Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation

To identify rate-limiting steps in T cell-independent type 2 (TI-2) antibody production against polysaccharide antigens, we performed a genome-wide screen by immunizing several hundred pedigrees of C57BL/6 mice segregating ENU-induced mis-sense mutations. Two independent mutations, Tilcara and Untied, were isolated that semi-dominantly diminished antibody against polysaccharide but not protein antigens. Both mutations resulted from single amino acid substitutions within the kinase domain of Protein Kinase C Beta (PKCβ). In Tilcara, a Ser552>Pro mutation occurred in helix G, in close proximity to a docking site for the inhibitory N-terminal pseudosubstrate domain of the enzyme, resulting in almost complete loss of active, autophosphorylated PKCβI whereas the amount of alternatively spliced PKCβII protein was not markedly reduced. Circulating B cell subsets were normal and acute responses to BCR-stimulation such as CD25 induction and initiation of DNA synthesis were only measurably diminished in Tilcara homozygotes, whereas the fraction of cells that had divided multiple times was decreased to an intermediate degree in heterozygotes. These results, coupled with evidence of numerous mis-sense PRKCB mutations in the human genome, identify Prkcb as a genetically sensitive step likely to contribute substantially to population variability in anti-polysaccharide antibody levels

Defect healing at room temperature in pentacene thin films and improved transistor performance

We report on a healing of defects at room temperature in the organic semiconductor pentacene. This peculiar effect is a direct consequence of the weak intermolecular interaction which is characteristic of organic semiconductors. Pentacene thin-film transistors were fabricated and characterized by in situ gated four-terminal measurements. Under high vacuum conditions (base pressure of order 10E-8 mbar), the device performance is found to improve with time. The effective field-effect mobility increases by as much as a factor of two and mobilities up to 0.45 cm2/Vs were achieved. In addition, the contact resistance decreases by more than an order of magnitude and there is a significant reduction in current hysteresis. Oxygen/nitrogen exposure and annealing experiments show the improvement of the electronic parameters to be driven by a thermally promoted process and not by chemical doping. In order to extract the spectral density of trap states from the transistor characteristics, we have implemented a powerful scheme which allows for a calculation of the trap densities with high accuracy in a straightforward fashion. We show the performance improvement to be due to a reduction in the density of shallow traps <0.15 eV from the valence band edge, while the energetically deeper traps are essentially unaffected. This work contributes to an understanding of the shallow traps in organic semiconductors and identifies structural point defects within the grains of the polycrystalline thin films as a major cause.Comment: 13 pages, 13 figures, to be published in Phys. Rev.

Exploring the space of human exploration using Entropy Mastermind

What drives people’s exploration in complex scenarios where they have to actively acquire information? How do people adapt their selection of queries to the environment? We explore these questions using Entropy Mastermind, a novel variant of the Mastermind code-breaking game, in which participants have to guess a secret code by making useful queries. Participants solved games more efficiently if the entropy of the game environment was low; moreover, people adapted their initial queries to the scenario they were in. We also investigated whether it would be possible to predict participants’ queries within the generalized Sharma-Mittal information-theoretic framework. Although predicting individual queries was difficult, the modeling framework offered important insights on human behavior. Entropy Mastermind opens up rich possibilities for modeling and behavioral research

