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Haplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. To date, these assemblies have been best created with complex protocols, such as cultured cells that contain a single-haplotype (haploid) genome, single cells where haplotypes are separated, or co-sequencing of parental genomes in a trio-based approach. These approaches are impractical in most situations. To address this issue, we present FALCON-Phase, a phasing tool that uses ultra-long-range Hi-C chromatin interaction data to extend phase blocks of partially-phased diploid assembles to chromosome or scaffold scale. FALCON-Phase uses the inherent phasing information in Hi-C reads, skipping variant calling, and reduces the computational complexity of phasing. Our method is validated on three benchmark datasets generated as part of the Vertebrate Genomes Project (VGP), including human, cow, and zebra finch, for which high-quality, fully haplotype-resolved assemblies are available using the trio-based approach. FALCON-Phase is accurate without having parental data and performance is better in samples with higher heterozygosity. For cow and zebra finch the accuracy is 97% compared to 80–91% for human. FALCON-Phase is applicable to any draft assembly that contains long primary contigs and phased associate contigs. Methods to produce haplotype-resolved genome assemblies often rely on access to family trios. The authors present FALCON-Phase, a tool that combines ultra-long range Hi-C chromatin interaction data with a long read de novo assembly to extend haplotype phasing to the contig or scaffold level.

The assembly of high-quality genomes from mixed microbial samples is a long-standing challenge in genomics and metagenomics. Here, we describe the application of ProxiMeta, a Hi-C-based metagenomic deconvolution method, to deconvolve a human fecal metagenome. This method uses the intra-cellular proximity signal captured by Hi-C as a direct indicator of which sequences originated in the same cell, enabling culture-free de novo deconvolution of mixed genomes without any reliance on a priori information. We show that ProxiMeta deconvolution provides results of markedly high accuracy and sensitivity, yielding 50 near-complete microbial genomes (many of which are novel) from a single fecal sample, out of 252 total genome clusters. ProxiMeta outperforms traditional contig binning at high-quality genome reconstruction. ProxiMeta shows particularly good performance in constructing high-quality genomes for diverse but poorly-characterized members of the human gut. We further use ProxiMeta to reconstruct genome plasmid content and sharing of plasmids among genomes tasks that traditional binning methods usually fail to accomplish. Our findings suggest that Hi-C-based deconvolution can be useful to a variety of applications in genomics and metagenomics.

Despite considerable social scientific attention to the impacts of the COVID-19 pandemic on urbanized areas, very little research has examined its impact on rural populations. Yet rural communities—which make up tens of millions of people from diverse backgrounds in the United States—are among the nation’s most vulnerable populations and may be less resilient to the effects of such a large-scale exogenous shock. We address this critical knowledge gap with data from a new survey designed to assess the impacts of the pandemic on health-related and economic dimensions of rural well-being in the North American West. Notably, we find that the effects of the COVID-19 pandemic on rural populations have been severe, with significant negative impacts on unemployment, overall life satisfaction, mental health, and economic outlook. Further, we find that these impacts have been generally consistent across age, ethnicity, education, and sex. We discuss how these findings constitute the beginning of a much larger interdisciplinary COVID-19 research effort that integrates rural areas and pushes beyond the predominant focus on cities and nation-states.

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression. The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.

•Dynamic conditional correlations (DCC) method used to investigate dynamic functional connectivity (FC).•Large sample from ABCD Study showed dynamic FC relationships with age, sex assigned at birth, and pubertal development.•Variability of FC within frontolimbic network increased from ages 9 to 14, especially in those assigned female at birth.•Controlling for age, both those assigned female at birth and those with advanced pubertal development showed decreased variability in all networks studied.•Variability of graph theoretical measures show differential patterns to overall FC variability. Understanding the relative influences of age, pubertal development, and sex assigned at birth on brain development is a key priority of developmental neuroscience given the complex interplay of these factors in the onset of psychopathology. Previous research has investigated how these factors relate to static (time-averaged) functional connectivity (FC), but little is known about their relationship with dynamic (time-varying) FC. The present study aimed to investigate the unique and overlapping roles of these factors on dynamic FC in children aged approximately 9 to 14 in the ABCD Study using a sample of 5122 low-motion resting-state scans (from 4136 unique participants). Time-varying correlations in the frontolimbic, default mode, and dorsal and ventral corticostriatal networks, estimated using the Dynamic Conditional Correlations (DCC) method, were used to calculate variability of within- and between-network connectivity and of graph theoretical measures of segregation and integration. We found decreased variability in global efficiency across the age range, and increased variability within the frontolimbic network driven primarily by those assigned female at birth (AFAB). AFAB youth specifically also showed increased variability in several other networks. Controlling for age, both advanced pubertal development and being AFAB were associated with decreased variability in all within- and between-network correlations and increased variability in measures of network segregation. These results potentially suggest advanced brain maturation in AFAB youth, particularly in key networks related to psychopathology, and lay the foundation for future investigations of dynamic FC.

