme must be urged to plan his study in such a way that he will be able to evaluate his findings rather than simply present a list of conditions discovered.--We are, etc., W. W. HOLLAND. A. E. BENNETT. M. H. TREVELYAN. Department of Clinical Epidemiology and Social Medicine, St. Thomas's Hospital Medical School, London S.E.l. U. M. P. KROLL. I. N. MANSER. J. D. PAULETT.


This study presents a chirp quasi-phase matching (QPM) waveguide to increase the conversion efficiency of the cascaded SHG+DFG effect for femtosecond pulses. The coupled mode theory is used to analyze the cascaded SHG+DFG process. In this paper, a constructive interference zone (or cascaded SHG+DFG region) is defined as when the conversion wave and its coupling component constructively interfere with each other and have a phase difference ranging from 0 to 0.5pi or from 1.5 to 2pi. On the other hand, the region is called a destructive interference zone (or back conversion region) when the phase difference ranges from 0.5 to 1.5pi . The proposed chirp QPM waveguide is designed to extend constructive interference length and shorten destructive interference length over the waveguide. The simulation results demonstrate that for a pulsewidth of 0.6 ps, the maximum conversion efficiency of a 50-mm chirp QPM waveguide can be increased to 25 times that of a uniform QPM waveguide.


In the large accumulation of studies referable to the thyroid gland, the vast majority are concerned chiefly with pathologic states, the most common being goiter with its various types and classifications. And yet not all goiters represent pathologic conditions. An enlargement of the thyroid gland is not an unusual event in the life of a person, especially in certain regions, and it often represents a physiologic response of the organ to certain stimuli. This gross change in the size of the gland is often associated with both chemical and microscopic changes. That increase in the activity of the thyroid gland is associated with an increase in the metabolism of the body is such a well known fact that it requires but little comment. This has been shown not only by an increase in the body's excretion of nitrogen, but by an increase in the consumption of oxygen. So definite is


This paper reports on our diagrammatic approach to characterize the gauge dependence of Quantum Electrodynamics in the linear covariant gauge. Our dimensionally independent technique is purely based on a perturbative analysis and allows us to construct the full expansion in the gauge parameter of a Green's function from its value in a particular gauge (such as the Feynman or Landau gauge). Further, we clarify the compatiblity of perturbation theory and the Landau–
Khalatnikov–Fradkin transform.


In his remarks on the comments by Yokoyama (see ibid., vol.43, no.5, p.541-42, 1995) and the reply by King and Sandler (see ibid., vol.43, no.5, p.542-44, 1995) regarding our paper (see ibid., vol.42, no.3, p.382-9, 1994) J. R. Wait (see ibid., vol.44, no.2, p.271-72, 1996) makes a number of statements that require correction. These are considered in turn, but since they all center about the definition of the Sommerfeld numerical distance, this is introduced first. In a paper by Norton (1937), which is later quoted and applied by Wait, a formula is given for the generalized numerical distance for the height z and radial distance /spl rho/ due to a vertical dipole at the height d in the air (region 2, real wave number k/sub z/) over a conducting or dielectric region 1 (complex wave number k/sub 1/). It is important to emphasize that the purpose of this response is not to belittle the important pioneer work of Norton, Wait, and others. Interest a half century ago was in communication over the surface of the Earth and sea with (z+d)/sup 2//spl Lt//spl rho//sup 2/. In this range, their formulas are accurate. However, recent progress which eliminates the restriction (z+d)/sup 2//spl Lt//spl rho//sup 2/ or k/sub 2//spl rho//spl Gt/1 should not be ignored by blindly using restricted formulas where they do not apply.


Having shown its good performance in many applications, variational Bayesian (VB) learning is known to be one of the best tractable approximations to Bayesian learning. However, its performance was not well understood theoretically. In this paper, we clarify the behavior of VB learning in probabilistic PCA (or fully-observed matrix factorization). More specifically, we establish a necessary and sufficient condition for perfect dimensionality (or rank) recovery in the large-scale limit when the matrix size goes to infinity. Our result theoretically guarantees the performance of VB-PCA. At the same time, it also reveals the conservative nature of VB learning--it offers a low false positive rate at the expense of low sensitivity. By contrasting with an alternative dimensionality selection method, we characterize VB learning in PCA. In our analysis, we obtain bounds of the noise variance estimator, and a new and simple analytic-form solution for the other parameters, which themselves are useful for implementation of VB-PCA.


Even though remittances to the Latin America and Caribbean (LAC) region are expected to slow down by around 6 percent in 2009 before recovering in 2010, their large recorded value of USD 63 billion in 2008 brings these flows to center stage as a source of growth in times of crisis. There is certainly much to be done if governments aim at having a proactive role in increasing the incentives for remittances. The so-called mobile payments, which make use of mobile technology, have the potential of becoming an essential tool for remittances. Firstly, while bank branches and cash machines account for merely 10 to 20 percent of the population in LAC on average, 80 percent in the region currently have a mobile phone. The key element of success of mobile payments is indeed the size of their distribution networks. Secondly, transaction costs of currently around 9 percent for USD 200, can be substantially reduced by increased competition and by the low capital and operational costs of mobile operators.


The many manifestations of money had and received have come to be treated as a single claim, to reverse a defective transfer of value. I show here that this tendency towards unification has led us to exaggerate the role of value, thus obscuring the normative role played by the notion of a 'transfer' from claimant to defendant. I argue that 'transfer' labels the legal mechanism through which the parties' balance sheet positions are affected. For cases that involve physical cash, the legal mechanism properly associated with a claim in unjust enrichment is a title transfer. For cases that involve bank money, the legal mechanism is a bank transfer, effected by participating banks as agents for payor and payee. I argue that we should welcome the move in Investment Trust Companies v Revenue and Customs Commissioners towards a transactional test, but that we must draw and defend narrow parameters for it.


When vocalizations transmit throughout the environment, attenuation and degradation may change the information of the signal; the loss of information is related to changes in both frequency and duration of vocalizations. The variation in frequency and duration of bird calls is related to the functions of each call type. Using a sound transmission experiment, the authors tested the transmission properties of two call types both produced by white-eared ground-sparrows Melozone leucotis; these calls vary in frequency and duration, suggesting that they may transmit at different distances. The authors broadcasted and re-recorded each call type at four different distances (4, 8, 16, and 32 m) inside ground-sparrow territories. The authors found that calls with a narrow bandwidth and longer duration transmitted at longer distances, and showed a lower attenuation and degradation than the calls with a broad bandwidth and shorter duration. These results support the relationship between the transmission properties of a call and the different functions (short and long distance communication) also evidence how the selection of these calls facilitates the communication over different distances.


