Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
ARTICLES Genome sequencing and analysis of the model grass Brachypodium distachyonThe International Brachypodium Initiative* Three subfamilies of grasses, the Ehrhartoideae, Panicoideae and Pooideae, provide the bulk of human nutrition and are poised to become major sources of renewable energy. Here we describe the genome sequence of the wild grass Brachypodium distachyon (Brachypodium), which is, to our knowledge, the first member of the Pooideae subfamily to be sequenced. Comparison of the Brachypodium, rice and sorghum genomes shows a precise history of genome evolution across a broad diversity of the grasses, and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat. The high-quality genome sequence, coupled with ease of cultivation and transformation, small size and rapid life cycle, will help Brachypodium reach its potential as an important model system for developing new energy and food crops.Grasses provide the bulk of human nutrition, and highly productive grasses are promising sources of sustainable energy 1 . The grass family (Poaceae) comprises over 600 genera and more than 10,000 species that dominate many ecological and agricultural systems 2,3 . So far, genomic efforts have largely focused on two economically important grass subfamilies, the Ehrhartoideae (rice) and the Panicoideae (maize, sorghum, sugarcane and millets). The rice 4 and sorghum 5 genome sequences and a detailed physical map of maize 6 showed extensive conservation of gene order 5,7 and both ancient and relatively recent polyploidization.Most cool season cereal, forage and turf grasses belong to the Pooideae subfamily, which is also the largest grass subfamily. The genomes of many pooids are characterized by daunting size and complexity. For example, the bread wheat genome is approximately 17,000 megabases (Mb) and contains three independent genomes 8 . This has prohibited genome-scale comparisons spanning the three most economically important grass subfamilies.Brachypodium, a member of the Pooideae subfamily, is a wild annual grass endemic to the Mediterranean and Middle East 9 that has promise as a model system. This has led to the development of highly efficient transformation 10,11 , germplasm collections  , genetic markers 14 , a genetic linkage map 15 , bacterial artificial chromosome (BAC) libraries 16,17 , physical maps 18 (M.F., unpublished observations), mutant collections (http://brachypodium.pw.usda.gov, http://www. brachytag.org), microarrays and databases (http://www.brachybase. org, http://www.phytozome.net, http://www.modelcrop.org, http:// mips.helmholtz-muenchen.de/plant/index.jsp) that are facilitating the use of Brachypodium by the research community. The genome sequence described here will allow Brachypodium to act as a powerful functional genomics resource for the grasses. It is also an important advance in grass structural genomics, permitting, for the first time, whole-genome comparisons between members of the three most economically import...
Aegilops tauschii is the diploid progenitor of the D genome of hexaploid wheat 1 (Triticum aestivum, genomes AABBDD) and an important genetic resource for wheat  . The large size and highly repetitive nature of the Ae. tauschii genome has until now precluded the development of a reference-quality genome sequence 5 .Here we use an array of advanced technologies, including orderedclone genome sequencing, whole-genome shotgun sequencing, and BioNano optical genome mapping, to generate a referencequality genome sequence for Ae. tauschii ssp. strangulata accession AL8/78, which is closely related to the wheat D genome. We show that compared to other sequenced plant genomes, including a much larger conifer genome, the Ae. tauschii genome contains unprecedented amounts of very similar repeated sequences. Our genome comparisons reveal that the Ae. tauschii genome has a greater number of dispersed duplicated genes than other sequenced genomes and its chromosomes have been structurally evolving an order of magnitude faster than those of other grass genomes.
Searching for new chemically durable and radiation-resistant absorbent materials for actinides and their fission products generated in the nuclear fuel cycle remain highly desirable, for both waste management and contamination remediation. Here we present a rare case of 3D uranyl organic framework material built through polycatenating of three sets of graphene-like layers, which exhibits significant umbellate distortions in the uranyl equatorial planes studied thoroughly by linear transit calculations. This unique structural arrangement leads to high β and γ radiation-resistance and chemical stability in aqueous solutions within a wide pH range from 3 to 12. Being equipped with the highest surface area among all actinide compounds known to date and completely exchangeable [(CH3)2NH2](+) cations in the structure, this material is able to selectively remove cesium from aqueous solutions while retaining the polycatenated framework structure.
