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Gain of function mutant CaV1.2 channels drive life-threatening hypoglycemia in the multisystem disorder Timothy syndrome, but the underlying mechanisms are unknown. Here the authors show the mutant channels have adverse effects on counterregulatory hormones and CNS control of glucose homeostasis.

In an integrated analysis of transcriptomic data from the SUBSPACE consortium and public datasets of patients with sepsis, acute respiratory distress syndrome, trauma and burns, dysregulation within four consensus molecular clusters related to myeloid and lymphoid cells is associated with mortality and illness severity.

The authors describe the isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals who received a monovalent H5N1 vaccine 15 years ago. They identify five mAbs that potently neutralized the majority of H5 clades and protected against lethal 2.3.4.4b H5N1 infection in mice.

It is important to know how the recent COVID-19 pandemic shaped the immune memory against the causal SARS-CoV-2 virus. Here authors show that long years following mild disease at primary infection, SARSCoV-2 spike-specific CD4 + T cells with distinct phenotypes and T cell receptor clonotypes, associated with viral suppression persist.

The Taiwan Precision Medicine Initiative recruited and genotyped more than half a million Taiwanese participants, almost all of Han Chinese ancestry, and performed comprehensive genomic analyses and developed polygenic risk score prediction models for numerous health conditions.

Here, the authors report that combining Army Liposome Formulation with QS21 saponin (ALFQ) and Alum to formulate the ΔV1gp120 boost decreases the risk of simian immunodeficiency virus (SIV) mac251 acquisition in female macaques.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

Probing endogenous protein localization and function in vivo remains challenging due to laborious gene targeting and monofunctional alleles. Here, using a toolkit consisting of genetically-encoded epitope probes, their cognate tags, and an array of adapter proteins, the authors describe a methodology that enables visualization and manipulation of endogenous proteins in vertebrate systems.

Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer. Here, the authors develop a NLPHL specific model to identify 34 distinct cell states across 14 cell types that co-occur within 3 lymphocyte predominant ecotypes (LPEs) for 171 cases.

Hypoimmune gene editing in human pluripotent stem cells (hPSCs) provides a promising platform for cellular therapies. Here, the authors report that CRISPR mediated deletion of ICAM-1 in hPSC-derived grafts reduces immune cell adhesion, dampens T cell activation, and protects against immune rejection.

Comparative genomics and high-resolution mass spectrometry reveal the biosynthetic gene clusters, and vast chemical diversity of natural products that they encode, in Photorhabdus and Xenorhabdus, bacteria that interact with hosts as symbionts and entomopathogens.

In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

The pathogenic bacterium Pseudomonas aeruginosa can be found in vacuoles and cytoplasm within infected cells. Here, Schator et al. show that extracellular bacteria use a type-III secretion system to induce Ca²⁺ influx into host cells and promote vacuole escape of intracellular bacteria and in vivo dissemination.

Head motion is an artifact in structural and functional MRI signals, and some traits or groups are more strongly correlated with motion than others. Here the authors describe a method to attribute a motion impact score to specific trait-functional connectivity relationships.

Simultaneous recordings were made of hundreds of neurons in the rat frontal cortex and striatum, showing that decision commitment involves a rapid, coordinated transition in dynamical regime and neural mode.

In a combined analysis of two large patient cohorts, three peripheral consensus transcriptomic subtypes of sepsis are identified, which can be linked to an 18-gene classifier associated with different odds of mortality and may offer a way to tailor care for patients with sepsis.

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.

Polycystic ovary syndrome (PCOS) is a common disorder, the causes of which remain incompletely understood. Here the authors report the discovery of gene regulatory mechanisms that help to explain genetic associations with PCOS in the GATA4, FSHB and DENND1A loci.