The reliable detection and identification of electrotelluric anomalies that could be considered as precursory phenomena of earthquakes become fundamental aspects of earthquake prediction research. Special arrangements, in local and/or regional scale, of the geoelectric structure beneath the measuring point, may act as natural real-time "filters" on the ULF electrotelluric data improving considerably the signal to "magnetotelluric-noise" ratio of anomalies originated by probably non-magnetotelluric sources. Linear polarization, i.e. local channelling of the electric field on the surface is expected in cases where 3D-local inhomogeneities, producing strong shear distortion, are present in the vicinity of the monitoring site and/or when a 2D-regional geoelectrical setting exhibits high anisotropy. By assuming different generation mechanisms and modes of propagation for the electrotelluric anomalies that could be considered earthquake precursory phenomena, a rotationally originated residual electrotelluric field results, eliminating background magnetotelluric-noise and revealing "hidden" transient variations that could be associated to earthquakes. The suggested method is applicable in real-time data collection, thus simplifies and accelerates the tedious task of identification of suspicious signals. As an indicative example, the case of Ioannina (located in Northwestern Greece) is presented. The local polarization of the electrotelluric field varies dramatically even at neighboring points although the regional geoelectric strike direction does not change.+


The basis of the submitted study are the continuously rising demands to alter the curricula with the aim to develop students' key competences in order to increase their professional versatility. The lack of scientific research and discussions show that little investigation has been done on the issue of development of key competences. Therefore, the primary objective of our study is to present the teaching methodology, the process of creating the educational model and the pilot verification aimed at the development of key competences through interactive whiteboard in the subject of Technology. The partial results of the pilot research conducted on the research sample of 6th and 8th grade students of primary schools on Slovakia show its usefulness especially in the development of teamwork, in terms of interpersonal competences, problem solving in terms of learning competences and reading comprehension in terms of communication competences. The presented educational model reflects the contemporary requirements in terms of using information and communication technologies in the teaching of the subject of Technology, in which the acquisition of key competences becomes considerably important.


Starting from a theoretical and methodological foundation of an academic ideology critique, the production, distribution and valorisation of science communication will be analysed in exemplary fashion. The focus is on the criticism of publishing houses' business models in the sphere of open Access publishing. These models are propagated and implemented by science and politics. Thus, academic publications continue to be traded as commodities. The existing relationships of power and domination are thereby reproduced. In contrast, the emancipatory potential of non-commercial science communication based on the digitalisation of production and distribution is shown.


The graph matching optimization problem is an essential component for many tasks in computer vision, such as bringing two deformable objects in correspondence. Naturally, a wide range of applicable algorithms have been proposed in the last decades. Since a common standard benchmark has not been developed, their performance claims are often hard to verify as evaluation on differing problem instances and criteria make the results incomparable. To address these shortcomings, we present a comparative study of graph matching algorithms. We create a uniform benchmark where we collect and categorize a large set of existing and publicly available computer vision graph matching problems in a common format. At the same time we collect and categorize the most popular open-source implementations of graph matching algorithms. Their performance is evaluated in a way that is in line with the best practices for comparing optimization algorithms. The study is designed to be reproducible and extensible to serve as a valuable resource in the future. Our study provides three notable insights: 1.) popular problem instances are exactly solvable in substantially less than 1 second and, therefore, are insufficient for future empirical evaluations; 2.) the most popular baseline methods are highly inferior to the best available methods; 3.) despite the NP-hardness of the problem, instances coming from vision applications are often solvable in a few seconds even for graphs with more than 500 vertices.


textabstractThe goal of this particular research has been to examine the role of information and
communication technologies (ICTs) in policy advocacy as applied by civil society. Taking
the Solidarity for African Women's Rights coalition and their work towards the ratification
of the Protocol on Women's Rights of Women in Africa as a case study, this research has
looked at the opportunities and challenges in using Pambazuka News as a way of promoting
the Protocol. Evaluated according to the theoretical notions of participatory, political and
public spaces, this research has utilised concepts related to civil society and representation,
policy advocacy and awareness raising as well as ICTs and their particular characteristics.
The findings of this research suggest that at the level of civil society communication and
network building, using ICTs in fact strengthens the work. With regards to political
lobbying, however, the usage of ICTs as a tool remains underutilized. Lobby work is more
affected by the relationships held between civil society members and political structures
and individuals. At the level of grassroots awareness raising access to ICTs remains a
barrier and thus requires a much broader strategy.


Abstract Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.


BACKGROUND
Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) induces apoptosis in non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a farnesyltransferase inhibitor that blocks Ras activation, in NSCLC cell lines.

METHODS
The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry-based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis.

RESULTS
The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels.

CONCLUSIONS
The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo. Simultaneous treatment with IGFBP-3 and SCH66336 may have the potential to be an effective therapeutic strategy in NSCLC.


Russian military invasion of Ukraine has caused life-threatening danger to over 7.5 million of Ukrainian children. As a result of the war there are 3 million children-refugees in Ukraine and over 2.2 million children are seeking shelter in other Ukraine friendly countries. Young generation needs urgent humanitarian help. Every two children of three are refugees inside or outside of Ukraine. Children who suffered from injuries, physical, sexual or psychological assaults, kidnepped children or forced to move out of the country or captives must be granted the status of children affected by hostilities and armed conflict. In the reality of martial law in Ukraine the most important aim for Ukrainian educators is to unite the efforts of teachers and communities on their way to protect children's rights and freedoms, teach the young generation, providing them with values and behaviour models they need nowadays. Under the condition of the russian-Ukrainian war, the path to the freedom and independence of Ukraine runs through the formation of the defense-oriented consciousness of the society, education of the younger generation based on the values of Ukraine-centrism, historical truth, and national dignity. The issue of affirmation of the Ukrainian national identity and the spiritual safety of the nation becomes particularly topical. This is because the development of the national culture was detrimentally affected by the long-lasting period of statelessness, restrictions, repressions, negative mythologization of the image of a Ukrainian, rewriting of history, and diminishing the role of Ukrainians in the life of the countries and empires to which they belonged. The educational process shall be in the context of new challenges based on the new historical achievements and moral values produced by the Ukrainian people within the centuries and nowadays realities which conditioned the choice of the topic of this Article. The author partially grounded the pedagogical conditions of affirmation of the bases of national identity of the primary school children, namely, through the formation of the national positive I-concept of the child (the image of I-Ukrainian). The methods of the reinforcement of the educative potential of the extra-class activity are determined through the creation and application of the person-oriented methodology of the formation of all components of the national cultural identity of the children, the ways and directions of further elaboration of this topic are defined.
Keywords: national identity, spiritual safety of the nation, defense consciousness, moral values, strategy, education, pedagogical interaction, children of war.


