The evolution of the natural killer complex; a comparison between mammals using new high-quality genome assemblies and targeted annotation.

Natural killer (NK) cells are a diverse population of lymphocytes with a range of biological roles including essential immune functions. NK cell diversity is in part created by the differential expression of cell surface receptors which modulate activation and function, including multiple subfamilies of C-type lectin receptors encoded within the NK complex (NKC). Little is known about the gene content of the NKC beyond rodent and primate lineages, other than it appears to be extremely variable between mammalian groups. We compared the NKC structure between mammalian species using new high-quality draft genome assemblies for cattle and goat; re-annotated sheep, pig, and horse genome assemblies; and the published human, rat, and mouse lemur NKC. The major NKC genes are largely in the equivalent positions in all eight species, with significant independent expansions and deletions between species, allowing us to propose a model for NKC evolution during mammalian radiation. The ruminant species, cattle and goats, have independently evolved a second KLRC locus flanked by KLRA and KLRJ, and a novel KLRH-like gene has acquired an activating tail. This novel gene has duplicated several times within cattle, while other activating receptor genes have been selectively disrupted. Targeted genome enrichment in cattle identified varying levels of allelic polymorphism between the NKC genes concentrated in the predicted extracellular ligand-binding domains. This novel recombination and allelic polymorphism is consistent with NKC evolution under balancing selection, suggesting that this diversity influences individual immune responses and may impact on differential outcomes of pathogen infection and vaccination

Final Report: Theory of Advanced High Efficiency Concentrator Cells

The goal of this project was to begin -developing accurate, and ultimately predictive, device models for III-V concentrator cells. The project consisted of extending a one-dimensional numerical device model previously developed at Purdue to III-V solar cells. We also began verifying the accuracy of the code by comparing computed and measured solar cell characteristics. Gallium arsenide was selected because it is the most mature III-V technology and because GaAs solar cells have demonstrated high conversion efficiency [l,2,3]. The present device model should be useful in optimizing GaAs solar cells and forms a foundation that can be extended to other III-V homo- and heterostructure solar cells. The numerical device model developed in this work solves Poisson’s equation simultaneously with the electron and hole continuity equations without making common assumptions such as low-level injection, piece-wise uniform doping, neglect of space-charge recombination, etc. Materials models for GaAs solar cells (e. g. intrinsic carrier concentration, carrier mobilities, lifetimes, optical absorption and reflection coefficients, etc.) were compiled, evaluated, and in some cases extended. These materials models were then implemented into the numerical device model. The device model was also extended to analyze optical absorption and reflection from bare and anti-reflection (AR) coated cells. To test the GaAs cell model, we compared its predictions to measured results for an N+P cell (the shallow homojunction cell reported by Fan and co-workers) and a P+N cell (fabricated by Borrego and co-workers). In general, good agreement between theory and experiment was obtained for both concentrated and unconcentrated conditions. Although detailed comparisons of the model’s predictions with measured results continue, the present model is a useful tool for GaAs cell design and optimization

Association of Air Pollution with Increased Incidence of Ventricular Tachyarrhythmias Recorded by Implanted Cardioverter Defibrillators

Epidemiologic studies have demonstrated a consistent link between sudden cardiac deaths and particulate air pollution. We used implanted cardioverter defibrillator (ICD) records of ventricular tachyarrhythmias to assess the role of air pollution as a trigger of these potentially life-threatening events. The study cohort consisted of 203 cardiac patients with ICD devices in the Boston metropolitan area who were followed for an average of 3.1 years between 1995 and 2002. Fine particle mass and gaseous air pollution plus temperature and relative humidity were measured on almost all days, and black carbon, sulfate, and particle number on a subset of days. Date, time, and intracardiac electrograms of ICD-detected arrhythmias were downloaded at the patients’ regular follow-up visits (about every 3 months). Ventricular tachyarrhythmias were identified by electrophysiologist review. Risk of ventricular arrhythmias associated with air pollution was estimated with logistic regression, adjusting for season, temperature, relative humidity, day of the week, patient, and a recent prior arrhythmia. We found increased risks of ventricular arrhythmias associated with 2-day mean exposure for all air pollutants considered, although these associations were not statistically significant. We found statistically significant associations between air pollution and ventricular arrhythmias for episodes within 3 days of a previous arrhythmia. The associations of ventricular tachyarrhythmias with fine particle mass, carbon monoxide, nitrogen dioxide, and black carbon suggest a link with motor vehicle pollutants. The associations with sulfate suggest a link with stationary fossil fuel combustion sources

Integrating resource selection into spatial capture-recapture models for large carnivores