Guard cells define microscopic stomatal pores for CO₂ uptake and water loss. Characterization of the extracellular metabolome revealed sugars as ‘mesophyll messengers’ from the leaf interior that enhance stomatal opening via regulation of the guard-cell H⁺-ATPase and anion channels.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

Modelling cardiomyocyte geometry reveals that mitochondrial–sarcoplasmic architecture enhances respiration by facilitating ion and lipid transfer for efficient cardiac metabolism.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

In this study, the authors analyzed iPSC-derived neurons from 180 ALS patients and controls, finding that TDP-43 dysfunction is variable and mirrors changes seen in postmortem brain and repairing nuclear pore damage is sufficient to reverse TDP-43 proteinopathy.

Researchers use a chimeric approach to reveal the first near-atomic resolution structures the yellow fever virion, showing key differences between vaccine and virulent strains that affect how antibodies recognise and neutralise the virus.

How age affect the immune response to malaria is not fully understood. Here, the authors characterise the transcriptome and serum inflammatory cytokines in children and adults in response to malaria, showing that there is an increase of inflammatory chemokine and cellular responses in adults compared to children.

STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

Parkinson’s disease (PD) involves toxic protein buildup and energy failure in neurons. Continuously breathing low-oxygen air protected mice from PD-like neuronal loss and reversed symptoms, even after they began, suggesting that hypoxia may protect neurons.

Here, the authors identify a copy number variation containing three enhancers (PIHEC) that drives bilateral constricted ear by co-ordinately regulating HMX1 expression, revealing how aberrant Hmx1 expression in neural crest-derived fibroblasts disrupts outer ear development.

Antibiotic resistance poses a critical global health threat. Here, the authors identify a carbapenem resistant clone of uropathogenic Escherichia coli with atypical virulence features as an increasing cause of urinary tract infection

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.

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.

Inventory data from more than 1 million trees across African, Amazonian and Southeast Asian tropical forests suggests that, despite their high diversity, just 1,053 species, representing a consistent ~2.2% of tropical tree species in each region, constitute half of Earth’s 800 billion tropical trees.

Chagas disease, caused by Trypanosoma cruzi, lacks an effective vaccine. Here, the authors report the cryo-EM structure of TcPOP, a potential vaccine antigen, in open and closed states and validate its immunogenic potential for invasion-blocking antibodies.

The number of individuals in a given space influences animal interactions and network dynamics. Here the authors identify general rules underlying density dependence in animal networks and reveal some fundamental differences between spatial and social dynamics.

Accorsi et al. show that the apple snail Pomacea canaliculata has eyes similar to humans and can fully regenerate them. They then developed genetic tools to establish these snails as a novel model system to study the mechanisms of eye regeneration

Dysregulation of ribonucleoprotein complex granules, previously implicated in neuromuscular disease, can drive pathogenesis in a genetic form of dilated cardiomyopathy, as shown in gene-edited pigs and patient-derived cardiomyocytes.

The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.

Transcription factors (TFs) represent an emerging class of therapeutic targets in oncology. Here, the authors develop Epiregulon, a computational method that constructs gene regulatory networks from ChIP-seq, ATAC-seq and RNA-seq data for accurate prediction of TF activity at the single-cell level, thereby facilitating the discovery of therapeutics targeting TFs.

This study combines lattice light sheet microscopy and single molecule imaging to study protein dynamics and chromatin structure in live cells. The authors describe how nucleosomes and proteins move and are organised in relation to chromatin density.

A 2.5-billion-year record of oxygen isotopes in sedimentary sulfate reveals the transitional oxygenation of the Earth’s surface and provides constraints on the dynamic, lengthy co-oxygenation of Earth’s atmosphere and oceans.

Placing particles at the interface between immiscible fluids usually enhances emulsification. However, now it is shown that if the particles are ferromagnetic, emulsification is suppressed and a non-planar recoverable interfacial shape develops.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.

Previously, OLIG2-expressing stems cells have been identified as having a role in medulloblastoma recurrence. Here, the authors investigate the effects of targeting this OLIG2+ stem cell population in Sonic Hedgehog (SHH) medulloblastoma using CT-179, an OLIG2 inhibitor.

Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Here, authors show that pluripotency and self-renewal processes have a high level of regulatory complexity and suggest that genetic factors contribute to cell state transitions in human iPSC lines.