A growing body of experimental and field data shows that selective pressures often differ between males and females. Surprisingly, to date, little attempt has been made to formalize a metric expressing the relative behavior of directional selection in the two sexes. We propose an index that describes the extent to which concordant or antagonistic selection is operating between the sexes for a given trait. This joint index could prove especially useful for the study of intralocus sexual conflict and the evolution of sexual dimorphism, providing a common scale to directly compare different traits within or among taxonomic levels, and allowing an assessment on how common sexually antagonistic selection might be in extant populations.


In this article, heat the dissipation effect of a ferrofluid on natural convection flow in an inclined cavity at the presence of an external magnetic source has been analyzed with the lattice Boltzmann method (LBM). The cavity is filled with the carrier fluid of kerosene and nanoscale ferromagnetic particle of cobalt. This study has been carried out for the pertinent parameters in the following ranges: the Rayleigh number of carrier fluid, Ra = 103–105, the volumetric fraction of nanoscale ferromagnetic particle between 0 and 4%, and inclined angles (θ = 0°, 30°, 60°, 90°, and 120°) is the size of the nanoscale ferromagnetic particle is fixed at 45 nm. Results show that the heat transfer decreases by the increment of the nanoscale ferromagnetic particle volume fraction for various Rayleigh numbers and inclined angles. The external magnetic source influences the nanoscale ferromagnetic particle at Ra = 104 more than other Raleigh numbers, as the least values were observed at Ra = 103. Just as the least value of heat transfer is obtained at the inclined angle of θ = 90° for multifarious Rayleigh numbers in the absence of nanoscale ferromagnetic particle of cobalt, so the least effect of the nanoscale ferromagnetic particle at Ra = 103 and 105 is perceived for it. Generally, the effective situation of heat dissipation ferrofluid is found at the inclined angle of θ = 0° among the studied inclined angles.


Recently Smart Mobile Access Point (SMAP) based architectures have emerged as a promising solution for creating smart solutions supporting monitoring of special phenomena. SMAP allow us to predict communication activities in a system using the information collected from the network, and select the best approach to support the network at any given time. To improve the network performance, SMAPs can autonomously change their positions. They communicate with each other and carry out distributed computing tasks, constituting a mobile fog-computing platform. However, the communication cost becomes a critical factor. In this paper, we propose a compound method to select the best near-optimal placement of SMAPs with the goal to maximize the monitoring coverage and to minimize the communication cost. Our approach combines a parallel implementation of the Imperialist Competitive Algorithm (ICA) with Kruskal's Algorithm.


Using a femoral head from one manufacturer on the stem of another manufacturer poses the risk that the taper interface between the components do not contact correctly and the performance of the joint will be impaired. The cohorts in this study are a combination of modular Birmingham Hip Resurfacing (BHR) and Adept femoral heads on CPT stems. The study reviews the geometry of the taper interfaces to establish if the taper clearance angles was outside of the normal range for other taper interfaces. In addition the rates of material loss from the bearings and taper and a ranking of the stem damage were reviewed to determine if the levels of loss were above that seen for other similar joints. The material loss analysis demonstrated that the rates or levels of loss from the bearings, taper and stem are no different to levels published for manufacturer matched joints and in many cases are lower. The results demonstrate that the taper clearance angles for the mixed manufacturer joints (BHR-CPT: 0.067 to −0.116, Adept-CPT: 0.101 to −0.056) were within the range of other studies and manufacturer matched clearances (0.134 to −0.149). Using components from different manufacturers has not in this instance increased the level of material loss from the joints, when compared to other similar manufacturer matched joints.


Latinos, or individuals from the Caribbean, South America, and Central America (Santiago, 1996), are affected by a wide variety of health issues, and in particular, obesity. In the United States alone, more than 40% of Latino adults are obese, and almost 23% of Latino children between the ages of 2 to 19 suffer from obesity (Trust for America's Health and the Robert Wood Johnson Foundation, 2014). Latinos are ranked second behind African Americans in obesity rates in the United States (Ogden et al., 2014). This literature review will examine the historical and socio-economic factors that contribute to the high obesity rates for Latinos in Detroit, Michigan, and discuss how living in lowincome areas can affect access to healthy food options.


Information gathering in a partially observable environment can be formulated as a reinforcement learning (RL), problem where the reward depends on the agent's uncertainty. For example, the reward can be the negative entropy of the agent's belief over an unknown (or hidden) variable. Typically, the rewards of an RL agent are defined as a function of the state-action pairs and not as a function of the belief of the agent; this hinders the direct application of deep RL methods for such tasks. This paper tackles the challenge of using belief-based rewards for a deep RL agent, by offering a simple insight that maximizing any convex function of the belief of the agent can be approximated by instead maximizing a prediction reward: a reward based on prediction accuracy. In particular, we derive the exact error between negative entropy and the expected prediction reward. This insight provides theoretical motivation for several fields using prediction rewards---namely visual attention, question answering systems, and intrinsic motivation---and highlights their connection to the usually distinct fields of active perception, active sensing, and sensor placement. Based on this insight we present deep anticipatory networks (DANs), which enables an agent to take actions to reduce its uncertainty without performing explicit belief inference. We present two applications of DANs: building a sensor selection system for tracking people in a shopping mall and learning discrete models of attention on fashion MNIST and MNIST digit classification.


