Clustering and Alignment of Polymorphic Sequences for HLA-DRB1 Genotyping

Located on Chromosome 6p21, classical human leukocyte antigen genes are highly polymorphic. HLA alleles associate with a variety of phenotypes, such as narcolepsy, autoimmunity, as well as immunologic response to infectious disease. Moreover, high resolution genotyping of these loci is critical to achieving long-term survival of allogeneic transplants. Development of methods to obtain high resolution analysis of HLA genotypes will lead to improved understanding of how select alleles contribute to human health and disease risk. Genomic DNAs were obtained from a cohort of n = 383 subjects recruited as part of an Ulcerative Colitis study and analyzed for HLA-DRB1. HLA genotypes were determined using sequence specific oligonucleotide probes and by next-generation sequencing using the Roche/454 GSFLX instrument. The Clustering and Alignment of Polymorphic Sequences (CAPSeq) software application was developed to analyze next-generation sequencing data. The application generates HLA sequence specific 6-digit genotype information from next-generation sequencing data using MUMmer to align sequences and the R package diffusionMap to classify sequences into their respective allelic groups. The incorporation of Bootstrap Aggregating, Bagging to aid in sorting of sequences into allele classes resulted in improved genotyping accuracy. Using Bagging iterations equal to 60, the genotyping results obtained using CAPSeq when compared with sequence specific oligonucleotide probe characterized 4-digit genotypes exhibited high rates of concordance, matching at 759 out of 766 (99.1%) alleles. © 2013 Ringquist et al

NGDEEP Epoch 1: Spatially Resolved Hα\alpha Observations of Disk and Bulge Growth in Star-Forming Galaxies at z∼z \sim 0.6-2.2 from JWST NIRISS Slitless Spectroscopy

We study the H$\alpha$ equivalent width, EW(H$\alpha$), maps of 19 galaxies at $0.6 < z < 2.2$ in the Hubble Ultra Deep Field (HUDF) derived from NIRISS slitless spectroscopy as part of the Next Generation Deep Extragalactic Exploratory Public (NGDEEP) Survey. Our galaxies mostly lie on the star-formation main sequence with a stellar mass range of $\mathrm{10^9 - 10^{11} M_\odot}$, and are therefore characteristic of "typical" star-forming galaxies at these redshifts. Leveraging deep HST and JWST broad-band images, spanning 0.4-4 $\mu$m, we perform spatially-resolved fitting of the spectral energy distributions (SEDs) for these galaxies and construct specific star formation rate (sSFR) and stellar-mass-weighted age maps. We compare these to the EW(H$\alpha$) maps with a spatial resolution of $\sim$1 kpc. The pixel-to-pixel EW(H$\alpha$) increases with increasing sSFR and with decreasing age, with the average trend slightly different from the relations derived from integrated fluxes of galaxies from the literature. Quantifying the radial profiles of EW(H$\alpha$), sSFR, and age, the majority (84%) of galaxies show positive EW(H$\alpha$) gradients, positive sSFR gradients, and negative age gradients, in line with the the inside-out quenching scenario. A few galaxies (16%) show inverse (and flat) trends possibly due to merging or starbursts. Comparing the distributions of EW(H$\alpha$) and sSFR to the star formation history models as a function of galactocentric radius, the central region of galaxies (e.g., their bulges) have experienced, at least one, rapid star-formation episodes, which leads to the formation of bulge, while their outer regions (e.g., disks) grow in a more steady-state. These results demonstrate the ability to study resolved star formation in distant galaxies with JWST NIRISS.Comment: 22 pages, 11 figure

Induced pseudoscalar coupling of the proton weak interaction

The induced pseudoscalar coupling $g_p$ is the least well known of the weak coupling constants of the proton's charged--current interaction. Its size is dictated by chiral symmetry arguments, and its measurement represents an important test of quantum chromodynamics at low energies. During the past decade a large body of new data relevant to the coupling $g_p$ has been accumulated. This data includes measurements of radiative and non radiative muon capture on targets ranging from hydrogen and few--nucleon systems to complex nuclei. Herein the authors review the theoretical underpinnings of $g_p$, the experimental studies of $g_p$, and the procedures and uncertainties in extracting the coupling from data. Current puzzles are highlighted and future opportunities are discussed.Comment: 58 pages, Latex, Revtex4, prepared for Reviews of Modern Physic

The Potential and Challenges of Nanopore Sequencing

A nanopore-based device provides single-molecule detection and analytical capabilities that are achieved by electrophoretically driving molecules in solution through a nano-scale pore. The nanopore provides a highly confined space within which single nucleic acid polymers can be analyzed at high throughput by one of a variety of means, and the perfect processivity that can be enforced in a narrow pore ensures that the native order of the nucleobases in a polynucleotide is reflected in the sequence of signals that is detected. Kilobase length polymers (single-stranded genomic DNA or RNA) or small molecules (e.g., nucleosides) can be identified and characterized without amplification or labeling, a unique analytical capability that makes inexpensive, rapid DNA sequencing a possibility. Further research and development to overcome current challenges to nanopore identification of each successive nucleotide in a DNA strand offers the prospect of ‘third generation’ instruments that will sequence a diploid mammalian genome for ~$1,000 in ~24 h.Molecular and Cellular BiologyPhysic

Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development

Caveolin regulates endocytosis of the muscle repair protein, dysferlin

Dysferlin and Caveolin-3 are plasma membrane proteins associated wtih muscular dystrophy. Patients with mutations in the CAV3 gene show dysferlin mislocalization in muscle cells

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements