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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.

Acetyl-CoA synthetases have been proposed as targets for development of new antimicrobial drugs. Here, Jezewski et al. identify isoxazole-based compounds with activity against the pathogenic fungus Cryptococcus neoformans, and describe their mechanism of action as inhibitors of fungal acetyl-CoA synthetases.

The authors report the implementation of a Transformer-based model on the same architecture used in Large Language Models in a 14nm analog AI accelerator with 35 million Phase Change Memory devices, which achieves near iso-accuracy despite hardware imperfections and noise.

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.

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.

Indonesian cattle are unique due to their history of admixture involving both zebu and banteng. Here, Wang et al. identify ~3.5 million novel introgressed SNP variants and provide a genomic map of banteng introgression within and across many cattle breeds, each with unique introgression histories.

SAVANA is a tool to detect somatic structural variants and copy number aberrations using long-read sequencing data, offering high sensitivity, specificity and compatibility with or without germline controls.

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.

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.

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

Analysis of nanopore long-read sequencing is challenged by technical noise, particularly in single cells. Here, authors introduce Isosceles, a toolkit for accurate isoform detection, quantification, and flexible downstream analysis of long-read data at single-cell, pseudo-bulk and bulk resolutions.

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.

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.

This study analysed genetic data of soil-transmitted helminths from 27 countries, revealing diversity impacting molecular test accuracy and highlighting the need to adapt diagnostics for effective STH surveillance.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

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.

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.

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.

Long-read sequencing allows the detection of RNA isoforms, but is hampered by low throughput and potential artefacts. Here, the authors develop the scTaILoR-seq hybridisation capture method for long-read RNA sequencing to improve transcript detection, and use this method to detect isoforms at the single-cell level in ovarian cancer.

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.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Hospital treatment for children with severe malnutrition may facilitate antibiotic resistance. Here, using rectal swabs from 1,371 children receiving treatment for severe acute malnutrition in Niger, the authors identify high rates of bacteria carrying carbapenemase genes, highlighting the urgent need to prioritize infection control.

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.

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.

There is a need for methods that allow the analysis of single-cell long-read sequencing data without depending on known barcode lists or short-read sequencing. Here, the authors develop scNanoGPS, a tool that can independently deconvolute long reads into single cells and single molecules, and apply it on tumour and cell line data.

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.

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.

The prognostic and diagnostic roles of DNA methylation in acute myeloid leukemia remains to be explored. Here, the authors develop DNA methylation-based models for the prediction of five-year survival and clinical molecular subtypes in both pediatric and adult test cohorts.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

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

Methods to produce haplotype-resolved genome assemblies often rely on access to family trios. The authors present FALCON-Phase, a tool that combines ultra-long range Hi-C chromatin interaction data with a long read de novo assembly to extend haplotype phasing to the contig or scaffold level.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

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.

Long-read metagenomics offers a valuable approach for profiling bacterial communities. This work presents a long-read assembler, metaFlye, that specifically addresses the challenges of assembling metagenomes.

MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

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.

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.

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.

Acute febrile illness is common in sub-Saharan Africa and causative agents are often unknown. Here, the authors perform metagenomic sequencing on samples from patients with acute febrile illness in Uganda for which no diagnosis was available through routine diagnostic screening.

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

A pangenome analysis of 76 wild and domesticated barley accessions in combination with short-read sequence data of 1,315 barley genotypes indicates that allelic diversity at structurally complex loci may have helped crop plants to adapt to agricultural ecosystems.

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.

The mechanism and extent to which transposons can alter the gene expression of their hosts is not well understood. This study finds that in the IS3 family of transposable elements in E.coli, de-novo promoter activity could evolve from single point mutations, most often from existing proto-promoter sequences.

Limited experimental platforms exist for assessing quantitative sequence-function relationships for multiple antibodies. Here, authors develop a deep-sequencing based technology called MAGMA-seq, that determines the quantitative properties of antibody libraries.

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.