Abstract.  Development of radio frequency identification (RFID) technology and passive integrated transponder (PIT) tags has substantially increased the ability of researchers and managers to monitor populations of aquatic organisms. However, use of transportable RFID antenna systems (i.e., backpack-mounted) is currently limited to wadeable aquatic environments (<1.4 m water depth). We describe the design, construction, and evaluation of a boat-mounted RFID antenna to detect individually PIT-tagged benthic aquatic organisms (mussels). We evaluated the effects of tag orientation on detection distances in water with a 32-mm half-duplex PIT tag. Detection distances up to 50 cm from the antenna coils were obtained, but detection distance was dependent on tag orientation. We also evaluated detection distance of PIT tags beneath the sediment to simulate detection of burrowing mussels with 23- and 32-mm tags. In sand substrate, the maximum detection distance varied from 3.5 cm and 4.5 cm (vertical tag orientation) to 24.7 cm and 39.4 cm (45° tag orientation) for the 23- and 32-mm PIT tags, respectively. Our results suggest a 1.4-m total detection width for tagged mussels on the substrate surface by the boat-mounted antenna system regardless of tag orientation. However, burrowed mussels may require multiple passes to increase detection that would be influenced by depth, tag orientation, and tag size. Construction of the boat-mounted antenna was relatively low in cost (<500 USD) and had several advantages (less labor and time intensive, increased safety) over traditional mussel sampling techniques (diving, snorkeling) in nonwadeable habitats.


The exciting applications of gold nanoparticles (AuNPs) in bio-diagnostics are not limited to use as signal transduction probes; the fascinating effect of AuNPs on enhancing the reactions of nucleic acids has also been increasingly recognized. Herein, we explored the power of AuNPs and their enhancing effect on isothermal amplification reactions. The EXPIATR assay, based on a programmed path of isothermal strand displacement amplifications, has been proven to be a sensitive assay for telomerase activity. However, the assay is not applicable to the complex, protein-rich samples which more closely resemble real clinical specimens, since the abundant cellular proteins in the complex samples can impair the specificity of the amplification reactions. In the presence of AuNPs, the sensitivity of the detection of telomerase activity in complex samples is improved five-fold compared with the traditional assay, providing an efficient way to enhance the reliability of the EXPIATR assay to a new level. In addition to the situation of low-specificity caused by the external interference of cell lysates, it was further demonstrated that AuNPs showed a similar effect on improving the low-specificity caused by the polymerase, which implies that AuNPs affect the amplification reactions in a very fundamental way, presumably by enhancing the activity and stability of the amplification enzymes. By revealing and demonstrating the beneficial role of AuNPs in nucleic-acid reactions, this study provides a new avenue to promote the clinical applications of isothermal nucleic acid amplification.


PDZ domains are important scaffolding modules that typically bind to the C-termini of their interaction partners. Several structures of such complexes have been solved, revealing a conserved binding site in the PDZ domain and an extended conformation of the bound peptide. A compendium of information regarding PDZ complexes demonstrates that dissimilar C-terminal peptides bind to the same PDZ domain, and different PDZ domains can bind the same peptides. A detailed understanding of the PDZ-peptide recognition is needed to elucidate this complexity. To this end, we have designed a family of docking protocols for PDZ domains (termed PDZ-DocScheme) that is based on simulated annealing molecular dynamics and rotamer optimization, and is applicable to the docking of long peptides (20-40 rotatable bonds) to both known PDZ structures and to the more complicated problem of homology models of these domains. The resulting protocol reproduces the structures of PDZ complexes with peptides 4-8 amino acids long within 1-2 A from the experimental structure when the docking is performed to the original structure. If the structure of the target PDZ domain is an apo structure or a homology model, the docking protocol yields structures within 3 A in 9 out of 12 test cases. The automated docking procedure PDZ-DocScheme can serve in the generation of a structural context for validation of PDZ domain specificity from mutagenesis and ligand binding data.


Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with 'injectable' DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.


The Finapres finger cuff recording system provides continuous calculations of beat-to-beat variations in cardiac output (CO), total peripheral resistance, heart rate (HR), and blood pressure (BP). This system is unique in that it allows experimental subjects to immediately, continuously, and noninvasively visualize changes in CO at rest and during exercise. This study provides evidence that using the Finapres system improves undergraduate student engagement, understanding, and learning of how the cardiovascular system responds to exercise. Second-year science students undertaking a physiology practical class in 2009 (n = 243) and 2010 (n = 263) used the Finapres system to record CO, BP, and HR during graded exercise on a cycle ergometer. Student experiences with the Finapres was evaluated with a survey (a 5-point scale from strongly disagree to strongly agree). This indicated that students appreciated the immediacy of the recordings (88% of students agreed or strongly agreed, average for 2009 and 2010), gained an understanding of how to record physiological data (84%), enjoyed the practical (81%), and would recommend the Finapres to other students (81%). To determine if the practical enhanced student learning of cardiovascular physiology, identical tests were given to the students at the beginning (pretest) and end (posttest) of the class. There was a significant improvement from the pretest to the posttest (4% in 2009 and 20% in 2010). In summary, the ability of the Finapres to continuously display CO, BP, and HR during experimental protocols provides students with immediate feedback and improves their understanding of cardiovascular physiology.


Hagendorf-North is a zoned Li-Nb-P-feldspar-quartz pegmatite located W of the village of Hagendorf and about 0.5 km north of the renown Hagendorf-South deposit which once was the largest feldspar pegmatite in Central Europe. Hagendorf-North also known as Meixner Mine was much smaller in size and its minerals assemblage is less variegated than that recorded from its larger "brother". However it was the site where mining began in 1860. But already before the onset of World War II, the pegmatite has no longer been considered an economic target and the mine was shut down. The reason for that small size in the shadow of this huge Hagendorf-South pegmatite is due to its overall role as feeder system to the Hagendorf-type stocklike pegmatites, which was truncated by the Pliocene chemical weathering and Pleistocene erosion, which however was comparatively moderate when compared with the western part of the pegmatite province. Hagendorf-North and South were both emplaced in the central parts of a first order anticline with its hinge line plunging towards the south and thereby providing much better structural, mineralogical and supergene conditions for Hagendorf-South than for Hagendorf-North in terms of accommodation space of the pegmatite body and preservation potential during Cenozoic supergene alteration. Both pegmatites resemble each other as to the temperature of formation spanning the range 500 degrees C to 550 degrees C. The lithogenic process giving rise to the Hagendorf-North pegmatite and its present-day size are as follows: (1) regional metamorphism-structural disturbances, (2) high temperature mobilization, (3) hydrothermal alteration, (4) epithermal mineralization, (5) weathering. The Hagendorf-Pleystein province may be subdivided roughly into two sections. The western section is best described as the Pleystein subzone and the eastern as the Hagendorf subzone. The Hagendorf Zone is marked by a ratio of chemical weathering >> erosion. Newly formed Al-phosphates are widespread and Fe-phosphates indicative of reducing conditions occur to a moderate extent. Chemical weathering was pervasive during the Pliocene, whereas the erosional shaping of the pegmatitic landscape evolved during the Pleistocene. This has also some implications as to the "weathering ruins". The Pleystein-Kreuzberg pegmatite has been depleted of its less resistant feldspar envelope and now morphologically stands out as a "quartz reef", while the Hagendorf-North is a feeder channel system, being deprived of the entire pegmatite body that still was preserved in the Hagendorf-South pegmatite.


