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Zhu et al. find that aging causes region-specific myelin damage in the spinal cord, which is counteracted by enhanced TGFβ signaling in microglia, revealing a protective mechanism for healthy aging.

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.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Promoter escape is a key step in bacterial transcription and a target of the antibiotic rifampicin. Here, the authors use cryo-EM to explore this step, finding seven structural intermediates of M. tuberculosis RNA polymerase during promoter escape.

By integrating large-scale genomic and proteomic data in cerebrospinal fluid and plasma, the authors identify 49 proteins linked to MRI markers of cerebral small vessel disease, highlighting extracellular matrix and immune pathways, with biomarker and therapeutic potential.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Clinical and genetic phenotyping of consanguineous family cases of neonatal syndromic diabetes and type 2 diabetes, combined with in-depth functional studies in pluripotent stem cells, reveals a role for genetic variants of ONECUT1 in monogenic and multifactorial diabetes.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

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.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

This study provides the first evidence in humans that tirzepatide modulates brain electrophysiology, with changes in low-frequency accumbens power linked to food preoccupation.

The role of pathogenic mitochondrial DNA (mtDNA) mutation in cancer remains to be studied. Here the authors show that high mtDNA mutation burden in lung cancer models leads to increased glycolysis but limited de novo serine synthesis, rendering sensitivity to dietary serine and glycine deprivation.

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.

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.

Analysis of the longest-lived mammal, the bowhead whale, reveals an improved ability to repair DNA breaks, mediated by high levels of cold-inducible RNA-binding protein.   

Here the authors develop a genetic priority score to predict side effects by integrating multiple lines of genetic evidence. By applying this score, they provide evidence of known side effects and suggest ones with no clinical trial evidence.

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.

Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

In Mycobacterium tuberculosis, the fitness cost of rifampicin resistance is partially due to excessive RNA polymerase pausing and is rescued by mutations in the pro-pausing transcription factor NusG.

The authors test whether social values have become converged or diverged across national cultures over the last 40 years using a 76-country analysis of the World Values Survey. They show that values have diverged, especially between high-income Western countries and the rest of the world.

Dedifferentiated liposarcomas (DDLPS) typically have dedifferentiated (DD) and well-differentiated (WD) components, although their cellular origins remain elusive. Here, the authors characterise primary DDLPS tumours using bulk and single-cell multi-omics and find adipocyte stem cells that could be a common ancestor of WD and DD components.

Time-resolved cryo-EM captured transient intermediates during E. coli RNAP promoter melting, revealing conformational changes affecting stepwise transcription bubble opening. Results inform how DNA sequence controls bacterial transcription initiation.

In vivo experiments and mathematical modelling in this work, show that alveolar macrophages lower phage densities and phage-bacteria contact rates, limiting the effectiveness of synergistic treatment of acute pneumonia by bacteriophage and the immune response.

Analysis of data from multiple instruments reveals a giant exoplanet in orbit around the 0.2-solar-mass star TOI-6894. The existence of this exoplanetary system challenges assumptions about planet formation and it is an excellent target for atmospheric characterization.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

After RNA release, Escherichia coli RNA polymerase (RNAP) stays on DNA in a post-termination complex (PTC). PTCs can initiate RNA synthesis but produce cytotoxic R-loops. RapA induces an RNAP conformational change, dissociating PTCs and controlling R-loop formation.

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.

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.

Clinical, genomic and transcriptomic analyses of paired samples of synchronous bilateral female breast cancer identify associations between tumor concordance and immune infiltrates levels and response to neoadjuvant treatment.

Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

Cryo-EM is used to visualize the SARS-CoV-2 RTC bound to each of the natural NTPs as well as remdesivir triphosphate (RDV-TP) in states poised for incorporation, explaining the interactions required for NTP recognition and RDV-TP selectivity.

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.

Erik Ingelsson and colleagues report a large-scale genome-wide meta-analysis for associations to the extremes of anthropometric traits, including body mass index, height, waist-to-hip ratio and clinical obesity. They identify four loci newly associated with height and seven loci newly associated with clinical obesity and find overlap in the genetic structure and distribution of variants identified for these extremes of the trait distributions and for the general population.

There is a requirement for improved adjuvants to improve responses to vaccines, including adjuvants that induce Th17 cells. Here, the authors use a MINCLE and TLR9 agonist-based vaccine adjuvant and show induction of Th17 and mucosal immune responses to vaccine recall antigens in mice and non-human primate models of vaccination.

Fishing has had a profound impact on global reef shark populations, and the absence or presence of sharks is strongly correlated with national socio-economic conditions and reef governance.

In a voter game, information gerrymandering can sway the outcome of the vote towards one party, even when both parties have equal sizes and each player has the same influence; and this effect can be exaggerated by strategically placed zealots or automated bots.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

Double Asteroid Redirection Test (DART) mission impact on asteroid Dimophos resulted in an elliptical ejecta plume. Here, the authors show that this elliptical ejecta is due to the curvature of the asteroid and makes kinetic momentum transfer less efficient.