Longitudinal analyses reveal immunological misfiring in severe COVID-19
Nature (2020)Published:
Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1–4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease(我们连续分析了113例中度（非ICU）和重度（ICU）疾病的COVID-19患者的免疫应答). Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in T cell number(先天细胞谱系总体增加，同时T细胞数量减少). We identify an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. Unsupervised clustering analysis identified 4 immune signatures, representing (A) growth factors, (B) type-2/3 cytokines, (C) mixed type-1/2/3 cytokines, and (D) chemokines that correlated with three distinct disease trajectories of patients. The immune profile of patients who recovered with moderate disease was enriched in tissue reparative growth factor signature (A), while the profile for those with worsened disease trajectory had elevated levels of all four signatures患有中度疾病的患者的免疫特征富含组织修复性生长因子标记（A），而疾病轨迹恶化的患者的所有四个标记水平均升高。. Thus, we identified development of a maladapted immune response profile associated with severe COVID-19 outcome and early immune signatures that correlate with divergent disease trajectories.
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing
Nature: Published: 24 July 2020
The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships我们报告鉴定了抑制病毒复制的100个分子，其中包括21种表现出剂量反应关系的已知药物。. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
Why COVID-19 made weather forecasts less reliable
The pandemic grounded many commercial flights, starving forecast models of valuable data acquired at high altitudes. 大流行使许多商业航班停飞，使在高海拔获得的宝贵数据的预测模型匮乏。
Smallpox and other viruses plagued humans much earlier than suspected
天花和其他病毒困扰人类的时间比怀疑的要早得多
European maize genomes highlight intraspecies variation in repeat and gene content
The diversity of maize (Zea mays) is the backbone of modern heterotic patterns and hybrid breeding. Historically, US farmers exploited this variability to establish today’s highly productive Corn Belt inbred lines from blends of dent and flint germplasm pools. Here, we report de novo genome sequences of four European flint lines assembled to pseudomolecules with scaffold N50 ranging from 6.1 to 10.4 Mb. Comparative analyses with two US Corn Belt lines explains the pronounced differences between both germplasms. While overall syntenic order and consolidated gene annotations reveal only moderate pangenomic differences, whole-genome alignments delineating the core and dispensable genome, and the analysis of heterochromatic knobs and orthologous long terminal repeat retrotransposons unveil the dynamics of the maize genome. The high-quality genome sequences of the flint pool complement the maize pangenome and provide an important tool to study maize improvement at a genome scale and to enhance modern hybrid breeding.
Genome-wide detection of tandem DNA repeats that are expanded in autism全基因组检测自闭症中扩增的串联DNA重复序列
Nature: Published:
Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with more than 40 monogenic disorders1. Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2–20-bp motifs in 17,231 genomes of families with autism2,3 and population controls4. We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.