The kind of lawsuits that dominate in a country, the place where they are settled, the procedure of settlement etc. may indicate the level of socioeconomic development of that country and the problems for development. This Study provides information on characteristics of lawsuits originating in 52 sample villages in Bangladesh. It appeared that 29 percent of the suits were filed with informal institutions while 78 percent were filed with various formal institutions. About 60 percent of the suits were of criminal nature and about 55 percent of the suits were in relation to land. Variables such as proportion of minority population, size and educational attainment of a village had significant influence on the incidence of suits in a village and proportion of suits taken to formal institutions. Extrapolation from available information suggest that every year the rural people in Bangladesh spend about 1050 million Taka on lawsuits of which about 850 million Taka go to urban dwellers. This has very grave implications for development in general and rural development in particular.


One of the most widespread human behavioral biases is the present bias -- the tendency to overestimate current costs by a bias factor. Kleinberg and Oren (2014) introduced an elegant graph-theoretical model of inconsistent planning capturing the behavior of a present-biased agent accomplishing a set of actions. The essential measure of the system introduced by Kleinberg and Oren is the cost of irrationality -- the ratio of the total cost of the actions performed by the present-biased agent to the optimal cost. This measure is vital for a task designer to estimate the aftermaths of human behavior related to time-inconsistent planning, including procrastination and abandonment.
 As we prove in this paper, the cost of irrationality is highly susceptible to the agent's choices when faced with a few possible actions of equal estimated costs. To address this issue, we propose a modification of Kleinberg-Oren's model of inconsistent planning. In our model, when an agent selects from several options of minimum prescribed cost, he uses a randomized procedure. We explore the algorithmic complexity of computing and estimating the cost of irrationality in the new model.


Phonetics have utmost importance in linguistics especially in the study of the Quran because it addresses the human being in such a unique linguistically sound the perfect way that whoever reads or listens to the Book of Allah abruptly finds an exceptional harmonization, beauty, and relief that is never felt while reading some book written by the man. There is no doubt that the listeners are spell-bound by the phonetics and the aesthetic phonemics of the Quran and most of them (who have been elevated by the Guidance of Allah) would be not only convinced with the very message of the Quran and eventually converted to Islam also. As far as the research methodology is concerned, a descriptive method has been adopted for the said research paper as this method deems appropriate for such topics and analyzing them briefly from all possible aspects. This research paper has discussed the aesthetic phonemic structure of the Holy Quran, especially focusing on the verses related to Moses (PBUH) and some of the main findings can be summarized as follows: The aesthetic phonetic structure of the Quran does have a definite effect on every human and each word of Quran with its specific phonetic force attracts the speaker and listener at the same time. Therefore, it can be concluded that Quran being the word of Allah leaves a very well-synchronized impact on the human beings.


We report on a microfluidic particle-separation device that makes use of the asymmetric bifurcation of laminar flow around obstacles. A particle chooses its path deterministically on the basis of its size. All particles of a given size follow equivalent migration paths, leading to high resolution. The microspheres of 0.8, 0.9, and 1.0 micrometers that were used to characterize the device were sorted in 40seconds with a resolution of ∼10nanometers, which was better than the time and resolution of conventional flow techniques. Bacterial artificial chromosomes could be separated in 10 minutes with a resolution of ∼12%.


ABSTRACT Understanding active sport tourists' profiles and nurturing their destination loyalty are important considerations in the tourism market. Loyal tourists are valuable because they tend to revisit a focal destination and elicit positive word-of-mouth. Focusing on a snow-based active sport tourism context, this study was conducted to examine (1) the usefulness of experience-use history (EUH) as a segmentation tool and (2) the relationship between perceived value factors (i.e. quality, emotional response, monetary price, behavioral price, and destination reputation) and destination loyalty in each EUH group. Data were collected from the Niseko ski resort in Japan (N = 328). Based on the EUH variables (i.e. length and frequency of snow-based sport participation), participants were categorized into four segments (i.e. novice, short-active, long-inactive, and expert). The results showed significant differences among EUH groups in terms of their socio-demographics (e.g. gender, age, and income). A series of regression analyses also showed that each segment's destination loyalty was uniquely enhanced by perceived value factors. Specifically, perceived quality was a significant antecedent of destination loyalty for sport tourists in the novice group. For those in the short-active, long-inactive, and expert groups, perceived emotional response significantly predicted destination loyalty. Perceived reputation of the destination was also important to enhance destination loyalty for the short-active group whereas perceived monetary price was positively associated with the long-inactive group's destination loyalty. Marketing managers in snow-based sport tourism destinations can utilize the findings to increase the loyalty of active sport tourists, which will improve their competitiveness in the marketplace.


BACKGROUND
Common purslane (Portulaca oleracea) and annual ryegrass (Lolium rigidum) are important infesting weeds of field crops. Herbicides are mostly used for weed suppression, while their environmental toxicity and resistance in weeds against them demand considering alternative options, such as the use of allelopathic crops for weed management. Wheat is an important allelopathic crop and present research focused on the identification and quantification of benzoxazinoids (BXZs) and polyphenols (phenolic acids and flavonoids) of the wheat accession 'Ursita' and to screen its allelopathic impact on P. oleracea and L. rigidum through Equal-Compartment-Agar (ECA) method.

