Longitudinal active sampling for respiratory viral infections across age groups.

BACKGROUND: Respiratory viral infections are a major cause of morbidity and mortality worldwide. However, their characterization is incomplete because prevalence estimates are based on syndromic surveillance data. Here, we address this shortcoming through the analysis of infection rates among individuals tested regularly for respiratory viral infections, irrespective of their symptoms. METHODS: We carried out longitudinal sampling and analysis among 214 individuals enrolled at multiple New York City locations from fall 2016 to spring 2018. We combined personal information with weekly nasal swab collection to investigate the prevalence of 18 respiratory viruses among different age groups and to assess risk factors associated with infection susceptibility. RESULTS: 17.5% of samples were positive for respiratory viruses. Some viruses circulated predominantly during winter, whereas others were found year round. Rhinovirus and coronavirus were most frequently detected. Children registered the highest positivity rates, and adults with daily contacts with children experienced significantly more infections than their counterparts without children. CONCLUSION: Respiratory viral infections are widespread among the general population with the majority of individuals presenting multiple infections per year. The observations identify children as the principal source of respiratory infections. These findings motivate further active surveillance and analysis of differences in pathogenicity among respiratory viruses

Active surveillance documents rates of clinical care seeking due to respiratory illness.

BACKGROUND: Respiratory viral infections are a leading cause of disease worldwide. However, the overall community prevalence of infections has not been properly assessed, as standard surveillance is typically acquired passively among individuals seeking clinical care. METHODS: We conducted a prospective cohort study in which participants provided daily diaries and weekly nasopharyngeal specimens that were tested for respiratory viruses. These data were used to analyze healthcare seeking behavior, compared with cross-sectional ED data and NYC surveillance reports, and used to evaluate biases of medically attended ILI as signal for population respiratory disease and infection. RESULTS: The likelihood of seeking medical attention was virus-dependent: higher for influenza and metapneumovirus (19%-20%), lower for coronavirus and RSV (4%), and 71% of individuals with self-reported ILI did not seek care and half of medically attended symptomatic manifestations did not meet the criteria for ILI. Only 5% of cohort respiratory virus infections and 21% of influenza infections were medically attended and classifiable as ILI. We estimated 1 ILI event per person/year but multiple respiratory infections per year. CONCLUSION: Standard, healthcare-based respiratory surveillance has multiple limitations. Specifically, ILI is an incomplete metric for quantifying respiratory disease, viral respiratory infection, and influenza infection. The prevalence of respiratory viruses, as reported by standard, healthcare-based surveillance, is skewed toward viruses producing more severe symptoms. Active, longitudinal studies are a helpful supplement to standard surveillance, can improve understanding of the overall circulation and burden of respiratory viruses, and can aid development of more robust measures for controlling the spread of these pathogens

A mass-dependent density profile for dark matter haloes including the influence of galaxy formation

We introduce a mass-dependent density profile to describe the distribution of dark matter within galaxies, which takes into account the stellar-to-halo mass dependence of the response of dark matter to baryonic processes. The study is based on the analysis of hydrodynamically simulated galaxies from dwarf to Milky Way mass, drawn from the Making Galaxies In a Cosmological Context project, which have been shown to match a wide range of disc scaling relationships. We find that the best-fitting parameters of a generic double power-law density profile vary in a systematic manner that depends on the stellar-to-halo mass ratio of each galaxy. Thus, the quantity M⋆/Mhalo constrains the inner (γ) and outer (β) slopes of dark matter density, and the sharpness of transition between the slopes (α), reducing the number of free parameters of the model to two. Due to the tight relation between stellar mass and halo mass, either of these quantities is sufficient to describe the dark matter halo profile including the effects of baryons. The concentration of the haloes in the hydrodynamical simulations is consistent with N-body expectations up to Milky Way-mass galaxies, at which mass the haloes become twice as concentrated as compared with pure dark matter runs. This mass-dependent density profile can be directly applied to rotation curve data of observed galaxies and to semi-analytic galaxy formation models as a significant improvement over the commonly used NFW profile

The dependence of dark matter profiles on the stellar-to-halo mass ratio: a prediction for cusps versus cores