On the formation of the welding seams with high speed

Целью настоящей работы является определение направлений исследований по установлению возможности повышения качества формирования сварочных швов с повышенной скоростью формирования тела шва. В статье вопрос решается путём отклонения сварочной дуги углом вперед, поперечным магнитным полем. Дополнительное магнитное поле в зоне сварки генерируют, пропуская часть сварочного тока по присадочной проволоке. Проволока подается в сварочную ванну позади дуги параллельно электроду в плоскости свариваемого стыка, в направлении, противоположном току дуги. Проведенный анализ отечественных и зарубежных литературных источников по рассматриваемой теме показал, что современный подход к определению влияния на повышение качества формирования сварочных швов с повышенной скоростью формирования тела шва, за счет дополнительного поперечного магнитного поля является актуальным в настоящее время и недостаточно изучен. Приведены сведения о формировании тела шва при скоростной сварке вольфрамовым электродом с присадочной проволокой, которые могут быть использованы для повышения производительности сварочных работ.The aim of this work is to determine the areas of research to establish the possibility of improving the quality of the formation of welds with an increased rate of formation of the joint body. In the article the problem is solved by the deviation of the arc angle forward transverse magnetic field. Additional magnetic field generated in the welding zone by passing part of the welding current for the filler wire. The wire is fed into the weld puddle behind the arc electrode in the plane parallel to the welded joint, in a direction opposite to the arc current. The analysis of domestic and foreign literature on the topic has shown that the modern approach to determine the effect on the improvement of quality of formation of welds with an increased rate of formation of the joint body, due to the additional transverse magnetic field is relevant in the present and not fully understood. Information is given about the formation of a seam in the tungsten electrode welding with filler wire, which can be used to improve the performance of welding

Genetic therapeutic advancements for Dravet Syndrome

Dravet Syndrome is a genetic epileptic syndrome characterized by severe and intractable seizures associated with cognitive, motor, and behavioral impairments. The disease is also linked with increased mortality mainly due to sudden unexpected death in epilepsy. Over 80% of cases are due to a de novo mutation in one allele of the SCN1A gene, which encodes the α-subunit of the voltage-gated ion channel NaV1.1. Dravet Syndrome is usually refractory to antiepileptic drugs, which only alleviate seizures to a small extent. Viral, non-viral genetic therapy, and gene editing tools are rapidly enhancing and providing new platforms for more effective, alternative medicinal treatments for Dravet syndrome. These strategies include gene supplementation, CRISPR-mediated transcriptional activation, and the use of antisense oligonucleotides. In this review, we summarize our current knowledge of novel genetic therapies that are currently under development for Dravet syndrome

Virtual Structure Constants as Intersection Numbers of Moduli Space of Polynomial Maps with Two Marked Points

In this paper, we derive the virtual structure constants used in mirror computation of degree k hypersurface in CP^{N-1}, by using localization computation applied to moduli space of polynomial maps from CP^{1} to CP^{N-1} with two marked points. We also apply this technique to non-nef local geometry O(1)+O(-3)->CP^{1} and realize mirror computation without using Birkhoff factorization.Comment: 10 pages, latex, a minor change in Section 4, English is refined, Some typing errors in Section 3 are correcte

The burden of proof: the current state of atrial fibrillation prevention and treatment trials

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015

Brauer group of moduli spaces of pairs

We show that the Brauer group of any moduli space of stable pairs with fixed determinant over a curve is zero.Comment: 12 pages. Final version, accepted in Communications in Algebr

Properties of Active Galaxies Deduced from H I Observations

We completed a new survey for H I emission for a large, well-defined sample of 154 nearby (z < 0.1) galaxies with type 1 AGNs. We make use of the extensive database presented in a companion paper to perform a comprehensive appraisal of the cold gas content in active galaxies and to seek new strategies to investigate the global properties of the host galaxies and their relationship to their central black holes (BHs). We show that the BH mass obeys a strong, roughly linear relation with the host galaxy's dynamical mass. BH mass follows a looser, though still highly significant, correlation with the maximum rotation velocity of the galaxy, as expected from the known scaling between rotation velocity and central velocity dispersion. Neither of these H I-based correlations is as tight as the more familiar relations between BH mass and bulge luminosity or velocity dispersion, but they offer the advantage of being insensitive to the glare of the nucleus and therefore are promising new tools for probing the host galaxies of both nearby and distant AGNs. We present evidence for substantial ongoing BH growth in the most actively accreting AGNs. In these nearby systems, BH growth appears to be delayed with respect to the assembly of the host galaxy but otherwise has left no detectable perturbation to its mass-to-light ratio or its global gas content. The host galaxies of type 1 AGNs, including those luminous enough to qualify as quasars, are generally gas-rich systems, possessing a cold interstellar medium reservoir at least as abundant as that in inactive galaxies of the same morphological type. This calls into question current implementations of AGN feedback in models of galaxy formation that predict strong cold gas depletion in unobscured AGNs. (Abridged)Comment: To appear in ApJ; 14 page