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Most H₂ used in the chemical industry is derived from fossil fuels. Now it has been shown that coupling native microbial H₂ pathways with engineered alkene biosynthesis and membrane-bound Pd catalysis enables biocompatible hydrogenation of metabolic intermediates in living bacteria. This hybrid chemo-microbial platform supports the carbon-negative synthesis of industrial chemicals from waste-derived feedstocks.

In vivo adenine base editing corrects a common Pex1 pathogenic allele in mouse models of Zellweger spectrum disorder, rescuing liver pathology, fatty acid levels, body weight and peroxisome function.

The genetically encoded voltage indicators JEDI3sub and JEDI3hyp enhance monitoring of subthreshold neuronal activity in the awake mouse brain using a variety of two-photon microscopy techniques.

Here, the authors conduct a metagenomic-based study of England’s rivers to show that biofilm bacteria are taxonomically and functionally diverse and are key to biogeochemical cycling, highlighting the importance of river biofilm bacteria in understanding and monitoring freshwater ecosystem health.

Catabolism of extracellular glutathione by γ-glutamyltransferases supports tumour growth and survival, and pharmacological targeting of these enzymes slows tumour growth.

Using single-cell tissue imaging and spatial proteomics to study mitochondria–lipid droplet coupling in hepatocytes, PLIN5 phosphorylation is identified as a mediator of lipid flux and nutrient stress responses.

NMDAR expression is sufficient to induce B cell recruitment and affinity maturation, resulting in receptor-modulating antibodies that connect anti-cancer immunity and autoimmunity.

A series of spontaneously blinking dyes in the far-red range facilitate single-molecule localization microscopy. These dyes vary in their blinking properties and can be matched to the applications and microscopy modalities as needed.

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.

Allosteric biosensors are constructed by combining reporter proteins with machine-learning-designed receptor domains.

Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.

Genome-wide analysis coupled with long-read sequencing identifies a repeat expansion in GOLGA8A associated with high risk for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.

Biallelic variants in RNU4-2 cause a recessive neurodevelopmental disorder that is phenotypically and molecularly distinct from dominant ReNU syndrome and associated with reduced RNU4-2 transcript levels, consistent with a loss-of-function mechanism.

PCNA–PAF15 has a key role in determining replisome dynamics during genome replication and protecting against genome instability.

Mucosal administration of a multivalent, adjuvanted vaccine against Clostridioides difficile promoted bacterial clearance and protected against morbidity, mortality, tissue damage and recurrence in mice.

SLCO2A1 (also known as OATP2A1) is responsible for the transport of eicosanoids, including prostaglandins (PGs), as well as of a subset of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, structures of SLCO2A1 bound to PGs and to four widely used drugs elucidate the molecular basis for PG and drug recognition.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

Temporal profiling of central carbon metabolism during Kras^G12D-driven acinar-to-ductal metaplasia reveals that disruptions in NADPH-producing enzymes accelerate the formation of pancreatic precancerous lesions.

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.

The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

Variation in responses to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda suggests population-level divergence under natural selection, with hunter-gatherers disproportionately showing signatures of positive selection.

Bång-Rudenstam et al. report that the acidic tumour microenvironment facilitates the assembly of chondroitin sulfate-enriched glycocalyx to disrupt lipid scavenging and prevent ferroptosis, thereby providing an adaptive mechanism upon tumour acidosis.

Multiomic single-cell analyses of 15 Down syndrome fetal cortical samples identify widespread disruption of neurodevelopmental transcriptional programs, driven by three dosage-sensitive chromosome 21 transcription factors.

An analysis of whole-exome sequencing data linked to longitudinal electronic health records from 44,028 British South Asians finds new gene–phenotype associations and identifies 2,991 genes with rare biallelic predicted loss-of-function genotypes.

Hodgson, Huang, Lang et al. show that TDP-43 limits ribonucleoprotein particle condensation into paraspeckles in a concentration- and polymerization-dependent manner. They also link paraspeckle condensation to stress response and neuroprotection.

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.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

The activity of the membrane-bound enzyme pMMO depends on copper but the location of the copper centers is still under debate. Here, the authors reconstitute pMMO in nanodiscs and use native top-down MS to localize its copper centers, providing insights into which sites are essential for activity.

Clostridium perfringens lacking perfringolysin O toxin isolated from preterm infants metabolizes human milk oligosaccharide disialyllacto-N-tetraose to produce metabolites that promote the growth of commensal bifidobacteria, inhibit pathogens and suppress inflammation in an organoid model.

Stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads using a two-vector system of enveloped delivery vehicles and adeno-associated viruses.

An analysis of rare disease cohorts from the UK, the USA, Italy and the Netherlands identifies a neurodevelopmental disorder caused by biallelic variants in RNU2-2. Individuals with this disorder have substantially reduced levels of U2-2 small nuclear RNA in blood.

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.

Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

The authors show that the CD4 mimetic CJF-III-288 stabilizes HIV-1 Env in an asymmetric “open” State-3 conformation, guiding anti-CoRBS antibodies to boost ADCC against infected cells and delay viral rebound in vivo, underscoring therapeutic promise.

Borneol has repelled mosquitoes for millennia, but how it worked was unknown. Here, the authors show the sensory pathway mosquitoes use to detect and avoid this ancient plant compound, opening the door to improved natural repellents.

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.

Fusion genes involving KMT2A rearrangements are frequent oncogenic drivers of acute myeloid leukaemia (KMT2A-r AML) but the cell of origin remains unclear. Here, using preclinical models of EVI1 positive KMT2A-r AML the authors investigate the cell of origin and find that the presence of exogenous factors influences AML initiation and the resulting phenotype.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Cationic amino acids are essential to protein synthesis and cellular signaling. Here, authors determine the structure of the cationic amino acid transporter 1 and determined how it is co-opted as a receptor for leukemia-causing animal viruses.

Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity

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.

Immune features and T cell characteristics that correlate with post-intervention control of HIV-1 viraemia inform the development of combination immunotherapies that may enhance the ability to elicit durable HIV remission.

The existing ENCODE registry of candidate human and mouse cis-regulatory elements is expanded with the addition of new ENCODE data, integrating new functional data as well as new cell and tissue types.

Hepatic glycogenolysis is essential for protein glycosylation and rhythmic secretion by the liver. Disruptions to hepatic glycogenolysis, caused by congenital diseases or physiological factors such as obesity, caloric restriction and changes to meal timing, alter hepatic protein secretion.

Authors show that all individuals have asymmetrically glycosylated IgGs—the glycans on each of the Fc protomers are not identical. Asymmetrically monofucosylated IgGs drive dengue disease and are functionally similar to afucosylated IgGs.

Yu et al. develop a platform to model genetic diversity in drug treatment at the single-cell level. Using KRAS-G12C inhibitors as a proof of concept, they identify the pathway driving cell death and potential resistance mechanisms.

Here the authors show DNGR-1 expressed by cDC1s promotes CD8⁺ T cell priming to cytoskeletal neoantigens from dying tumor cells, thereby shaping cancer immune visibility and tumor evolution through immunoediting.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.