The primary purpose of this study was to report differences in calf intermuscular adipose tissue (IMAT), muscle strength (peak torque), power, and physical function in individuals with obesity, diabetes mellitus (DM), and peripheral neuropathy (PN) compared with those without these impairments. A secondary purpose was to assess the relationship between IMAT and muscle strength, power, and physical function. Six participants with obesity, DM, and PN (2 women, 4 men; mean age=58 years, SD=10; mean body mass index=36.3, SD=5; mean modified Physical Performance Test [PPT] score=22, SD=3) and 6 age- and sex-matched control subjects without these impairments were assessed and compared in muscle strength, muscle power, physical functioning, and muscle and fat volume, including IMAT in the calf muscles. Muscle, adipose tissue, and IMAT volumes of each calf were quantified by noninvasive magnetic resonance imaging. Muscle strength and power of the plantar-flexor and dorsiflexor muscles were quantified using isokinetic dynamometry. The modified PPT was used to assess physical function. Leg muscle and fat volumes were similar between groups, although IMAT volumes were 2.2-fold higher in the subjects with obesity, DM, and PN (X=120 cm(3), SD=47) than in the control subjects (X=54 cm(3), SD=41). Muscle strength, muscle power, ratio of leg muscle power to leg muscle volume, and modified PPT scores were lower in subjects with obesity, DM, and PN compared with the control subjects. The data indicate that excess fat infiltration in leg skeletal muscles is associated with low calf muscle strength, low calf muscle power, and impaired physical function in individuals who are obese with DM and PN.

As shown during the SARS-CoV-2 pandemic, phylogenetic and phylodynamic methods are essential tools to study the spread and evolution of pathogens. One of the central assumptions of these methods is that the shared history of pathogens isolated from different hosts can be described by a branching phylogenetic tree. Recombination breaks this assumption. This makes it problematic to apply phylogenetic methods to study recombining pathogens, including, for example, coronaviruses. Here, we introduce a Markov chain Monte Carlo approach that allows inference of recombination networks from genetic sequence data under a template switching model of recombination. Using this method, we first show that recombination is extremely common in the evolutionary history of SARS-like coronaviruses. We then show how recombination rates across the genome of the human seasonal coronaviruses 229E, OC43 and NL63 vary with rates of adaptation. This suggests that recombination could be beneficial to fitness of human seasonal coronaviruses. Additionally, this work sets the stage for Bayesian phylogenetic tracking of the spread and evolution of SARS-CoV-2 in the future, even as recombinant viruses become prevalent. Genetic recombination can confound standard phylogenetic approaches. Here, the authors present a method to reconstruct virus recombination networks, and show the importance of recombination in shaping the ongoing evolution of SARS-like, MERS and 3 human seasonal coronaviruses.

Non-hematopoietic lymphoid stromal cells (LSC) maintain lymph node architecture and form niches allowing the migration, activation, and survival of immune cells. Depending on their localization in the lymph node, these cells display heterogeneous properties and secrete various factors supporting the different activities of the adaptive immune response. LSCs participate in the transport of antigen from the afferent lymph as well as in its delivery into the T and B cell zones and organize cell migration via niche-specific chemokines. While marginal reticular cells (MRC) are equipped for initial B-cell priming and T zone reticular cells (TRC) provide the matrix for T cell-dendritic cell interactions within the paracortex, germinal centers (GC) only form when both T- and B cells successfully interact at the T-B border and migrate within the B-cell follicle containing the follicular dendritic cell (FDC) network. Unlike most other LSCs, FDCs are capable of presenting antigen via complement receptors to B cells, which then differentiate within this niche and in proximity to T follicular helper (T FH ) cells into memory and plasma cells. LSCs are also implicated in maintenance of peripheral immune tolerance. In mice, TRCs induce the alternative induction of regulatory T cells instead of T FH cells by presenting tissue-restricted self-antigens to naïve CD4 T cells via MHC-II expression. This review explores potential implications of our current knowledge of LSC populations regarding the pathogenesis of humoral immunodeficiency and autoimmunity in patients with autoimmune disorders or common variable immunodeficiency (CVID), the most common form of primary immunodeficiency in humans.

Changes in intronic polyadenylation of the Pdgfra in fibro/adipogenic progenitors lead to increased expression of a shorter variant with a truncated kinase domain, which modulates pro-fibrotic pathways to reduce tissue fibrosis in muscle. Alternative PDGFRα polyadenylation moderates stem cells Muscle-resident fibrotic and adipogenic progenitors are essential to muscle regeneration but can be detrimental to the repair process if over-activated following prolonged exposure to platelet-derived growth factor (PDGF), leading to the formation of fibrotic tissues. Thomas Rando and colleagues found that these progenitors also induce the production of variants of PDGF receptors, one of which can act as a decoy to inhibit PDGF signalling and prevent the formation of fibrotic tissues. Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle 1 , 2 . However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis 3 , 4 . This excessive collagen deposition, which is seen in aged and diseased muscle 5 , 6 , 7 , interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders 8 , 9 . Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated 10 , 11 , 12 , 13 . We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.

In a randomized, double-blind, placebo-controlled phase 3 trial of the ChAdOx1 nCoV-19 vaccine in over 32,000 participants from the United States, Chile, and Peru, the incidence of serious adverse effects was low (including no cases of vaccine-induced immune thrombotic thrombocytopenia) and the vaccine efficacy was 74%. Efficacy was documented in a range of demographic subgroups.