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Cortical neurons comprising an output pathway form a specialized population code that enhances the propagation of information to a downstream target, potentially improving the accuracy of decision-making.

The identification of high-affinity molecular mimicry between the Epstein–Barr virus (EBV) transcription factor EBNA1 and the CNS protein GlialCAM provides a mechanistic link between multiple sclerosis and EBV.

The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.

Trends in global H₂ sources and sinks are analysed from 1990 to 2020, and a comprehensive budget for the decade 2010–2020 is presented.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The replicative helicase CMG is targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP. This study describes how the de-ubiquitylating enzyme USP37 protects genome stability by preventing premature TRAIP-dependent CMG unloading when replication stress impedes timely termination.

Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.

Challenges in mapping modern molecular and anatomical datasets into a common atlas are not fully addressed. Here authors present approaches to aligning multimodal neuroimaging data and quantifying geometric variability. Authors also make sure open-source code, dataset standards, and a web interface are available, enabling large scale integration of datasets essential to modern neuroscience.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Tissue-resident macrophages (TRM) are important mediators of local immunity. Here the authors show that the deficiency or inhibition of a kinase, WNK1, unlinks macrophage colony-stimulating factor signaling and resulted macropinocytosis with the downstream, potentially IRF8-mediated genetic program to bias progenitor differentiation to neutrophil instead of TRM.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

A set of neurons in the peri-locus coeruleus region controls arousal and avoidance states, providing an understanding of the neurobiological basis of arousal and exploratory behaviours.

Glioblastoma (GBM) is an aggressive tumor characterized by an immunosuppressive microenvironment. Here, the authors present a therapeutic approach based on the implantation of a biodegradable scaffold for the sustained, local release of a TLR7/8 agonist at the time of tumor resection, to achieve anti-tumor immunity and protection from future tumor challenge.

Activity-dependent oligodendroglial plasticity contributes to neuronal functions. Here the authors show that adaptive oligodendrocyte progenitor cell responses are disrupted in neurofibromatosis 1, impairing oligodendroglial dynamics and resulting in motor learning deficits in Nf1-deficient and Nf1-mutant mice.

PD-L2 can bind the immune checkpoint PD-1. However, its potential as a therapeutic target for immune checkpoint blockade in cancer has not been extensively explored. Here, the authors demonstrate that αPD-L2 is effective in aged, but not young, melanoma murine models.

The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled in the faeces.

Most studies of autism spectrum disorder (ASD) have focused on neuronal mechanisms. Here, the authors describe vascular impairments in a mouse model of 16p11.2 deletion syndrome using physiological and genetic approaches to examine endothelial-dependent phenotypes.

Artis and colleagues show that enteric neurons produce CGRP-related ADM2 to promote intestinal tissue-protective functions in ILC2s.

This protocol outlines an extracellular vesicle detection approach in which reagent-loaded liposomes fuse with extracellular vesicles directly in patient blood to sensitively detect RNA within the extracellular vesicles.

Sajti and colleagues identify TREM2 as a critical factor in myeloid cells in response to hyperoxia-induced lung injury in neonates, finding that TREM2 deficiency protects mice from bronchopulmonary dysplasia.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

Exposure of mice to high fructose during gestation or early postnatal life causes decreased microglial phagocytosis during brain development and leads to anxiety-like behaviour in adolescence.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Dopamine regulates multiple brain functions through coexisting tonic and phasic release modalities. Here, the authors describe an approach for monitoring tonic and phasic dopamine release simultaneously via on-demand chemogenetic tuning of a dopamine sensor.

Coufal and colleagues generated microglia from human iPS cells to examine mechanistic roles of the transcription factor MEF2C and how these roles might relate to the autism phenotype seen following the loss of MEF2C in human microglia.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The response to respiratory virus exposure can currently not be predicted by pre- or early post-exposure molecular signatures. Here, the authors conduct a community-based analysis of blood gene expression from healthy individuals exposed to respiratory viruses and provide predictive models and biological insight into the physiological response.

RUVBL1 and RUVBL2 are AAA+ ATPases that are involved in transcriptional regulation. Here, the authors discover that RUVBL1/2 regulation of KLF5 modulates both classical and basal-like transcriptional lineage programs in pancreatic cancer.

Promising clinical activity of Claudin (CLDN) 18.2-directed CAR-T cell therapy in patients with gastric cancer has been recently reported, however gastrointestinal toxicities have also been described. Here the authors recapitulate the on-target off-tumor toxicity of CLDN18.2-directed CAR-T cells due to gastric mucosa damage in preclinical models, suggesting an AND-gate strategy targeting CLDN18.2 and mesothelin to overcome CAR-T cell toxicity

Single-cell transcriptomic analysis of mouse hypothalamus and behavioural experiments show that specific hypothalamic networks regulate conflicting feeding versus parenting behaviours of female mice.

Oxide heterostructures are attractive for their tuneable properties such as magnetism. Here, the authors find that SrTiO₃/SmTiO₃heterostructures with very high sheet carrier densities show quantum critical behaviour, sensitive also to variations in layer thickness.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.

Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating widely in birds and have recently caused large outbreaks in mammals. Here, Furey et al. develop a clade 2.3.4.4b HA-expressing mRNA-LNP vaccine and show that it elicits strong protective immune responses in mice and ferrets.

Early drivers of T2D include ectopic fat accumulation that impairs insulin sensitivity. Here, the authors show that GLP1/GCGR dual agonism provides multimodal benefits in obese male mice by reducing liver fat and improving insulin sensitivity resulting in endogenous β-cell recovery.

Self-assembled multidomain supramolecular peptide hydrogels that engage in dynamic covalent bonding with small-molecule drugs and biologics are shown to offer sustained release, extend the activity, and maintain safe and potent drug levels in vivo.

Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.

A population of tumour-specific PD1⁺TCF1⁺ CD4 T cells in tumour-draining lymph nodes is capable of self-renewal and differentiation into CD4 effector cells, thereby controlling CD8 T cell activity.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

PD-1 is a critical modulator of CD8⁺ T cell activation and exhaustion. Sen and colleagues show that a cell-state-specific enhancer tunes PD-1 expression exclusively in exhaustion and that deletion of this enhancer improves CD8⁺ T cell function.

A pan-betacoronavirus vaccine will likely require the elicitation of antibodies against spike regions conserved across diverse coronaviruses. Here, authors computationally engineer and experimentally validate immunogens to elicit antibodies against two such spike regions.

The development of a new genetic tool to selectively deplete or modify group 2 innate lymphoid cells (ILC2s) addresses the debate regarding the non-redundant functions of this immune cell type.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.