Influenza A Gradual and Epochal Evolution: Insights from Simple Models

The recurrence of influenza A epidemics has originally been explained by a “continuous antigenic drift” scenario. Recently, it has been shown that if genetic drift is gradual, the evolution of influenza A main antigen, the haemagglutinin, is punctuated. As a consequence, it has been suggested that influenza A dynamics at the population level should be approximated by a serial model. Here, simple models are used to test whether a serial model requires gradual antigenic drift within groups of strains with the same antigenic properties (antigenic clusters). We compare the effect of status based and history based frameworks and the influence of reduced susceptibility and infectivity assumptions on the transient dynamics of antigenic clusters. Our results reveal that the replacement of a resident antigenic cluster by a mutant cluster, as observed in data, is reproduced only by the status based model integrating the reduced infectivity assumption. This combination of assumptions is useful to overcome the otherwise extremely high model dimensionality of models incorporating many strains, but relies on a biological hypothesis not obviously satisfied. Our findings finally suggest the dynamical importance of gradual antigenic drift even in the presence of punctuated immune escape. A more regular renewal of susceptible pool than the one implemented in a serial model should be part of a minimal theory for influenza at the population level

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.This study made use of data generated by the UK10K Project and we acknowledge the contribution of the UK10K Consortium. This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.) and the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310

Evaluating Nuclei Concentration in Amyloid Fibrillation Reactions Using Back-Calculation Approach

Background: In spite of our extensive knowledge of the more than 20 proteins associated with different amyloid diseases, we do not know how amyloid toxicity occurs or how to block its action. Recent contradictory reports suggest that the fibrils and/or the oligomer precursors cause toxicity. An estimate of their temporal concentration may broaden understanding of the amyloid aggregation process. Methodology/Principal Findings: Assuming that conversion of folded protein to fibril is initiated by a nucleation event, we back-calculate the distribution of nuclei concentration. The temporal in vitro concentration of nuclei for the model hormone, recombinant human insulin, is estimated to be in the picomolar range. This is a conservative estimate since the back-calculation method is likely to overestimate the nuclei concentration because it does not take into consideration fibril fragmentation, which would lower the amount of nuclei Conclusions: Because of their propensity to form aggregates (non-ordered) and fibrils (ordered), this very low concentration could explain the difficulty in isolating and blocking oligomers or nuclei toxicity and the long onset time for amyloid diseases

Improved Limits on Scattering of Weakly Interacting Massive Particles from Reanalysis of 2013 LUX Data

We present constraints on weakly interacting massive particles (WIMP)-nucleus scattering from the 2013 data of the Large Underground Xenon dark matter experiment, including 1.4×104 kg day of search exposure. This new analysis incorporates several advances: single-photon calibration at the scintillation wavelength, improved event-reconstruction algorithms, a revised background model including events originating on the detector walls in an enlarged fiducial volume, and new calibrations from decays of an injected tritium β source and from kinematically constrained nuclear recoils down to 1.1 keV. Sensitivity, especially to low-mass WIMPs, is enhanced compared to our previous results which modeled the signal only above a 3 keV minimum energy. Under standard dark matter halo assumptions and in the mass range above 4 GeV c-2, these new results give the most stringent direct limits on the spin-independent WIMP-nucleon cross section. The 90% C.L. upper limit has a minimum of 0.6 zb at 33 GeV c-2 WIMP mass

Radiogenic and muon-induced backgrounds in the LUX dark matter detector

The Large Underground Xenon (LUX) dark matter experiment aims to detect rare low-energy interactions from Weakly Interacting Massive Particles (WIMPs). The radiogenic backgrounds in the LUX detector have been measured and compared with Monte Carlo simulation. Measurements of LUX high-energy data have provided direct constraints on all background sources contributing to the background model. The expected background rate from the background model for the 85.3 day WIMP search run is (2.6±0.2stat±0.4sys)×10-3 events keVee-1kg-1day-1 in a 118 kg fiducial volume. The observed background rate is (3.6±0.4stat)×10-3 events keVee-1kg-1day-1 , consistent with model projections. The expectation for the radiogenic background in a subsequent one-year run is presented

Results on the Spin-Dependent Scattering of Weakly Interacting Massive Particles on Nucleons from the Run 3 Data of the LUX Experiment

We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×104 kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σn=9.4×10-41 cm2 (σp=2.9×10-39 cm2) at 33 GeV/c2. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date

Chromatographic separation of radioactive noble gases from xenon

The Large Underground Xenon (LUX) experiment operates at the Sanford Underground Research Facility to detect nuclear recoils from the hypothetical Weakly Interacting Massive Particles (WIMPs) on a liquid xenon target. Liquid xenon typically contains trace amounts of the noble radioactive isotopes 85 Kr and 39 Ar that are not removed by the in situ gas purification system. The decays of these isotopes at concentrations typical of research-grade xenon would be a dominant background for a WIMP search experiment. To remove these impurities from the liquid xenon, a chromatographic separation system based on adsorption on activated charcoal was built. 400 kg of xenon was processed, reducing the average concentration of krypton from 130 ppb to 3.5 ppt as measured by a cold-trap assisted mass spectroscopy system. A 50 kg batch spiked to 0.001 g/g of krypton was processed twice and reduced to an upper limit of 0.2 ppt

Year in review in Intensive Care Medicine 2009: II. Neurology, cardiovascular, experimental, pharmacology and sedation, communication and teaching

N/

Effective field theory analysis of the first LUX dark matter search

The Large Underground Xenon (LUX) dark matter search was a 250-kg active mass dual-phase time projection chamber that operated by detecting light and ionization signals from particles incident on a xenon target. In December 2015, LUX reported a minimum 90% upper C.L. of 6×10-46 cm2 on the spin-independent WIMP-nucleon elastic scattering cross section based on a 1.4×104 kg·day exposure in its first science run. Tension between experiments and the absence of a definitive positive detection suggest it would be prudent to search for WIMPs outside the standard spin-independent/spin-dependent paradigm. Recent theoretical work has identified a complete basis of 14 independent effective field theory (EFT) operators to describe WIMP-nucleon interactions. In addition to spin-independent and spin-dependent nuclear responses, these operators can produce novel responses such as angular-momentum-dependent and spin-orbit couplings. Here we report on a search for all 14 of these EFT couplings with data from LUX's first science run. Limits are placed on each coupling as a function of WIMP mass

Ultra-Low Energy Calibration of LUX Detector using 127^{127}Xe Electron Capture

We report an absolute calibration of the ionization yields(\textit{Q_y}) and fluctuations for electronic recoil events in liquid xenon at discrete energies between 186 eV and 33.2 keV. The average electric field applied across the liquid xenon target is 180 V/cm. The data are obtained using low energy $^{127}$Xe electron capture decay events from the 95.0-day first run from LUX (WS2013) in search of Weakly Interacting Massive Particles (WIMPs). The sequence of gamma-ray and X-ray cascades associated with $^{127}$I de-excitations produces clearly identified 2-vertex events in the LUX detector. We observe the K- (binding energy, 33.2 keV), L- (5.2 keV), M- (1.1 keV), and N- (186 eV) shell cascade events and verify that the relative ratio of observed events for each shell agrees with calculations. The N-shell cascade analysis includes single extracted electron (SE) events and represents the lowest-energy electronic recoil $\textit{in situ}$ measurements that have been explored in liquid xenon