Unlike non-mammalian vertebrates, mammals cannot convert inner ear cochlear supporting cells (SCs) into sensory hair cells (HCs) after damage, thus causing permanent deafness. Here, we achieved in vivo conversion of two SC subtypes, pillar cells (PCs) and Deiters’ cells (DCs), into HCs by inducing targeted expression of Atoh1 at neonatal and juvenile ages using novel mouse models. The conversion only occurred in ~10% of PCs and DCs with ectopic Atoh1 expression and started with reactivation of endogenous Atoh1, followed by expression of 11 HC and synaptic markers; a process that took at least 3 weeks in vivo. These new HCs resided in the outer HC region, formed stereocilia, contained mechanoelectrical transduction channels, and survived for more than 2 months in vivo; however, they surprisingly lacked prestin and oncomodulin expression and mature HC morphology. In contrast, adult PCs and DCs no longer responded to ectopic Atoh1 expression, even after outer HC damage. Finally, permanent Atoh1 expression in endogenous HCs did not affect prestin expression, but caused cell loss of mature HCs. Together our results demonstrate that in vivo conversion of PCs and DCs into immature HCs by Atoh1 is age-dependent, and resembles normal HC development. Therefore combined expression of Atoh1 with additional factors holds therapeutic promise to convert PCs and DCs into functional HCs in vivo for regenerative purposes.
Human genetic studies implicate LRRK2 and RAB7L1 in susceptibility to Parkinson disease (PD). These two genes function in the same pathway, as knockout of Rab7L1 results in phenotypes similar to LRRK2 knockout, and studies in cells and model organisms demonstrate LRRK2 and Rab7L1 interact in the endolysosomal system. Recently, a subset of Rab proteins have been identified as LRRK2 kinase substrates. Herein, we find that Rab8, Rab10, and Rab7L1 must be membrane and GTP-bound for LRRK2 phosphorylation. LRRK2 mutations that cause PD including R1441C, Y1699C, and G2019S all increase LRRK2 phosphorylation of Rab7L1 four-fold over wild-type LRRK2 in cells, resulting in the phosphorylation of nearly one-third the available Rab7L1 protein in cells. In contrast, the most common pathogenic LRRK2 mutation, G2019S, does not upregulate LRRK2-mediated phosphorylation of Rab8 or Rab10. LRRK2 interaction with membrane and GTP-bound Rab7L1, but not Rab8 or Rab10, results in the activation of LRRK2 autophosphorylation at the serine 1292 position, required for LRRK2 toxicity. Further, Rab7L1 controls the proportion of LRRK2 that is membrane-associated, and LRRK2 mutations enhance Rab7L1-mediated recruitment of LRRK2 to the trans-Golgi network. Interaction studies with the Rab8 and Rab10 GTPase-activating protein TBC1D4/AS160 demonstrate that LRRK2 phosphorylation may block membrane and GTP-bound Rab protein interaction with effectors. These results suggest reciprocal regulation between LRRK2 and Rab protein substrates, where Rab7L1-mediated upregulation of LRRK2 kinase activity results in the stabilization of membrane and GTP-bound Rab proteins that may be unable to interact with Rab effector proteins.
Facilitated by the rapid progress of high-throughput sequencing technology, a large number of long noncoding RNAs (lncRNAs) have been identified in mammalian transcriptomes over the past few years. LncRNAs have been shown to play key roles in various biological processes such as imprinting control, circuitry controlling pluripotency and differentiation, immune responses and chromosome dynamics. Notably, a growing number of lncRNAs have been implicated in disease etiology. With the increasing number of published lncRNA studies, the experimental data on lncRNAs (e.g. expression profiles, molecular features and biological functions) have accumulated rapidly. In order to enable a systematic compilation and integration of this information, we have updated the NONCODE database (http://www.noncode.org) to version 3.0 to include the first integrated collection of expression and functional lncRNA data obtained from re-annotated microarray studies in a single database. NONCODE has a user-friendly interface with a variety of search or browse options, a local Genome Browser for visualization and a BLAST server for sequence-alignment search. In addition, NONCODE provides a platform for the ongoing collation of ncRNAs reported in the literature. All data in NONCODE are open to users, and can be downloaded through the website or obtained through the SOAP API and DAS services.
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