Wildlife managers need reliable methods to estimate large carnivore densities and population trends; yet large carnivores are elusive, difficult to detect, and occur at low densities making traditional approaches intractable. Recent advances in spatial capture-recapture (SCR) models have provided new approaches for monitoring trends in wildlife abundance and these methods are particularly applicable to large carnivores. We applied SCR models in a Bayesian framework to estimate mountain lion densities in the Bitterroot Mountains of west central Montana. We incorporate an existing resource selection function (RSF) as a density co-variate to account for heterogeneity in habitat use across the study area and include data collected from harvested lions. We identify individuals through DNA samples collected by (1) biopsy darting mountain lions detected in systematic surveys of a study area, (2) opportunistically collecting hair and scat samples, and (3) sampling all harvested mountain lions. We included 80 DNA samples collected from 62 individuals in the analysis. Including information on predicted habitat use as a co-variate on the distribution of activity centers reduced the median estimated density by 44% the standard deviation by 7% and the width of 95% credible intervals by 10% as compared to standard SCR models. Within the two management units of interest, we estimated a median mountain lion density of 4.5 mountain lions/100 km2 (95% CI=2.9, 7.7) and 5.2 mountain lions/100 km2 (95% CI=3.4, 9.1). Including harvested individuals (dead recovery) did not create a significant bias in the detection process by introducing individuals that could not be detected after removal. However, the dead recovery component of the model did have a substantial effect on results by increasing sample size. The ability to account for heterogeneity in habitat use provides a useful extension to SCR models, and will enhance the ability of wildlife managers to reliably and economically estimate density of wildlife populations, particularly large carnivores

Thermally activated switching in the presence of non-Gaussian noise

We study the effect of a non-Gaussian noise on interstate switching activated primarily by Gaussian noise. Even weak non-Gaussian noise can strongly change the switching rate. The effect is determined by all moments of the noise distribution. The explicit analytical results are compared with the results of simulations for an overdamped system driven by white Gaussian noise and a Poisson noise. Switching induced by a purely Poisson noise is also discussed.Comment: 4 pages, 2 figures, unsolicited repor

Probing the role of the cation–π interaction in the binding sites of GPCRs using unnatural amino acids

We describe a general application of the nonsense suppression methodology for unnatural amino acid incorporation to probe drug–receptor interactions in functional G protein-coupled receptors (GPCRs), evaluating the binding sites of both the M2 muscarinic acetylcholine receptor and the D2 dopamine receptor. Receptors were expressed in Xenopus oocytes, and activation of a G protein-coupled, inward-rectifying K^+ channel (GIRK) provided, after optimization of conditions, a quantitative readout of receptor function. A number of aromatic amino acids thought to be near the agonist-binding site were evaluated. Incorporation of a series of fluorinated tryptophan derivatives at W6.48 of the D2 receptor establishes a cation–π interaction between the agonist dopamine and W6.48, suggesting a reorientation of W6.48 on agonist binding, consistent with proposed “rotamer switch” models. Interestingly, no comparable cation–π interaction was found at the aligning residue in the M2 receptor

Lynx X-Ray Observatory: An Overview

Lynx, one of the four strategic mission concepts under study for the 2020 Astrophysics Decadal Survey, provides leaps in capability over previous and planned x-ray missions and provides synergistic observations in the 2030s to a multitude of space- and ground-based observatories across all wavelengths. Lynx provides orders of magnitude improvement in sensitivity, on-axis subarcsecond imaging with arcsecond angular resolution over a large field of view, and high-resolution spectroscopy for point-like and extended sources in the 0.2- to 10-keV range. The Lynx architecture enables a broad range of unique and compelling science to be carried out mainly through a General Observer Program. This program is envisioned to include detecting the very first seed black holes, revealing the high-energy drivers of galaxy formation and evolution, and characterizing the mechanisms that govern stellar evolution and stellar ecosystems. The Lynx optics and science instruments are carefully designed to optimize the science capability and, when combined, form an exciting architecture that utilizes relatively mature technologies for a cost that is compatible with the projected NASA Astrophysics budget

Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system

<p>Abstract</p> <p>Background</p> <p>Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the <it>Xenopus laevis </it>tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits.</p> <p>Results</p> <p>Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-α on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-α resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-α treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-α-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures.</p> <p>Conclusions</p> <p>Taken together our data are consistent with a model in which TNF-α causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.</p

Patent Foramen Ovale: Current Pathology, Pathophysiology, and Clinical Status

Patent foramen ovale (PFO) is experiencing increased clinical interest as a congenital cardiac lesion persisting into adulthood. It is implicated in several serious clinical syndromes, including stroke, myocardial infarction, and systemic embolism. The PFO is now amenable to percutaneous interventional therapies, and multiple novel technologies are either available or under development for lesion closure. The PFO should be better understood to take advantage of emerging percutaneous treatment options. This paper reviews PFO anatomy, pathology, pathophysiology, and clinical impact and discusses current therapeutic options