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Quiescent and senescent cells often arise side by side after stress, yet their molecular relationship remains unclear. Here, the authors combine live-cell imaging and single-cell RNA sequencing to reveal a continuum of cell-cycle withdrawal.

The complement cascade is increasingly recognized in the brain. Here, with MERFISH, the authors showed developmentally regulated brain endogenous expression of complement genes and a potential role of the alternative pathway in brain development.

Mutations of the histone H3K36-specific methyltransferase ASH1L have been linked to several human diseases. Here, the authors report the mechanism by which three C-terminal domains in ASH1L regulate its enzymatic activity and interact with chromatin.

This study links the genomic basis of behavioral variation to specific cell populations in the brain. Here, authors find evidence for involvement of neural stem cells in the evolution and expression of bower-building behavior in cichlid fishes.

Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.

Current intracortical brain-computer interfaces are subject to recording interface instabilities that degrade decoding performance. Here, the authors present a platform for Nonlinear Manifold Alignment with Dynamics (NoMAD), which stabilizes decoding using models of dynamics for at least 3 months.

YEATS domains are histone acylation readers that recognize crotonyllysine and acetyllysine. Here the authors provide structural insights into how YEATS domains recognize acetyllysines and further show that the human AF9 YEATS domain also binds DNA.

Using an autonomous underwater vehicle, this study presents an integrated biogeochemical and multiomic analysis of microbial eukaryotes from the North Atlantic Ocean. The work highlights diverse communities that shift through depth zones, with signatures of nutrient biomarkers changing across a coastal-offshore spatial gradient.

Graft-versus-host disease, a T cell-driven inflammatory condition, is associated with altered microbial bile acid metabolism in both mice and humans and this is linked to outcomes.

It is often assumed that neuronal responses to value are linear, in part because this is important for rational economic decision-making. Here, the authors find, in two male macaques, that value is encoded along a curved manifold in the prefrontal cortex and that this curvature imposes bounds on rational decision-making.

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.

Secondary malignancies and chimeric antigen receptor (CAR)-T-derived malignant T cell transformation have been reported after CAR-T therapy. Here, the authors describe a patient with diffuse large B-cell lymphoma (DLBCL) who developed new lymphadenopathy 2.5 years after CAR-T in the context of COVID-19 infection with histopathologic features consistent with T-cell lymphoma (TCL).

Pyramidal cells are classically thought to comprise the excitatory output of the subiculum. Here, the authors show the existence of “ovoid cells”, excitatory subiculum neurons with specialized gene expression, morphology, projections, and function.

Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.

JADE is a subunit of human acetyltransferase complex HBO1 that is essential in transcriptional regulation. Gaurav et al. characterize the molecular mechanism by which JADE mediates genomic association and enzymatic and pathological activities of the HBO1 complex.

Spatial transcriptomics was combined with single-nucleus RNA sequencing to annotate healthy and fibrotic human livers, improving spatial resolution of hepatocytes and receptor-ligand interactions and identifying cell populations that expand with injury.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Chromosomal translocations involving the AF10 gene, especially with CALM, are associated with aggressive leukemias. Here the authors show that the PZP domain of AF10, a histone reader, is always excluded/impaired in AF10 fusions, whereas incorporation of this domain downregulates Hoxa genes and blocks leukemogenesis.

Oblique line scan microscopy achieves nanoscale spatial and sub-millisecond temporal resolution across a large field of view, enabling improved and robust single-molecule biophysical measurements and single-molecule tracking in both cells and solution.

Using degron approaches, the authors show that cancer cells experiencing prolonged DNA methylation loss—without substantial DNA damage—undergo non-canonical senescence. This has important potential implications for cancer treatment.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

There are stable relationships between diet and microbiome in humans and lab animals. A study on African buffalo finds that diet influences microbiome variation and enterotype formation. Three pathogens may associate with microbiome depending on host diet, suggesting nutrition impacts relationships between gut microbiome and host health.

This study defined spatial gene expression in the human dorsolateral prefrontal cortex. It reveals layer-enriched expression of genes associated with schizophrenia and autism, highlighting the clinical relevance of spatially defined expression.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.

