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How mammalian genomes are packaged and the heritability of structural variations in genome folding is incomplete. Here, the authors investigate the impact of chromosomal fusions on three-dimensional genome topology and meiotic recombination, highlighting the implications of large-scale genome reorganizations on genome function, evolution, and fertility.

In a multicenter research program coordinated by the International Mouse Phenotyping Consortium, Spielmann et al. analyze the cardiac function and structure in ~4,000 monogenic mutant mice and identify 705 mouse genes involved in cardiac function, 75% of which have not been previously linked to cardiac heritable disease in humans. Using the UK Biobank human data, the authors validate the link between cardiovascular disease and some of the newly identified genes to illustrate the resource value and potential of their mutant mouse collection.

Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.

Existing methods for tissue dissociation are inefficient and lead to variable outcomes and biases. Here, the authors present a microfluidic platform that combines digestion, disaggregation and filtration of tissue to allow single cell analysis and RNA sequencing.

Peptides that disrupt Ca²⁺-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.

Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry. Here, Kandeil et al. show that the Western movement of this clade was followed by reassortment with viruses circulating in wild birds in North America which resulted in different genotypes exhibiting a wide range of disease severity in mammal models (mice, ferrets, chicken) ranging from asymptomatic disease to severe neurological pathology.

The identification of patient-specific disease mechanisms and druggable targets is crucial for precision medicine in glioblastoma. Here, the authors show that comparing patients-matched glioma-initiating cells with neural stem cells enables the discovery of patient-specific mechanisms of disease and the identification of effective drugs

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

This study presents gene expression responses of cultured brain cells to hundreds of chemicals found in the environment and in food. The authors identified chemicals that induce transcriptomic profiles that overlap those seen in human brains affected with autism, aging, and neurodegeneration.

The autonomic nervous systems densely innervate the pancreas, but its contribution to pancreatic ductal adenocarcinoma (PDAC) progression is not fully understood. Here, the authors characterize the pattern of sympathetic innervation by 3D imaging in a murine model of PDAC and show that sympathectomy aggravates cancer progression.

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.

Measures of biodiversity and ecosystem functioning show variable responses to perturbations, complicating the prediction of responses to global change. This study shows that the variability of community-level responses itself is predictable and can be used to study species’ responses to perturbations and contributions to functions.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

A distinct cell cycle redeploys many canonical cell cycle regulators to control the differentiation of multiciliated cells, with the transcription factor E2F7 playing a pivotal part in this modified cell cycle.

Antigen-activated B cells are short lived in the absence of a second signal provided by CD4⁺ T cells or cytokines. Zikherman and colleagues report that the NR4A family of nuclear receptors (NUR77 and NOR-1) are responsible for enforcing this ‘tolerance’ to self-antigen (signal 1 only) and explain, in part, why B cells are dependent upon a second signal.

An organoid-based screening platform maps the genetic interactions underlying intestinal development and regeneration, showing that retinoic acid metabolism maintains the balance between regeneration and homeostasis, and that an antagonist of the retinoid X receptor promotes regeneration in vivo.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

In mice that have undergone Pavlovian reward conditioning, dopaminergic neurons regulate conditioned movements in a temporally restricted manner, consistent with a primary contribution to associative learning rather than online movement generation.

The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.

Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

Integration of single-cell RNA sequencing with genome-wide association data implicates specific brain cell types in schizophrenia. Gene sets previously associated with schizophrenia implicate the same cell types, which include pyramidal cells and medium spiny neurons.

Astroviruses are the leading cause of pediatric diarrhea, but which cells are the main targets in the gut remains unclear. Here, using an in vivo model of murine astrovirus, the authors show that the virus infects goblet cells and that this alters mucus production and increases mucus-associated bacterial communities in the gut.

The hydroxylase EgIN2 contributes to triple negative breast cancers. Here, using an enzyme-substrate trapping strategy, the authors identify ASDL as a bona fide substrate of EgIN2 promoting aggressive properties of TNBC via the activation of cMYC signaling.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

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.

AgRP neurons in the hypothalamus elicit feeding behavior. Here the authors show that interfering with AgRP neuron function, either by selective knockout of Sirt1 or by early postnatal ablation, leads to increased exploratory behavior and enhanced response to cocaine, which is associated with increased forebrain dopamine levels.

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.

Methylation of CHMP2B regulates abscission timing by modulating ESCRT-III dynamics during cytokinesis. This methylation also plays a role in HIV-1 budding, highlighting the broader significance of ESCRT-III methylation.

One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.

In Drosophila embryos, Piwi-interacting RNAs (piRNAs) loaded into the PIWI protein Aubergine target and destabilize maternal mRNAs. Here, the authors provide evidence that piRNAs and Aubergine cooperate with the Wispy poly(A) polymerase to stabilize these mRNAs in the germ plasm.

Zihni et al. discover a role for Cdc42–MRCK signalling in establishing contractility at the apical pole, which in turn controls epithelial polarity in mammalian cells and Drosophila photoreceptors.

Influenza viruses carry their own RNAdependent RNA-polymerase that is highly conserved and a promising anti-viral target. Combining functional and structural data, Keown et al. characterise the inhibitory effect of nanobodies on 1918 pandemic H1N1 influenza strain polymerase complex and identify sensitive sites interfering with polymerase activity in vitro.

Subsets of ILC3s upregulate the immunoregulatory checkpoint molecule CTLA-4 after stimulation in a microbiota-dependent manner, and advances to support CTLA-4⁺ ILC3s may represent a treatment opportunity in IL-23-driven chronic inflammation.

ILC3s expressing MHC class II control the fate of inflammatory versus tolerogenic T cells that respond to the microbiota by selecting for antigen-specific RORγt⁺ T_reg cells and against T_H17 cells, establishing intestinal homoeostasis.

Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.

Mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation and displaying chemoattractant receptors and endothelial-cell-binding molecules function as effective vehicles for the delivery of therapeutics to diseased tissue.

TRPV4 dominant mutations cause neuropathy. Here, the authors show that TRPV4 binds and interacts with RhoA, modulating the actin cytoskeleton. Neuropathy-causing mutations of TRPV4 disrupt this complex, leading to RhoA activation and impairment of neurite extension in cultured cells and flies.

Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells.

A rare sub-population of people living with HIV-1 experience long-lasting viral remission after interrupting antiretroviral therapy and are considered post-treatment controllers. Here the authors characterise the humoral immune response to HIV-1 in a cohort of post-treatment controllers.

David Jackson and colleagues identify FEA3, encoding an LRR-receptor-like protein in maize, which responds to signals from organ primordia to the stem cell niche to regulate stem cell proliferation, a function that is conserved in Arabidopsis. They find that weak alleles of fea3 enhance hybrid maize yield traits.

This study demonstrates the existence of a novel retinal narrow-field amacrine cell subtype that is neither GABAergic nor glycinergic. These cells arise from a late-born glycinergic population and are specified by expression of the transcription factor Neurod6.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Experiments in a mouse model of natural parainfluenza virus transmission show that tissue-resident memory T cells in the respiratory tract have important interferon-γ-dependent roles in protection against and limiting the transmission of viral disease.