Severinsenhudson5064

screening tool among patients referred for CCTA.

Simultaneous recordings of gene network dynamics across large populations have revealed that cell characteristics vary considerably even in clonal lines. Inferring the variability of parameters that determine gene dynamics is key to understanding cellular behavior. However, this is complicated by the fact that the outcomes and effects of many reactions are not observable directly. Unobserved reactions can be replaced with time delays to reduce model dimensionality and simplify inference. However, the resulting models are non-Markovian, and require the development of new inference techniques.

We propose a non-Markovian, hierarchical Bayesian inference framework for quantifying the variability of cellular processes within and across cells in a population. We illustrate our approach using a delayed birth-death process. In general, a distributed delay model, rather than a popular fixed delay model, is needed for inference, even if only mean reaction delays are of interest. Using in silico and experimental data we show that the proposed hierarchical framework is robust and leads to improved estimates compared to its non-hierarchical counterpart. We apply our method to data obtained using time-lapse microscopy and infer the parameters that describe the dynamics of protein production at the single cell and population level. The mean delays in protein production are larger than previously reported, have a coefficient of variation of around 0.2 across the population, and are not strongly correlated with protein production or growth rates.

Accompanying code in Python is available at https//github.com/mvcortez/Bayesian-Inference.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.Lysozyme enzymes provide classic examples of molecular adaptation and parallel evolution, however, nearly all insights to date come from chicken-type (c-type) lysozymes. Goose-type (g-type) lysozymes occur in diverse vertebrates, with multiple independent duplications reported. Most mammals possess two g-type lysozyme genes (Lyg1 and Lyg2), the result of an early duplication, although some lineages are known to have subsequently lost one copy. Here we examine g-type lysozyme evolution across >250 mammals and reveal widespread losses of either Lyg1 or Lyg2 in several divergent taxa across the mammal tree of life. At the same time, we report strong evidence of extensive losses of both gene copies in cetaceans and sirenians, with an additional putative case of parallel loss in the tarsier. To validate these findings, we inspected published short-read data and confirmed the presence of loss of function mutations. Despite these losses, comparisons of selection pressures between intact g- and c-type lysozyme genes showed stronger purifying selection in the former, indicative of conserved function. Although the reasons for the evolutionary loss of g-type lysozymes in fully aquatic mammals are not known, we suggest that this is likely to at least partially relate to their hairlessness. Indeed, although Lyg1 does not show tissue-specific expression, recent studies have linked Lyg2 expression to anagen hair follicle development and hair loss. Such a role for g-type lysozyme would explain why the Lyg2 gene became obsolete when these taxa lost their body hair.

The evolutionary processes of mutation and recombination, upon which selection operates, are fundamental to understand the observed molecular diversity. Unlike nucleotide sequences, the estimation of the recombination rate in protein sequences has been little explored, neither implemented in evolutionary frameworks, despite protein sequencing methods are largely used.

In order to accommodate this need, here I present a computational framework, called ProteinEvolverABC, to jointly estimate recombination and substitution rates from alignments of protein sequences. The framework implements the approximate Bayesian computation approach, with and without regression adjustments, and includes a variety of substitution models of protein evolution, demographics and longitudinal sampling. It also implements several nuisance parameters such as heterogeneous amino acid frequencies and rate of change among sites and, proportion of invariable sites. The framework produces accurate coestimation of recombination and substitution rates under diverse evolutionary scenarios. As illustrative examples of usage, I applied it to several viral protein families, including coronaviruses, showing heterogeneous substitution and recombination rates.

ProteinEvolverABC is freely available from https//github.com/miguelarenas/proteinevolverabc, includes a graphical user interface for helping the specification of the input settings, extensive documentation and ready-to-use examples. Conveniently, the simulations can run in parallel on multicore machines.

Supplementary information is available at Bioinformatics online.