Mosquito salivary glands and malaria parasites exhibit daily rhythms, which impact blood feeding and sporozoite gene expression.

Acetylation of histone H3K23 has emerged as an essential posttranslational modification, yet this epigenetic mark remains poorly understood. Here, the authors identify the native MORF complex as a histone H3K23-specific acetyltransferase and show that interaction of the MORF subunit with acylated H3K14 promotes acetylation of H3K23 by this complex to activate transcription.

Inhibitor of apoptosis BIRC2 mediates cell death and survival. Tencer et al. report the molecular mechanism underlying BIRC2 cellular localization and describe the effect of BIRC2 inhibition on the death of cancer cells and HIV-1-infected T cells.

Human acetyltransferases MOZ and MORF mediate development programs and are dysregulated in diseases. Here the authors identified two winged helix (WH) domains in MORF/MOZ and characterized their DNA binding functions, including targeting of CpG by WH1.

Human Microrchidia 4 (MORC4) ATPase has been implicated in acute and chronic pancreatitis, inflammatory disorders and cancer. Here the authors describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation.

Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.

Bioinformatic and chemoproteomic approaches resulted in the identification of a homolog of human dipeptidyl peptidase 4 in the gut bacterium Bacteroides thetaiotaomicron that regulates envelope integrity and community fitness.

Spatial transcriptomics reveals distinct composition and organization of cells and circuits in the mouse prefrontal cortex (PFC) relative to adjacent cortices, which concur with PFC’s diverse functions, and also help detect neurons involved in chronic pain.

Body size and composition are complex traits that are challenging to characterize due to environmental and genetic influences. Here, Arehart et al. disentangle shared and distinct genetic signals underlying body size and composition.

Population receptive fields (pRFs) in the visual system are key information-processors, but how they develop is unknown. Here, authors use fMRI and pRF modeling in children and adults to show that in the ventral stream only pRFs in face- and word-selective regions continue to develop, mirroring changes in viewing behavior.

Senescence and quiescence are considered different cell states but are hard to distinguish. Here, single-cell imaging followed by immunostaining reveals that the intensities of senescence biomarkers are graded rather than binary, reflecting the duration of cell-cycle withdrawal rather than irreversible cell-cycle arrest.

Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.

Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.

Here, the authors show that deletion of Pglyrp1 promotes antitumor immunity owing to its inhibitory function in CD8⁺ T cells and that targeting it can inhibit development of autoimmune neuroinflammation. These findings indicate that PGLYRP1 might be a target for immunotherapy.

An analysis of the localization and intensity of intracortical microstimulation in three participants with cervical spinal cord injury shows that overlapping projected fields from multiple electrodes produce sensations that are more easily localizable.

DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.

Previous work decoding linguistic meaning from imaging data has generally been limited to a small number of semantic categories. Here, authors show that a decoder trained on neuroimaging data of single concepts sampling the semantic space can robustly decode meanings of semantically diverse new sentences with topics not encountered during training.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Biallelic mutations in the sorbitol dehydrogenase gene SORD are identified as a common cause of hereditary neuropathy. Functional studies suggest that SORD deficiency may be treatable with aldose reductase inhibitors.

Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.

Dendritic cells in individuals with cancer and in mouse tumor models show an increase in triacylglycerides that seems to impair their antigen-processing capability and could thus contribute to tumor immune tolerance. This aberrant lipid load results from tumor-induced elevation of the scavenger receptor Msr1 on dendritic cells, and it can be targeted therapeutically to improve the efficiency of anticancer vaccines.

Yudina et al. present clinical validation guidelines for an integrated RNA and DNA sequencing assay. Applied to over 2000 tumors, the assay enhances precision oncology by capturing complex variants missed by DNA-only testing.

Using genome-wide miRNA mimic and hairpin inhibitor screens, Li et al. identify 31 miRNAs that either inhibit or promote hepatitis C virus (HCV) replication at different steps of the viral life cycle. Furthermore, human liver biopsies show that HCV down-regulates identified miRNAs with antiviral function.

Single nucleus RNA-seq and spatial transcriptomics reveal a detailed picture of the cichlid fish forebrain. Comparisons with atlases in other vertebrates uncover striking transcriptional similarities and lend new insights into forebrain evolution.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.