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Here the authors analyze data from COVAIL trial participants receiving an mRNA second COVID-19 vaccine boost and show that, while neutralizing antibody titer is correlated with Omicron COVID-19 risk, the correlation is weak in naïve individuals compared to previously infected ones.

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Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks. Here, the authors present the cryo-EM structure and mechanism of action of NrdR, the RNR-specific repressor, that controls transcription of RNR genes in bacteria.

During senescence, minority mitochondrial outer membrane permeabilization leads to the release of mtDNA into the cytosol through BAX and BAK macropores, in turn activating the cGAS–STING pathway, a major regulator of the senescence-associated secretory phenotype.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Designing efficient, fast and low power consumption phase change memories remains a challenge. Aryana et al. propose a strategy to reduce operating currents by manipulating the interfacial thermal resistance between the phase change unit and the electrodes without incorporating additional insulating layers.

The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.

Through fluid-injection fault-reactivation experiments and analysis, the authors here define and report the relationship between the maximum seismic magnitude and injection volume for fluid-injection triggered earthquakes.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Quantitative systems toxicology (QST) models have the potential to increase confidence in the safety assessment of drug candidates and to inform project progression decisions. This article overviews the fundamentals of constructing and using QST models, presents the state-of-the-art for models of cardiovascular, gastrointestinal, hepatic and renal toxicities, and it provides recommendations for their application in drug discovery and development.

An exciting genome-wide association study in the British population for seven common diseases. This analysis confirms previously identified loci and provides strong evidence for many novel disease susceptibility loci.

A method called neutron-encoding SILAC will enable higher-order multiplexing with high accuracy in quantitative proteomics experiments.

Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

Here, using cryogenic electron microscopy and cryoDRGN, the authors delineate how the anaphase-promoting complex/cyclosome is reconfigurated to interact with its cognate E2s and thus polyubiquitinate its target. Unexpectedly, multiple ubiquitin moieties are shown to interact with the anaphase-promoting complex/cyclosome machinery, including its activator Cdh1.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The authors propose Detect, a browser-based anomaly detection framework for diffusion magnetic resonance imaging tractometry data. The tool leverages normative microstructural brain features derived from healthy participants using deep autoencoders to detect anomalies at the individual level.

Phase separation is being revealed as important in many biological processes. Most attempts to mimic and deconstruct this use engineered natural proteins. Now it is shown that de novo proteins can be designed from first principles to undergo liquid–liquid phase separation in cells, with the potential to organize multi-enzyme pathways.

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.

Double Asteroid Redirection Test (DART) mission impact on asteroid Dimophos resulted in an elliptical ejecta plume. Here, the authors show that this elliptical ejecta is due to the curvature of the asteroid and makes kinetic momentum transfer less efficient.

An efficient computational pipeline starting from validated peptide assemblies has been used to design two families of α-helical barrel proteins with functionalizable channels. This rationally seeded computational protein design approach delivers soluble, monomeric proteins that match the design targets accurately and with high success rates.

An individual tumour is often heterogeneous and its various features can be visualised noninvasively using medical imaging. Here, the authors analyse large computed tomography data sets using radiomic algorithms to identify heterogeneity, and find that some of these tumour features have prognostic value across cancer types.

Girls are tenfold more likely than boys to require surgical treatment for idiopathic scoliosis, a common paediatric skeletal disorder. Here, Sharma et al. identify the first sexually dimorphic idiopathic scoliosis risk locus, and demonstrate that it may play a role in the regulation of spinal cells.

Rivers are the dominant source of many elements and isotopes in the ocean, but the fluxes vary with time. Derek Vance and colleagues suggest that the pulse of rapid chemical weathering initiated at the last deglaciation has not yet decayed away, and that weathering rates remain about two to three times the average for an entire late Quaternary glacial cycle. Consideration of such variability largely ameliorates long-standing problems with chemical and isotopic mass balances in the ocean.

GS-9209 is spectroscopically confirmed as a massive quiescent galaxy at a redshift of 4.658, showing that massive galaxy formation and quenching were already well underway within the first billion years of cosmic history.

Analyses of single-cell whole-genome sequencing data show that somatic mutations are increased in the brain of individuals with Alzheimer’s disease compared to neurotypical individuals, with a pattern of genomic damage distinct from that of normal ageing.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Typhoid fever is caused by Salmonella enterica serovar Typhi (S. Typhi). This study examines ∼2,000 clinical isolates of S. Typhi to show highly structured/geographically restricted genomes except rapidly disseminating H58 subclade, and design a genotyping framework for tracking the disease.

Abbasi et al. evaluate the value of source data verification, a costly but traditional element of clinical trials. They find it is largely redundant when used with a systematic strategy to promote efficient and accurate data capture, monitoring, and safety in a phase II platform trial.

Trial Registration: https://clinicaltrials.gov/study/NCT04488081

Human brain structure changes throughout the lifespan. Brouwer et al. identified genetic variants that affect rates of brain growth and atrophy. The genes are linked to early brain development and neurodegeneration and suggest involvement of metabolic processes.

Wound healing involves a transient regeneration of tissue, but, if this process continues unabated, pathology occurs in the form of fibrosis, which can prevent normal organ function and even death. Derek Mann and his colleagues have found that serotonin-responsive profibrogenic hepatic stellate cells inhibit the growth of neighboring liver cells during the termination phase of liver injury. They also found that inhibiting serotonin signaling during established disease improved liver fibrosis in various mouse models of liver injury.

Toghani, Gupte et al. identify semaphorin 4A as a cell-extrinsic factor that protects myeloid-biased hematopoietic stem cells from inflammaging, mainly produced by their progeny—neutrophils—and acting via a negative feedback loop.

A new specific, small-molecule activator of the PI3Kα isoform (UCL-TRO-1938) identified through high-throughput screening can transiently activate PI3K signalling and biological responses in cells and tissues, with potential therapeutic applications in tissue protection and regeneration.

Improved biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE) are needed. Here, the authors show that Complement Factor H Related 5 protein, a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker in 5 independent cohorts.

By incorporating germanium, single-photon avalanche diode detectors using silicon-based platforms are applied to infrared light detection. Here, a cost-effective planar detector geometry is presented yielding high detection efficiency suitable for applications such as sparse photon imaging or LIDAR.

Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.

To overcome limitations of previous genome-wide association studies of coronary artery disease, this study incorporates a cohort of individuals containing large fractions of Black and Hispanic individuals to provide a wider view of the genetic landscape of this disease.

Klunk and colleagues identify signatures of natural selection imposed by Yersinia pestis and demonstrate their effect on genetic diversity and susceptibility to certain diseases in the present day.

Studies of humans, mice and nematodes reveal a conserved role of neural activity and the transcription factor REST in extended longevity.

Zekavat, Matesanz, Viana-Huete et al. show an increased risk of peripheral artery disease and atherosclerosis in different vascular beds in patients with clonal hematopoiesis of indeterminate potential (CHIP) caused by mutations in DNA damage repair genes, such as TP53. Validations in a mouse model support the causal contribution of TP53-mutant CHIP to atherosclerosis.

Common polygenic variation at chromosome 16p and rare recurrent deletions of 16p11.2 influencing autism risk are associated with reduced expression of genes throughout the 16p region, suggesting functional convergence of rare and common variant effects.

Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.

New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.