We use a suite of 31 simulated galaxies drawn from the MaGICC project to investigate the effects of baryonic feedback on the density profiles of dark matter haloes. The sample covers a wide mass range: 9.4×109 <Mhalo/M� <7.8×1011, hosting galaxies with stellarmasses in the range 5.0×105 <M∗/M� < 8.3×1010, i.e. from dwarf to L∗. The galaxies are simulated with blastwave supernova feedback and, for some of them, an additional source of energy from massive stars is included. Within this feedback scheme we vary several parameters, such as the initial mass function, the density threshold for star formation, and energy from supernovae and massive stars. The main result is a clear dependence of the inner slope of the dark matter density profile, α in ρ ∝ rα, on the stellar-to-halo mass ratio, M∗/Mhalo. This relation is independent of the particular choice of parameters within our stellar feedback scheme, allowing a prediction for cusp versus core formation. When M∗/Mhalo is low, �0.01 per cent, energy from stellar feedback is insufficient to significantly alter the inner dark matter density, and the galaxy retains a cuspy profile. At higher stellar-to-halo mass ratios, feedback drives the expansion of the dark matter and generates cored profiles. The flattest profiles form where M∗/Mhalo ∼ 0.5 per cent. Above this ratio, stars formed in the central regions deepen the gravitational potential enough to oppose the supernova-driven expansion process, resulting in cuspier profiles. Combining the dependence of α on M∗/Mhalo with the empirical abundance matching relation between M∗ and Mhalo provides a prediction for how α varies as a function of stellar mass. Further, using the Tully–Fisher relation allows a prediction for the dependence of the dark matter inner slope on the observed rotation velocity of galaxies. The most cored galaxies are expected to have Vrot ∼ 50 km s−1, with α decreasing for more massive disc galaxies: spirals with Vrot ∼ 150 km s−1 have central slopes α ≤−0.8, approaching again the Navarro–Frenk–White profile. This novel prediction for the dependence of α on disc galaxy mass can be tested using observational data sets and can be applied to theoretical modelling of mass profiles and populations of disc galaxies

Importance of a C-Terminal Conserved Region of Chk1 for Checkpoint Function

BACKGROUND: The protein kinase Chk1 is an essential component of the DNA damage checkpoint pathway. Chk1 is phosphorylated and activated in the fission yeast Schizosaccharomyces pombe when cells are exposed to agents that damage DNA. Phosphorylation, kinase activation, and nuclear accumulation are events critical to the ability of Chk1 to induce a transient delay in cell cycle progression. The catalytic domain of Chk1 is well-conserved amongst all species, while there are only a few regions of homology within the C-terminus. A potential pseudosubstrate domain exists in the C-terminus of S. pombe Chk1, raising the possibility that the C-terminus acts to inhibit the catalytic domain through interaction of this domain with the substrate binding site. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate this hypothesis, we characterized mutations in the pseudosubstrate region. Mutation of a conserved aspartic acid at position 469 to alanine or glycine compromises Chk1 function when the mutants are integrated as single copies, demonstrating that this domain of Chk1 is critical for function. Our data does not support, however, the hypothesis that the domain acts to inhibit Chk1 function as other mutations in the amino acids predicted to comprise the pseudosubstrate do not result in constitutive activation of the protein. When expressed in multi-copy, Chk1D469A remains non-functional. In contrast, multi-copy Chk1D469G confers cell survival and imposes a checkpoint delay in response to some, though not all forms of DNA damage. CONCLUSIONS/SIGNIFICANCE: Thus, we conclude that this C-terminal region of Chk1 is important for checkpoint function and predict that a limiting factor capable of associating with Chk1D469G, but not Chk1D469A, interacts with Chk1 to elicit checkpoint activation in response to a subset of DNA lesions

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Conformational effects of a common codon 751 polymorphism on the C-terminal domain of the xeroderma pigmentosum D protein

<b>Aim:</b> The xeroderma pigmentosum D (XPD) protein is a DNA helicase involved in the repair of DNA damage, including nucleotide excision repair (NER) and transcription-coupled repair (TCR). The C-terminal domain of XPD has been implicated in interactions with other components of the TFIIH complex, and it is also the site of a common genetic polymorphism in XPD at amino acid residue 751 (Lys->Gln). Some evidence suggests that this polymorphism may alter DNA repair capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XPD induced by the polymorphism. <b> Materials and Methods:</b> Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the C-terminal domain of XPD and differences in structure produced by the polymorphic substitution were determined. <b> Results:</b> The results indicate that, although the general configuration of both proteins is similar, the substitution produces a significant conformational change immediately N-terminal to the site of the polymorphism. <b> Conclusion:</b> These results provide support for the hypothesis that this polymorphism in XPD could affect DNA repair capability, and hence cancer risk, by altering the structure of the C-terminal domain