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The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

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.

Application of a nanopore sequencing workflow for real-time analysis of brain tumors results in molecular classification within a 30-minute intraoperative window, followed by comprehensive profiling within 24 hours.

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.

In a previous clinical trial, the authors reported that SCFA-yielding biotherapy in adults with type 1 diabetes remodels the gut proteome and metabolome. Here, the show that colonization of the post-therapy microbiome into mice delayed diabetes and increased aryl-hydrocarbon receptor ligand and IgA production in the gut.

Transcriptomic and proteomic analyses show that high levels of the extracellular-matrix protein osteopontin are associated with the attenuated foreign-body response elicited by breast silicone implants wrapped with acellular dermal matrix.

Several multi-cancer GWAS loci within the region encoding telomerase reverse transcriptase (TERT) have been identified. Here, the authors explore the locus within TERT intron 4, link it with a variable number tandem repeat (VNTR), and investigate its biological significance and role in cancer.

Vector saliva can affect infectivity and pathogenesis of vector-borne viruses, but this hasn’t been studied for Zika virus infection. Here, Dudley et al. show that mosquito-mediated Zika infection of macaques results in altered replication kinetics and greater sequence heterogeneity.

Michelle Francl looks at chemistry in a new light.

Large-volume volcanic eruptions can occur despite only limited precursory activity. Here the authors show that modelling the combined effects of buoyant magma, viscoelastic earth behaviour, and sustained magma channels can explain such behaviour of volcanoes and gives an estimate of pressure evolution in magma bodies.

In a prespecified interim analysis of the randomized, double-blind phase 3 COMPASSION-15 trial, patients with advanced HER2-negative gastric/GEJ cancer treated with the anti-PD-L1/CTLA-4 bispecific Ab cadonilimab plus chemotherapy showed significantly improved overall survival compared with patients treated with placebo plus chemotherapy as first-line treatment.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

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.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Era+ breast cancer patients often develop resistance to endocrine therapy. Here, the authors show that FGFR1 amplification is a resistance mechanism to CDK4/6 inhibitor and endocrine therapy and that combined treatment with FGFR, CDK4/6, and anti-estrogens is a potential therapeutic strategy in Era+ breast cancer tumors.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Michelle Francl wonders how much time chemists should spend learning history.

FUT10 and FUT11, originally annotated as α1,3-fucosyltransferases, are actually protein O-fucosyltransferases participating in a non-canonical ER quality control pathway for EMI ___domain-containing protein secretion.

MacroH2A histone variants originated before the split of fungi and animals. ADP-ribose binding is an ancestral feature of their macrodomains and is linked to the compartmental regulation of NAD metabolism. This function was selected for during the evolution of metazoans.

Genome-wide association analyses of prostate cancer in men from sub-Saharan Africa identify population-specific risk variants and regional differences in effect sizes. Founder effects contribute to continental differences in the genetic architecture of prostate cancer.

Catch bonds where lifetime increases with force applied can form when T cell receptors (TCR) interact with agonist peptide-MHC (pMHC) complexes. Here the authors use a modelling and experimental approach to analyse 55 TCR–pMHC bond lifetime curves measured under force to further characterise the structural bases and functional relevance of catch bonds.

Human activities affect marine predators in complex ways, yet we lack spatial understanding of cumulative impacts across key habitats. Here the authors analyse distribution and movements of eight marine predators, and find that species and human impacts vary across space and overlap within marine sanctuaries.

Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

Analysis of the relationships between transcription, replication, and stability of large genes associated with common fragile sites suggests that high transcription levels alleviate genome instability by altering replication timing and allowing cells to complete replication before mitosis.

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.

In the COMPASSION-04 trial, first-line treatment with a bispecific antibody targeting CTLA-4 and PD-1 and chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma resulted in clinical responses with a manageable safety profile.

Michelle Francl wonders if scientists ought to pen poetry.

BACH2 is required for lymphocyte differentiation. Afzali et al. describe mutations that cause BACH2 disruption, immunodeficiency and autoinflammatory disease via haploinsufficiency, a mechanism shared by other super-enhancer-regulated genes.

Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca²⁺ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca²⁺ concentration and excretion.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Braxton et al. report structures of human p97/VCP bound to the UBXD1 adaptor involved in autophagy. The structures reveal how UBXD1 utilizes multiple interaction domains to remodel and open the hexamer ring, revealing its role in p97 regulation.

Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.

Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2. A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

Individuals over eighty years of age are less likely to mount a good immune response against SARS-CoV-2 (measured by neutralization titres) after the first dose of the BNT162b2 mRNA vaccine, but achieve good neutralization after the second dose.

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.