RESULTS
Weed germination, radicle length, biomass and photosynthetic pigments were altered following co-growth of weeds with Ursita for 10-days. Root exudates from Ursita reduced (29-60%) the seedling growth and photosynthetic pigments of L. rigidum depending on co-culture conditions of planting density. Weed pressure caused significantly increased in the production of phenolic acids (vanillic, ferulic, syringic and p-coumaric acids) and root exudation of BXZs, in particular benzoxazolin-2-one (BOA), 2-hydroxy-7-methoxy-1,4-benzoxazin-3-one (HMBOA), 2-hydroxy-1,4-benzoxazin3-one (HBOA) and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) in wheat tissues (shoots, roots) and exudate in root rhizosphere agar medium in response to co-cultivation with L. rigidum and P. oleracea, depending on weed/crop density.

CONCLUSION
The work revealed that Ursita is allelopathic in nature and can be used in breeding programs to enhance its allelopathic activity. Meanwhile, there are opportunities to explore allelopathic effect of wheat cultivars to control P. oleracea and L. rigidum under field conditions.


This article provides a brief overview of the quantum chemical auxiliary density functional theory program deMon2k. A basic introduction into its key computational features is given. By selected examples, it is shown how deMon2k can contribute to the elucidation of problems in chemistry, biology, and materials science such as finite temperature effects, nuclear magnetic resonance studies, structure determinations, heterogeneous, and enzymatic catalysis. © 2011 John Wiley & Sons, Ltd.


Splenic sequestration is a potentially life threatening event that is characteristic for sickle cell disease. For reasons unknown a fraction of or even the entire blood volume is trapped in the splenic sinuses within a few hours and thus is no longer available for circulation. The result is splenomegaly, hypovolemia, anemia and extreme reticulocytosis. If the sequestered blood volume is very large the patient goes into fatal hypovolemic shock unless transfused instantly. If the sequestered volume is small there is a chance of spontaneous resolution. The etiology of splenic sequestration is not known. Children with homozygous sickle cell disease (HbSS) are at risk until age 6 years while individuals with compound heterozygous disease (HbSβThal, HbSC, HbSD) may develop splenic sequestration even in adulthood. Parents of infants and toddlers with sickle cell disease need to learn how to palpate the spleen in order to detect splenomegaly as early as possible and take the child to the hospital. Splenic sequestration with a drop in hemoglobin of more than 3 g/dl below the patient's usual hemoglobin level is a clear indication for splenectomy regardless of the patient's age as splenic sequestration tends to recur.


Part I of the thesis describes the preparation of some linear tris-onium ethers and Part II spectral studies on acetylcholine and related compounds. The influence of chemical structure upon biological activity is the unifying concept. In Part I a general review of the development and use of neuromuscular blocking agents serves as an introduction to the receptor theory of neuromuscular blocking activity end to a survey of natural and synthetic neuromuscular blocking agents containing ether linkages. To extend previous studies on the influence of alphatic ether linkages on the muscle relaxant activity of bis- and tris-onium salts come linear tris-onium compounds possessing an asymmetric ether linkage have been synthesised. A new method has been devised for the synthesis of 3-alkoxypropylamines and 3-alkoxybutylamines. The base catalysed addition of dialkylaminoethanols and dialkylaminopropanols to N-alkylacrylamides and N-alkylcrotonamides afforded respectively 3-dialkylaminoalkoxy-propion-N-alkyl-amides and -butyr-N-alkylamides. The relationship between these additions and the Michael addition is discussed. Reduction of the propion-N-alkylamides and butyr-N-alkylamides with lithium aluminium hydride gave the 3-alkoxypropylamines and 3-alkoxybutylamines but cleavage of the ether linkage also occurred. The reduction of 3-(2-diethylaminoethoxy) propion-N-ethylamide yielded 3-(2-diethylaminoethoxy)propyl-ethylamine, N,N'-diethyl-1,3- diaminopropane, 2-diethylamino-othanol, a polymeric amide and an unidentified amine. A mechanism for the cleavage is proposed. Some bis-(3-alkoxy propyl)-alkylamines and a bis-(3-alkoxybutyl)ethylamins, the triamines required for quaternisation, have similarly been synthesised. The attempted preparation of 3-(2-diethylaminoethoxy)-propionie acid by the addition of 2-diethylaminoethanol to ethyl serylate gave chiefly 2-diethylaminoethyl acrylate, 2-diothylminoethyl 3-ethoxypropionate, and 2-diethylamino-ethyl 3-(2-diethylaminoethoxy)propionate. Acid hydrolysis of 3-(2-diethylaminoethoxy)propionitrile caused appreciable cleavage of the ether linkage. Tontativo mechanisms have been advanced for both reactions. The ultraviolet spectra of acrylamide, cretenamide and some of their N-substituted derivatives have been recorded. N-Alkyl and N, N-dialkyl substitution in the acrylamide series is accompanied by the appearance of new bands. The effect of N-substitution is less obvious in the erotonamide series. The triamines were readily quaternised but many of the salts were hygroscopic. These tris-onium ethers have not yet been tested pharmacologically but may provide information on the suggested anti-bonding effect of ether oxygen atoms at the myonearal synaptic receptor. In Part II the biological actions of acetylcholine arc reviewed and the possible role of conformational isemerism in its biological activity is discussed. Kinetic and infrared studies in the literature may be rainterprated to mean that the quasi-ring form of acetylcholine exists in ethanolic and aqueous solution. The hypothesis is advanced that the quasi-ring conformation is involved at the "muscarinie" receptor and that the extended conformation is complomantery to the "nicotinic" receptor. To establish whether two conformations of acetylcholine co-existed in solution infrared studies of the N-mathyl C-H stretching and deformation frequencies and of the carbonyl stretching frequencies of acetylcholine and related compounds were undertaken. No suitable solvent could be found for the examination of the C-H stretching and deformation frequencies. Infrared spectra were accordingly measured in the solid state for the trimathylammonium salts and these were compared with the spectra of some of the corresponding tertiary bases measured in the liquid state. The spectra were complex in the 3100-2700 cm-1 region. No effect attributable to the influence of either a quaternary nitrogen atom or to intramolecular NC-H-O hydrogen bonding on the C-H stretching frequencies was apparent. The examination of the C-H deformation frequencies provided some evidence for NC-H-O bonding in acetylcholine, acetyl-methylcholine and succinylcholine but the results are not unambiguous Solution spectra of acetylcholine and acetyl-methylcholine in dry dioxan showed split cerbonyl abeorptions. Low intensity absorption, indicative of hydrolysis, precluded definite assignment of these absorptions to conform atonal effects. A series of acetoxyalkyl sulphones formally related to acetylcholine have been synthesised. From measurements of their carbonyl absorptions in dry dioxan the high frequency carbonyl absorption of acetylcholine is best interpreted by inductive effects. The N.N.R. spectra of acetylcholine and acetyl-methyl-choline in D2O solution gave no indication of intramolecular NC-H-O hydrogen bonding.


