Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017

Content and performance of the MiniMUGA genotyping array: A new tool to improve rigor and reproducibility in mouse research

The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC, and an important new tool to increase the rigor and reproducibility of mouse research

Measurement of the νe and total 8B solar neutrino fluxes with the Sudbury Neutrino Observatory phase-III data set

This paper details the solar neutrino analysis of the 385.17-day phase-III data set acquired by the Sudbury Neutrino Observatory (SNO). An array of 3He proportional counters was installed in the heavy-water target to measure precisely the rate of neutrino-deuteron neutral-current interactions. This technique to determine the total active 8B solar neutrino flux was largely independent of the methods employed in previous phases. The total flux of active neutrinos was measured to be 5.54-0.31+0.33(stat.)-0.34+0.36(syst.)×106 cm-2 s-1, consistent with previous measurements and standard solar models. A global analysis of solar and reactor neutrino mixing parameters yielded the best-fit values of Δm2=7.59-0.21+0.19×10 -5eV2 and θ=34.4-1.2+1.3degrees

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Supplementary Material for: FABP1 and FABP3 Have High Predictive Values for Renal Replacement Therapy in Patients with Acute Kidney Injury

<b><i>Background/Aims:</i></b> Early initiation of renal replacement therapy (RRT) is recommended in order to improve the clinical outcome of patients who develop an acute kidney injury (AKI). However, markers that guide an early RRT initiation do not really exist currently. <b><i>Methods:</i></b> Urine and serum samples were prospectively collected from 120 AKI patients. Depending on the necessity of initiating RRT, patients were divided into 2 different groups: dialysis (n = 52) and non-dialysis (n = 68). <b><i>Results:</i></b> Comparative urinary proteomic analyses identified 4 different proteins (fatty acid binding proteins 1 and 3 (FABP1 and FABP3), β-2-microglobulin (B2M), cystatin-M (CST6)) that discriminate AKI patients with high risk for RRT. Western blot analysis confirmed the proteomics data for FABP1 and FABP3 but not for B2M and CST6. Validation analysis confirmed that the FABP1 and FABP3 fulfilled the requirement of functioning as markers for AKI patients with risk to dialysis (p < 0.001). <b><i>Conclusion:</i></b> The release of high amounts of FABP1 and FABP3 in urine of AKI patients could serve as a diagnostic/prognosis marker for RRT initiation in these patients