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The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA Rmrp; the DDX5–RORγt complex coordinates transcription of selective T_H17 genes and is required for the pathogenicity of T_H17 cells.

Cellular heterogeneity in cancer is complex and difficult to study. Here, the authors introduce Protein-indexed Assay of Transposase Accessible Chromatin (Pi-ATAC), which combines single cell chromatin and proteomic profiling to provide deep insight into the tumor microenvironment, and reveal the role of hypoxia in shaping the regulome of a subset of breast cancer cells in vivo.

Cheryl Winkler and colleagues use admixture mapping to identify risk variants in MYH9 associated with focal segmental glomerulosclerosis and end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Linda Kao and colleagues.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.

A computational approach to generate reference-free protein families from the sequence space in metagenomes reveals an enormously diverse functional space.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

In April 2021, Eli Lilly voluntarily asked the FDA to revoke the Emergency Use Authorization for the monoclonal antibody bamlanivimab due to reduced susceptibility in vitro to SARS-CoV-2 variants, not for safety. In this work, authors carry out a placebo-controlled phase 2 evaluation of bamlanivimab in non-hospitalized adults with COVID-19, to determine safety and efficacy.

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

The authors measured the variability of neuronal responses across a large number of datasets and cortical areas. They found that variability decreased in response to all stimuli tested, whether the animal was awake, behaving or anesthetized, suggesting that the stabilization of cortex in response to an input is a general cortical property.

The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model

Conventional type 1 dendritic cells perform antigen processing and priming of CD4⁺ and CD8⁺ T cells against tumour antigens, orchestrating their cross-talk to effect anti-tumour immunity.

Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.

Tools for gaining long-term genetic access to mu-opioid receptor (MOR) neural cell types are limited. Here, the authors develop a suite of adeno-associated viral tools allowing selective genetic access to MOR cell types, and showcase their use across species.

A pediatric cancer dependency map generated with genome-scale CRISPR–Cas9 loss-of-function screens in 82 pediatric cancer cell lines highlights genetic dependencies across a range of tumor types.

Analysis of ancient proteins suggests that Early Bronze Age dairying and horse domestication catalysed eastern Yamnaya migrations.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

Savini et al. report that lysosomal lipolysis in peripheral adipose depots produces polyunsaturated fatty acids (PUFAs). PUFAs and the lipid chaperone LBP-3 induce a nuclear hormone receptor, neuropeptide-mediated cascade in neurons to extend lifespan.

Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Here, the authors identify 2 compounds that target the binding of STAT3/5 specifically to the TET1 promoter, inhibiting its expression and AML cell viability.

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

The small molecule Nobiletin enhances circadian rhythms and protects against obesity-associated metabolic dysfunction in mice. Here the authors test its effect on health and lifespan, reporting that circadian enhancement promotes fitness and healthy aging in metabolically challenged mice.

Trajectory-coding neurons in the hippocampus convey important information for performing memory tasks. Here, Kinsky et al. track long-term neural activity in the hippocampus to find that trajectory-coding emerges rapidly and remains stable across long time-scales.

Compound MMV006833 inhibits ring-stage development of Plasmodium falciparum. Here, the authors show that it targets lipid transfer enzyme PfSTART1 and prevents PfSTART1 from expanding the vacuole membrane encasing the parasite after red blood cell invasion, thereby blocking parasite growth.

High-coverage, ultra-long-read nanopore sequencing is used to create a new human genome assembly that improves on the coverage and accuracy of the current reference (GRCh38) and includes the gap-free, telomere-to-telomere sequence of the X chromosome.

The plant growth hormone auxin is involved in hypocotyl elongation in response to shade and high temperatures. The vas3 mutant now shows that local auxin conjugation is as important for controlling hormone homeostasis as biosynthesis and transport.

In geographic atrophy, a type of macular degeneration, retinal pigmented epithelium (RPE) cells die. This paper finds that DICER1, which processes miRNA precursors, is reduced in RPE from individuals with geographic atrophy. Cell death is not due to loss of miRNA processing, however; rather, the absence of DICER1 allows accumulation of pathological Alu repeat sequence RNAs. This work reveals a novel function of Dicer in degrading Alu RNAs.

Computational methods for the de novo design of conformationally restricted peptides produce exceptionally stable short peptides stabilized by backbone cyclization and/or internal disulfide bonds that are promising starting points for a new generation of peptide-based drugs.

LncRNA loci potentially contain multiple modes that can exert function, including DNA regulatory elements. Here, the authors generated genetic models in mice to dissect the role of the syntenically conserved lncRNA Firre in the context of hematopoiesis.

During the initiation of bacterial DNA replication, loader proteins transfer the hexameric helicase ring onto replication origin DNA. Liu et al.report the crystal structure of a 570-kDa prepriming complex and suggest that the release of loader proteins is associated with the transition of the helicase ring to a spiral configuration.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

Analysis of peripheral mycobacteria-reactive CD4⁺ T cell receptor sequences from individuals infected with Mycobacterium tuberculosis shows a high degree of overlap between progressors and controllers, but points to some distinct clonotypes that are enriched in either group.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

Constructing genome graphs directly from genome assemblies overcomes single-reference bias.

A computational approach is used to design modular proteins that bind to synthetic peptides and disordered regions of human proteins with high affinity and specificity.

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Movement of secretory cargoes from the endoplasmic reticulum relies on the COPII protein complex. Here, authors combine gene editing technology with state-of-the-art fluorescence microscopy to define the native dynamics of COPII recruitment at ER subdomains for the first time.

Structural analysis reveals how certain designed peptides adopt unusual spiraling cross-α amyloid-like structures and also rearrange to helical polymers upon mutation of small nonpolar residues that are critical for packing and stabilization.

Immunoglobulin genes are further diversified by the cytidine deaminase AID. Gearhart and colleagues show immunoglobulin genes accumulate AID-dependent uracil residues within the first 24 hours of B cell stimulation.

Koh et al. show that loci active in differentiated effector T cells are poised in early T precursors before the expression of T cell antigen receptors in a manner dependent on the chromatin remodeling complex mammalian SWItch/Sucrose Non-Fermentable and the PU.1–RUNX1 and BCL11B–RUNX1 complexes.

Pubertal timing in mammals depends on the function of GnRH neurons that innervate the median eminence (ME) of the hypothalamus. Here, the authors show that Semaphorin 6A regulates GnRH innervation and puberty onset by tuning vascular permeability at the ME.

Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

During development, groups of cells sometimes have to order themselves relative to a tissue in a coordinated manner, and this is true of ommatidial cells in the eye. Using a genetic and molecular approach, the Nemo kinase is shown to be involved in regulating the rate of ommatidial rotation; the study also links this event to cellular interaction through cadherin, important for coordinating reorientation.

Whereas vertebrate genomes are highly methylated at CpG positions, invertebrate genomes are typically sparsely methylated. Here, the authors report a highly methylated genome in a marine sponge and show striking similarities with vertebrates.