The query processing in a mobile computing environment involves join processing among different sites which include static servers and mobile computers. Because of the presence of asymmetric features in a mobile computing environment, the conventional query processing for a distributed database cannot be directly applied to a mobile computing system. In this paper, we first explore some unique features of a mobile environment and then, in light of these features, devise query processing methods for both join and query processing. Remote mobile joins are said to be effectual if they are, when being interleaved into a join sequence, able to reduce the amount of data transmission cost required for distributed mobile query processing. Since mobile relations are employed as reducers in our proposed query processing cost model, more mobile joins in the query processing lead to less data transmitted through the network. With proper scheduling, interleaving effectual remote mobile joins into a query scheduling can significantly reduce the total amount of data transmission among different sites. A simulator is developed to evaluate the performance of algorithms devised. Our results show that the approach of interleaving the processing of distributed mobile queries with effectual remote mobile joins is not only efficient, but also effective in reducing the total amount of data transmission cost required to process distributed mobile queries.


Introduction – Kanban system is a card system that becomes markers. During its development, the kanban system experiences a number of variations. In the context of delivery system in hospital, delivery pack can be considered as a kanban. Delivery packs have complete data of patient information. They serve to monitor pregnant women in labor, childbirth, and the implementation of exclusive breastfeeding. By looking at the delivery packs, the doctor or midwife can determine the condition of mothers who give birth. Each card is stored in a pack in accordance with the estimated labor. This way, the doctor, midwife and mother can know the condition of pregnancy from time to time, including the danger signs of pregnancy and the risk of complications. the study sought to examine the performance of the delivery packs in customer retention in RSIA Kemang/Kemang Medical Care. Method – Researchers examined data on the number of patients maternity (SC and normal deliveries) in accordance with the estimated delivery using document analysis and report of medical record and audit results of kanban (delivery packs). The research sample was acquired in 6 (six) months from January to June 2015. The analysis was done by descriptive analytical design.Result – This study shows that the highest number of patients who gave birth happened in June 2015. In that month, there were 105 births, 19 of them did not have delivery packs. Even so, there were 96 patients who had delivery packs. It means that there are 10 patients with obstructed labor that did not have delivery records in the KMC. The evidence by the percentage of retention failures that goes up and down in the range of 6%-17%. There is failed retention as much as 11% every month. It means that in year 2015 and probably the year 2016, there are approximately 11% of patients KMC who do not want to give birth at the hospital, despite having the complete data of delivery packs.Discussion – The reasons which cause static retention may vary. They do not have to because of the low quality of services at KMC. They can be caused by KMC location which is far away from the patient when the patient is about to give birth. Indeed, KMC still have to improve the quality of service because if the consumer retention is seen as an indicator of quality of service. Conclusion - The use of delivery packs as a measuring tool of consumer retention shows the alternative benefits of kanban on hospital quality management system. This article gives examples of its use in hospitals KMC in Jakarta.


Oscillatory flow is the type of flow found in the greener thermoacoustic based technologies. Understanding the behavior of the less understood oscillatory flow of this kind is one of the key feature for the success of the system. Heat exchanger is one of the important part of the system. In this study, oscillatory flow across pile of hot and cold parallel-plates heat exchanger with three different shape of edges (i.e. rectangular, round and triangular shape of edges) were investigated. A suitable computational model was created in ANSYS. The results were compared to theoretical predictions and a good match was found. The study shows that the shape of the edge affects the flow and heat transfer of the system. A triangle-shaped edges with shorter length provides the higher heat transfer between plates and the oscillating fluid compared to plates with round and square edges. The results indicated that the entrance effect could be the reason for the change of heat transfer performance as the shape of edge changes.


SIR,-With regard to the article by Ms Christiane Harris and Dr Richard Smith (25 April, p 1076), health authorities can be active in the primary prevention of the ill health caused by unemployment.' 2 A national network of product development agencies has been formed by over 30 groups involved in "alternative technology"-developing products for which there is an identified social need, using the skills of workers who are unemployed or working in armaments manufacture, and locally available resources. Ideas for products for which local people have identified a need are developed with groups of workers with the necessary skills. Technical support to existing businesses further enhances local employment prospects. Many of these agencies are based in polytechnics and use student project work-in engineering, design, computing, management, and marketing-to develop products. Among these agencies are the Sheffield centre for product development and technological resources at Sheffield City Polytechnic and the unit for the development of alternative products at Coventry (Lanchester) Polytechnic. The economic development units of some councils and cooperative development agencies are also participating. Among the products that have been developed in this way are the Monseco advanced dehumidifier to combat dampness; Audiocalc, the speaking spreadsheet for blind people; telescopic implants for children with osteogenesis imperfecta (by the Sheffield centre and Sheffield Employment Department); the Covloc display board system; the BEA lift bath aid for handicapped children; a ventilator alarm; a domestic ventilator for patients with neurological breathing problems; and electric and hybrid powered (combined petrol and electric) vehicles (by the unit at Coventry). Health services can contribute actively to local employment prospects by establishing links with local authority economic development units, higher education centre economic or engineering departments, and alternative technology agencies. Health workers can identify needs for products for the sick or handicapped, they can help to evaluate new health care products, and they can advocate the purchase of products developed in this way. A special health authority for National Health Service procurement would be able to buy products built in this country and state requirements for products that were needed by the National Health Service and could be made here. Intermediate, appropriate, or development technology agencies work mainly on projects with the developing world. These agencies do not export products that are disabling to a developing economy but provide skills, designs, or tools that workers in developing countries can use. Appropriate Technology Design and Development of Moreton-in-Marsh, Gloucestershire, has produced designs for metal rolling and pipe bending machines that have been built in African countries to cannibalise scrap metal for farming equipment, cooking utensils, and even tricycles for polio victims. The unit at Coventry has designed a small scale smelter and a small scale brick maker, both of which use old engine oil, a plentiful commodity in developing countries. In addition, a Coventry firm is building a containerised toolshop to the specifications of Indian farm workers. Arms conversion-the use of military technology for peaceful purposes-is another element of the work of some of these agencies. It is widely acknowledged that military industries provide fewer jobs for a given investment; they are major consumers of raw materials, energy, and research funds and thus contribute to high inflation rates, high interest rates, and poor potential for investment in socially useful, peaceful production.' 2 Alternative technology embraces the principles of "Health for all": healthy work practices, community participation, democracy, and local initiatives leading to international cooperation and to "peace which is more than the absence of war."


