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Tumour-antigen-pulsed mature dendritic cells (DC) have not been as efficient for cancer therapy as hoped to be, due to their sub-optimal antigen-presentation and migration capacities. Here the authors utilise DC progenitors, constitutively expressing IL-12 and an engineered extracellular vesicle-internalizing receptor (EVIR), which give rise to mature conventional type 1 DCs with improved antigen presenting capacities, resulting in improved anti-tumour immunity in a mouse model of melanoma.

A multiancestry genome-wide association study of chronic alanine aminotransferase elevation identifies candidate risk loci for nonalcoholic fatty liver disease, with replication in external cohorts defined by histology or imaging.

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.

Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.

Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.

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.

Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTp^WT-IDH^WT glioblastoma). Here, the authors present a genetic landscape of TERTp^WT-IDH^WT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.

Some cancer cells lacking telomerase activity extend their telomeres via an alternative, recombination-based mechanism, termed ALT. A new study shows that depletion of histone chaperone ASF1 can induce ALT in both primary and cancer cells, suggesting that the ALT pathway may be triggered by changes in chromatin state.

Here the authors show that mice exposed to a variety of pathogens initially have impaired innate type 2 responses to lung allergens, but reactivity resets over time, indicating that microbial experience does not stably inhibit innate immunity to allergens.

A multi-ancestry genome-wide association study of liver cirrhosis and its associated endophenotypes identifies and validates 14 risk variants. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

Metabolic and alcohol-related liver disease presents challenges in clinical trials due to complex pathophysiology. This Review discusses noninvasive imaging, serum biomarkers and adaptive designs as modalities to enhance patient-centric end points, aiming to refine diagnostics and improve drug development.

Short-lived RNA folding intermediates have important roles in the folding of RNA. Here, the authors combine ¹⁵N relaxation dispersion NMR with chemical probing to visualise one of these intermediates, and are able to show it is a secondary structural switch, that might help with folding.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

Here the authors show a function for lymph nodes in the maintenance of effector T cell differentiation and function during chronic infection and checkpoint blockade, identifying a spatial component in the regulation of exhausted T cell fitness.

A reinforcement learning-based virtual reality system, implementing a series of sport sessions with coaching, was as effective as standard physical activity in reducing fat mass in adolescents, with positive effects on cognition.

Cas9 DNA targeting is inherently sequence specific but not temporally controlled. Here, authors spatiotemporally couple Cas9 activity to target site transcription in eukaryotes and exploit this to preferentially edit the more highly transcribed of two alleles that harbor identical Cas9 targets.

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.

The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients.

A precision medicine approach used unsupervised clustering to identify five distinct phenotypic profiles that can better predict risks of cardiometabolic disease compared with those ascertained based on the additive value of body mass index and other biomarkers, and validated these findings across four independent cohorts.

The oral drug obeldesivir confers 80% survival when given after lethal Marburg virus exposure in cynomolgus macaques and also delays viral replication and disease onset, suggesting a potential treatment option for an infection with no approved therapies.

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.

Prasad et al. assess four therapeutics in preventing lethal disease in an established nonhuman primate model of Ebola virus infection. They find that each therapy results in ~ 40% survival, suggesting the use of alternative strategies, such as combining therapeutics to combat Ebola.

Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes.

Tetrandrine is one of the most potent inhibitors of Ebola Virus infection. Here the authors identify LIMP-2 as a direct cellular target of Tetrandrine and establish a functional connection between lysosomal sphingosine homeostasis and calcium regulation.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

Mercury’s exosphere is known to predominately contain hydrogen, helium, sodium, potassium, calcium, magnesium, aluminum, iron, and manganese. Here, the authors show evidence of the presence of lithium (Li) in the exosphere of Mercury, most likely originating from meteoroids.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.

Employing a candidate gene approach, Mancina et al. identify a genetic variant of the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene that reduces susceptibility to fatty liver disease. Functional studies in vitro and in vivo demonstrate that targeting PSD3 protects against fatty liver disease.

The genomic landscape of diffuse gliomas remains to be characterised. Here, the authors perform whole genome sequencing of 403 tumours and identify recurrent coding and non-coding genetic mutations, their associations with clinical outcomes and potential therapeutic targets.

Pheochromocytomas and paragangliomas (PCC/PGL) are tumours of the autonomic nervous system. Here, the authors identify ATRX mutations in PCC/PGL and suggest that ATRXloss is important for tumorigenesis in a subset of PCC/PGL.

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.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

A combination of engineering approaches is used to improve the function of IscB for a variety of editing activities in vivo.

Using a newly developed spatiotemporal phylogeographic path analysis method combined with phylogenetic niche modelling, the authors estimate clade-wide dispersal maps spanning the early Permian to end-Triassic periods for archosauromorph reptiles.

Blockade of intrahepatic accumulation and function of platelets represents a potential approach to treat non-alcoholic steatohepatitis (NASH) and prevent subsequent progression to hepatocellular carcinoma

Sutures and staples can impair wound healing in fragile tissues. Here, the authors present a battery-free, self-contracting triboelectric strip that achieves strong wet adhesion and delivers impedance-matched electrical stimulation, enabling sutureless, accelerated wound repair.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Detection of circulating tumor DNA using MRD-EDGE, a machine-learning-guided single-nucleotide variant and copy-number variant detection platform for signal enrichment, enables monitoring of minimal residual disease and immunotherapy response in settings of low tumor burden.

Few cancer drivers in non-coding regions have been identified so far. Here, the authors develop a transcription factor-aware burden test to predict non-coding variants and analyze the impact on transcription factor binding - especially ETS factors - as well as their impact on transcriptional activity.

CRISPRme is an off-target nomination tool that accounts for human genetic diversity. Ancestry-dependent allele-specific off-target edits can occur with therapies currently in clinical trials, highlighting the importance of genetic variation-aware assessment.

In CHIP, somatic mutations in a hematopoietic stem cell lead to a clonal subpopulation of blood cells. Here, the authors perform a CHIP meta-EWAS to establish its epigenetic features and age-related outcomes.

Ligand detection is an essential component of pre-clinical drug development. Here, the authors develop an assay directly coupling protein ligand binding to the luminescence intensity of NanoLuc luciferase; enabling a compound discovery strategy for a broad spectrum of potential drug targets.

Cardiovascular events are the main cause of mortality in patients with metabolic dysfunctionassociated steatohepatitis (MASH). Here, the authors show that lanifibranor improves cardiometabolic health - insulin sensitivity, lipid and glucose metabolism, systemic inflammation and hepatic steatosis.