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Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

Inhibitors of α_vβ₃ and α_vβ₅ integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo. Such effects could compromise the anticancer efficacy of these agents in humans.

The number and diversity of organisms known to produce the environmentally important sulfur compound dimethylsulfoniopropionate (DMSP) is expanded with the discovery of a family of DMSP synthesis enzymes.

Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.

Using whole-genome data for single-nucleotide polymorphism and results from genome-wide association studies, the authors show that people’s preference for pairing with those with similar phenotypic traits has genetic causes and consequences.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Fagaceae are diverse family including trees of ecological and economic importance. This phylogenomic analysis of nuclear and plastid genomes reconstructs evolutionary history and finds evidence of multiple adaptive introgression events in this important plant family.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

Here the authors reveal how telomeres signal mitotic stress. A key protein network alters their structure exposing telomere ends to signal mitotic stress, ultimately triggering a controlled DNA damage response to remove faulty cells.

Multi-ancestry genome-wide association meta-analysis of major depression identifies new risk loci, assesses the transferability of risk loci across ancestry groups, and improves fine-mapping resolution and prioritization of candidate effector genes.

SCENT is a nonparametric method that models association between chromatin accessibility and gene expression in single-cell multimodal datasets, enabling construction of cell-type-specific enhancer–gene maps to aid mapping of candidate causal variants and genes for common diseases.

Carbon dioxide concentration has previously been used as a proxy for overall ventilation efficiency to indirectly estimate the risk of indoor SARS-CoV-2 transmission. Here, authors investigate whether the concentration of carbon dioxide also has a direct mechanistic role in improving transmission efficiency.

Linking epigenetic marks to clinical outcomes promises insight into the underlying processes. Here, the authors introduce a statistical approach to estimate associations between a phenotype and all epigenetic probes jointly, and to estimate the proportion of variation captured by epigenetic effects.

Emerging variants of SARS-CoV-2 raise concerns about vaccine efficiency. Here, the authors present a post-hoc analysis for the ChAdOx1 nCoV-19 (AZD1222) vaccine trial in Brazil and provide efficacy against symptomatic COVID-19 caused by the Zeta (P.2) and other variants.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

Lim and colleagues present the UK PROSECO study where they assess humoral and cellular immune responses to one, two and three doses of vaccination against SARS-CoV-2 in patients with B-cell malignancies in a prospective observational study.

Phylogenetic reconciliation traces the evolution of glycopeptide antibiotic biosynthesis gene clusters from pre-existing gene pools to 150–400 million years ago; resistance to these antibiotics also arose contemporaneously.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance.

Reconstruction of one billion years of mantle flow shows that mobile basal mantle structures are just as consistent with the Earth’s volcanic history as are fixed mantle structures.

Floods and fires aside, the tricky science of prediction is explained in a book that treads a careful line between analysis and anecdotes of awful events, says Andrew Robinson.

Increasing compositional uniqueness of the gut microbiome, and corresponding changes in microbial metabolites in the blood, are identified as a signature of healthy ageing in humans.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Single-cell transcriptomic and proteomic data from synovial tissue from individuals with rheumatoid arthritis classify patients into groups based on abundance of cell states that can provide insights into pathology and predict individual treatment responses.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Investigating how proteins acquire specific metals in cells is challenging. Here, the authors use a cyanobacterial Mn^II-cupin (MncA) as a metal trap to test predictions of metalation, and determine metal-preferences by refolding MncA in buffered competing metals.

Phylogenetic analysis of trait heritability (PATH) applies phylogenetic correlations to single-cell lineage tracing data, quantifying cell state plasticity and transition probabilities. PATH offers insights into cell state heritability and transition dynamics in cancers.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

Abrupt changes are developing across Antarctica’s ice, ocean and biological systems; some of these changes are intensifying faster than equivalent Arctic changes, potentially irreversibly, and their interactions are expected to worsen other impacts across the Antarctic environment and global climate system.

The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.

Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.

Health effects of dietary restriction are uncoupled from longevity.

Asian soybean rust caused by Phakopsora pachyrhizi is an important plant pathogen, but an accurate genome assembly for this fungus has been lacking. This study sequenced three independent P. pachyrhizi isolates and generated reference quality assemblies and genome annotations, representing a critical step for further in-depth studies of this pathogen and the development of new methods of control.