OBJECTIVES The purpose of this research was to determine the effect of intravenous adenosine on clinical outcomes and infarct size in ST-segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy. BACKGROUND Previous small studies suggest that adenosine may reduce the size of an evolving infarction. METHODS Patients (n 2,118) with evolving anterior STEMI receiving thrombolysis or primary angioplasty were randomized to a 3-h infusion of either adenosine 50 or 70 g/kg/min or of placebo. The primary end point was new congestive heart failure (CHF) beginning 24 h after randomization, or the first re-hospitalization for CHF, or death from any cause within six months. Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography. RESULTS There was no difference in the primary end point between placebo (17.9%) and either the pooled adenosine dose groups (16.3%) or, separately, the 50g/kg/min dose and 70g/kg/ min groups (16.5% vs. 16.1%, respectively, p 0.43). The pooled adenosine group trended toward a smaller median infarct size compared with the placebo group, 17% versus 27% (p 0.074). A dose-response relationship with final median infarct size was seen: 11% at the high dose (p 0.023 vs. placebo) and 23% at the low dose (p NS vs. placebo). Infarct size and occurrence of a primary end point were significantly related (p 0.001). CONCLUSIONS Clinical outcomes in patients with STEMI undergoing reperfusion therapy were not significantly improved with adenosine, although infarct size was reduced with the 70g/kg/ min adenosine infusion, a finding that correlated with fewer adverse clinical events. A larger study limited to the 70g/kg/min dose is, therefore, warranted. (J Am Coll Cardiol 2005; ublished by Elsevier Inc. doi:10.1016/j.jacc.2005.02.061


Vaccination in autoimmunity can have beneficial, but also detrimental effects. In this thesis, we tried to identify factors that contribute to a favourable or an unfavourable outcome of vaccination in Juvenile Idiopathic Arthritis (JIA) and experimental arthritis. In the first part, we focused on the potential unwanted effects of vaccination against Meningitis type C in two studies in JIA patients receiving the Meningococcal C vaccine. In chapter 2 we describe that no clinical disease aggravation was detected after MenC vaccination in a large cohort of JIA patients. Although geometric mean titers of anti-MenC antibodies were lower in treatment groups receiving immune suppressive medication, functional MenC bactericidal capacity of these antibodies was adequate in all patients. These were encouraging results, supporting the positive advice of administration of vaccines to children with JIA. However, the results of chapter 3 raise a concern for JIA patients with non-remitting disease. The increased pro-inflammatory cytokine profile raised by vaccine specific T cells after vaccination in these patients in combination with an aberrant FOXP3+ regulatory T cell (Treg) response theoretically could hold a risk for aggravating autoimmunity, although this potential clinical effect was not observed in our study. For the second part of this thesis, we studied the potential protective effects of nasal peptide vaccination against rat adjuvant induced arthritis. First, we hypothesized that mucosal vaccination with a bystander antigen like heat shock protein (HSP) (peptide immunotherapy) may be able to protect against autoimmune arthritis (reviewed in chapter 4). In chapter 5 we show that mucosal administration of such a bystander peptide derived from bacterial HSP60 protects against experimental arthritis, and that this protection was transferable by CD4+ T cells. Skewing of the peptide-specific immune response towards a regulatory phenotype might have played a role, as peptide treatment was associated with a reduction of peptide specific tumour necrosis factor α (TNFα) production by CD4+Tcells and the presence of suppressive CD4+FoxP3+ Treg cells. Addition of a mucosal adjuvant (CpG) to peptide specific immunotherapy clearly enhanced clinical efficacy in experimental arthritis (chapter 6). Co-treatment of p1 with CpG increased both the number and activation status of plasmacytoid DC in draining MLN, which was accompanied by augmented p1-specific T cell proliferation and IL-10 production. After arthritis induction, p1- and p1/CpG-treated rats showed increased amounts of CD4+FoxP3+ Tregs in the joint draining lymph nodes, which correlated with lower arthritis scores. The data in chapter 7 show an improvement in the clinical and immunological effect of nasal HSP peptide immunotherapy in a therapeutic (instead of preventive) setting. Peptide immunotherapy with a bacterial HSP60 peptide after initiation of adjuvant arthritis was most effective when combined with low dose TNFα receptor blockade (Etanercept), reaching the same level of protection as full dose Etanercept treatment. Combination treatment led to an increase in peptide specific IL-10 production by CD4+ T cells and an upregulation of FoxP3 gene expression in CD4+CD25+ Treg cells. These new approaches for more effective peptide immunotherapy could pave the way for a promising future of peptide specific immunotherapy in autoimmune diseases


Multilayered skin substitutes comprising allogeneic cells have been tested for the treatment of non-healing cutaneous ulcers. However, such non-native skin grafts fail to permanently engraft because they lack dermal vascular networks important for integration with the host tissue. Here we describe the fabrication of an implantable multi-layered vascularized bioengineered skin graft using 3D bioprinting. The graft is formed using one bioink containing human foreskin dermal fibroblasts (FBs), human endothelial cells (ECs) derived from cord blood human endothelial colony forming cells (HECFCs), and human placental pericytes (PCs) suspended in rat tail type I collagen to form a dermis followed by printing with a second bioink containing human foreskin keratinocytes (KCs) to form an epidermis. In vitro, KCs replicate and mature to form a multilayered barrier while the ECs and PCs self-assemble into interconnected microvascular networks. The PCs in the dermal bioink associate with EC-lined vascular structures and appear to improve KC maturation. When these 3D printed grafts are implanted on the dorsum of immunodeficient mice, the human EC-lined structures inosculate with mouse microvessels arising from the wound bed and become perfused within 4 weeks after implantation. The presence of PCs in the printed dermis enhances the invasion of the graft by host microvessels and the formation of an epidermal rete.