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A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

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).

This study used fine-mapping to analyze genetic regions associated with bipolar disorder, identifying specific risk genes and providing new insights into the biology of the condition that may guide future research and treatment approaches.

The study advances the use of serological surveys to guide trachoma elimination program decisions and provides a way to set thresholds for whether or not to continue an intervention program.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.

Our annual survey highlights startups taking on gene therapy, adoptive immune cell therapy, gene editing, and drugs targeting RNA modifications and the unfolded protein response. Ken Garber, Esther Landhuis, Melanie Senior, Cormac Sheridan and Laura DeFrancesco report.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

Ventures focusing on gene therapy, adoptive T-cell therapy, protein homeostasis and the microbiome are among those selected by the editors in 2013's crop of startups.

X chromosomes evolve faster than autosomes, but confounding factors make this a difficult phenomenon to study. Utilising the unusual sex determination system of Sciaridae flies, this study finds a slower evolution of the X chromosomes which appears to be driven by strong purifying selection.

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.

This study maps regulatory variation in blood using whole-genome and transcriptome data from 614 South Africans, providing a resource to aid the interpretation of genome-wide association studies in African populations.

The Mass Spectrometry Query Language (MassQL) is an open-source language that enables instrument-independent searching across mass spectrometry data for complex patterns of interest via concise and expressive queries without the need for programming skills.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

The zoonotic pathogen Coxiella burnetiiestablishes a unique intracellular niche within a lysosome-derived vacuole. Here Bird et al. undertook proteomic, cell biology and microbiology approaches to characterise this niche and the strategies employed by C. burnetii to maintain a balance between intracellular success and maintaining host cell homoeostasis.

T cell responses can be generated to either pathogen infection or from priming with a vaccine. Here the authors compare T cell generation, phenotype and single cell transcriptome of participants vaccinated with a mpox vaccine or infected with the virus showing that the virus induced T cells showed more effective function and phenotype.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.

The authors show that the cell-penetrating peptide DG9 enhances PMO delivery to skeletal and cardiac muscles via multiple endocytic pathways. DG9-PMO significantly boosts dystrophin restoration and cardioprotection, addressing a key challenge in the therapy of Duchenne muscular dystrophy.

This study identifies a unique multiple sclerosis lesion, the broad rim lesion, which is associated with rapid disease progression and marked by a distinct inflammatory profile involving innate inflammation, cellular stress, unfolded protein response and apoptosis.

This paper describes a framework for classifying small insertions and deletions from genomic data and applies it to a large dataset comprising seven tumor types. The analysis highlights new insertion and deletion signatures and a classifier of postreplicative repair dysfunction.

Our bodies continuously change their shape. Prosthetic users need smart prosthetic liners to compansate these changes. Here, the authors developed a dynamically adaptive human- machine interface, Roliner, with the potential to revolutionize the daily lives of amputees.

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.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Perturbed B cell responses have been associated with Crohn’s disease. Here, the authors sequence the B cell receptor repertoire in patients with Crohn’s disease and identify shared B cell clones, thus implicating the presence of common Crohn’s disease-associated antigens driving a pathogenic B cell response.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

A rare case of asymptomatic dominantly inherited Alzheimer’s reveals confined tau pathology and unique proteomic features, highlighting potential resilience mechanisms decades beyond expected onset.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

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.

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.

The aging immune system is characterized by changes in immune cell frequencies and functionality. Here the authors report dynamics of age-related divergence of circulating immune responses in patients with solid tumors treated with immune checkpoint inhibitors

‘T cell engagers promote antitumor immunity, but how macrophage modulates this activity in tumor is still unclear. Here the authors show, using biopsies from patients with uveal melanoma and single cell analyses, that a T cell engager, tebentafusp, reprograms tumor-associated macrophages and ameliorates, in synergy with IL-2, immunosuppression to cancer.

The DNA breaks that initiate recombination during meiosis are resected by nucleases, but the mechanism of this resection in mammals is poorly understood. Here, the authors examine the roles of the MRE11-RAD50- NBS1 complex in beginning and extending resection during meiosis in male mice.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.