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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).

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

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.

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.

The properties of materials can be drastically modified under extreme pressure. Here the authors investigate ramp-compressed sodium to 5 million atmospheres with in situ X-ray diffraction and optical reflectivity, revealing a complex temperature-driven polymorphism and suggesting the formation of a previously predicted electride phase.

What prevents a generalist predator from evolving and outperforming specialist predators? By combing analyses of natural variation with experimental evolution, Stewart et al. suggest that predator variation persists because most mutations have prey-specific effects, which results in relaxed selection

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Childhood radioactive iodine exposure from the Chornobyl accident led to an increased papillary thyroid carcinoma (PTC) risk and potentially higher invasiveness depending on tumour genetic profiles. Here, the authors use genomics to characterise and predict cervical lymph node metastases in PTC patients affected by the Chornobyl accident.

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.

Archaeological discoveries from Malta suggest that humans were present on the Maltese islands from around 8,500 years ago, providing evidence that Mesolithic hunter-gatherers made sea crossings as long as 100 km.

The ability to manage ill health and care needs might be affected by who a person lives with. Here, authors show that living alone or with co-residents with multimorbidity poses additional risk for unplanned hospitalisation and care home transition beyond an individual’s characteristics.

In preclinical studies, Hutt, Loi and colleagues find that mice treated with checkpoint blockade have impaired ovarian function and reserve, associated with increased immune infiltrate, raising considerations about fertility implications for female patients.

In this work, authors show that randomized water, sanitation, hygiene and nutrition interventions reduced child antibiotic use in Bangladesh (in parallel with high intervention uptake and reduced infections) but not Kenya (in parallel with lower uptake and no effect on infections).

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 expression of each of the roughly 22,000 genes of the mouse genome has been mapped, at cellular resolution, across all major structures of the mouse brain, revealing that 80% of all genes appear to be expressed in the brain.

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.

An open-label clinical trial of an oral absorbent that sequesters phenolic molecules in the gut shows safety and tolerability in adolescents with autism, reduces levels of gut-derived metabolites in circulation and reduces anxiety and irritability.

A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

Intraspecies response to climate change is expected to align with genetic affinity. Using the American pika as a case study suggests that divisions of species distributions best explain intraspecific heterogeneity in climate relationships.

Geographic location can be a key determinant of human health outcomes. Here, the authors show that in large-scale trials, randomization that is pair matched by geography can lead to substantial improvements in statistical efficiency and enable insights into spatially varying intervention effects.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

During cellular senescence in human and mouse cells, L1 transposons become transcriptionally derepressed and trigger a type-1 interferon response, which contributes to age-associated inflammation and age-related phenotypes.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Eberhardt et al. show that SARS-CoV-2 infects human coronary lesions where it preferentially targets plaque macrophages, triggering plaque inflammation and potentially leading to acute cardiovascular complications and long-term cardiovascular risks in patients with COVID-19.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Mutations in the mechanotransduction channel component TMC1/2 cause deafness. Here, the authors use a synthetic AAV to replace TMC1 and 2 in the inner ear and show restoration of cochlear and vestibular function, of neuronal reponses in the auditory cortex and of hearing and balance in mice.

Whole-genome sequencing of lung cancer in never smokers identifies different copy number subtypes and shows a lack of tobacco smoking signatures, even in cases exposed to secondhand smoke.

A new discovery strategy, ‘reverse metabolomics’, facilitates high-throughput matching of mass spectrometry spectra in public untargeted metabolomics datasets, and a proof-of-concept experiment identified an association between microbial bile amidates and inflammatory bowel disease.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

The effects of climate on vector-borne disease systems are highly context-dependent. Here, the authors incorporate laboratory-measured physiological traits of the mosquito Aedes aegypti into climate-driven mechanistic models to predict number, timing, and duration of outbreaks in Ecuador and Kenya.

Mabe et al. find that GD2 levels correlate with lineage plasticity in neuroblastoma and identify ST8SIA1 as the key enzyme in GD2 synthesis. EZH2 inhibition in mesenchymal neuroblastoma cells elevates ST8SIA1, synergizing with anti-GD2 antibodies.

Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.

Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

Axonal swellings have been found on Purkinje cell axons in the cerebellum both during development and disease. The authors show that axons with swellings propagate action potentials with higher fidelity than those without and that mice with more axonal swellings learn cerebellar-related tasks better.

Rossjohn, van der Vliet and colleagues develop single-domain antibodies binding composite CD1d and NKT T-cell receptor antigens, inducing specific antitumor immune subsets.

FAM72A differentially controls mutation rates by regulating uracil processing at different stages of the cell cycle, thereby regulating somatic hypermutation and class-switch recombination in B cells.

Deep sequencing technology could soon be competitive with certain array applications. But the jury remains out on which of the myriad platforms will have the greatest impact and broadest application. Amy Coombs investigates.

Archaeogenetic study of ancient DNA from medieval northwestern Europeans reveals substantial increase of continental northern European ancestry in Britain, suggesting mass migration across the North Sea during the Early Middle Ages.

The underlying transcriptional and cellular events mediating the reduction of dendritic spines on medium spiny neurons of the nucleus accumbens (NAc) remains unknown. Here, authors demonstrate that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc, which is shown to be transcriptionally repressed by the histone modifier HDAC2, and that overexpression of drebrin is sufficient to decrease drug seeking and increase dendritic spine density

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

Peter Balint-Kurti, Qin Yang and colleagues report that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase, is a gene within the quantitative trait locus qMdr_9.02, which confers resistance to southern leaf blight and gray leaf spot. Their findings suggest that resistance might be caused by differences in levels of lignin and other metabolites in the phenylpropanoid pathway.

The insecticidal protein Mpf2Ba1 shows potent control against corn rootworm. Here, the authors present detailed structural analyses revealing transitions between its three main stages of pore formation. These findings uncover molecular mechanisms of bacterial pore assembly and advance both crop biotechnology and food security.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Ditches have many overlooked environmental and societal roles, including impact on biodiversity and pollution, and management strategies to enhance their multifunctional landscape-scale benefits are needed, according to a review of physical, biotic, chemical, and human factors.