Supplementary information is available at Bioinformatics online.Immune mechanisms are critically involved in the pathogenesis of atherosclerosis and its clinical manifestations. Associations of specific antibody levels and defined B cell subsets with cardiovascular disease activity in humans as well as mounting evidence from preclinical models demonstrate a role of B cells and humoral immunity in atherosclerotic cardiovascular disease. These include all aspects of B cell immunity, the generation of antigen-specific antibodies, antigen presentation and co-stimulation of T cells, as well as production of cytokines. Through their impact on adaptive and innate immune responses and the regulation of many other immune cells, B cells mediate both protective and detrimental effects in cardiovascular disease. Several antigens derived from (oxidised) lipoproteins, the vascular wall and classical autoantigens have been identified. The unique antibody responses they trigger and their relationship with atherosclerotic cardiovascular disease are reviewed. In particular, we focus on the different effector functions of specific IgM, IgG, and IgE antibodies and the cellular responses they trigger and highlight potential strategies to target B cell functions for therapy.

AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.

We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 21 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. 7,12-Dimethylbenz[aanthracene] Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses.

Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%.

Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

The NCI Transcriptional Pharmacodynamics Workbench (Monks 2018) is an extensive compilation of directly measured transcriptional responses to anti-cancer agents across the well-characterized NCI-60 cancer cell lines. The NCI TPW data are publicly available through a web interface that allows limited user interaction with the data. We developed "TPWshiny" as a standalone, easy to install, R application to facilitate more interactive data exploration.With no programming skills required, TPWshiny provides an intuitive and comprehensive graphical interface to help researchers understand the response of tumor cell lines to 15 therapeutic agents. The data are presented in interactive scatter plots, heatmaps, time series and Venn diagrams. Data can be queried by drug concentration, time point, gene and tissue type. Researchers can download the data for further analysis.

Users can download the ready-to-use, self-extracting package for Windows or macOS, and R source code from the project website (https//brb.nci.nih.gov/TPWshiny/). TPWshiny documentation and additional information can be found on the project website.

Users can download the ready-to-use, self-extracting package for Windows or macOS, and R source code from the project website (https//brb.nci.nih.gov/TPWshiny/). TPWshiny documentation and additional information can be found on the project website.A test-negative case-control study was conducted to assess inactivated influenza vaccine effectiveness (VE) in children aged 6 months-17 years. The database was developed from the US Department of Defense Global Respiratory Pathogen Surveillance Program over four consecutive influenza seasons from 2016 to 2020. A total of 9,385 children including 4,063 medically attended, laboratory-confirmed influenza-positive cases were identified for VE analysis. A generalized linear mixed model with logit link and binomial distribution was used to estimate the VE. The adjusted VE for children was 42% [95% confidence interval (CI) 37-47%] overall, including 55% (95% CI 47-61%) for influenza A(H1N1)pdm09, 37% (95% CI 28-45%) for influenza A(H3N2), and 49% (95% CI 41-55%) for influenza B. The analysis by age groups indicated that the adjusted VE in children aged 6 months-4 years was higher against influenza A(H1N1)pdm09 and influenza B, and comparable against influenza A(H3N2), compared to those in children aged 5-17 years. Further age-stratified analysis showed that the VE against any types of influenza was low and non-significant for children aged 6-11 months (33%; 95% CI-2-56%), but it was high (54%; 95% CI 34-67%) in children aged 12-23 months, and then declined linearly with increasing age. In conclusion, the inactivated influenza vaccination was moderately effective against influenza infection, based on the analysis from a large number of children aged 6 months-17 years over multiple influenza seasons.In order to adapt to the quick and large amount of necessity in data flow for 5G cloud generation, it is necessary to develop a technology of warm storage device in market which takes a great balance between the reading/writing performance and the price per storage capacity. The technologies of warm storage devices are assumed to adopt phase change memory (PCM), resistive random access memory or magnetoresistive random access memory which have the highest possibilities to 5G structures and magnetic properties of Co on non-hydrogenated diamond like carbon (DLC)/Si(100) films and Co/DLC interface are investigated. The self-assembled magnetic heterostructure is firstly reported in hexagonal close packing Co layers perpendicular magnetic anisotropy (PMA) on Co carbide layers (in-plane) during Co deposited on DLC/Si(100). A PMA/in-plane magnetic heterostructure is expected to have the highest switching current to the energy barrier ratio of near 4 in previous report, which has great potential for developing warm memory devices.