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Analysis of over 6000 single-site variants of SARS-CoV-2 Papain-Like protease uncovers critical mutations involved in enzymatic function and highlight the potential for drug-escape.

TMEM127 is a tumor suppressor protein, loss of which predisposes to catecholamine-secreting tumors. Here the authors show that TMEM127 expression is modulated by nutritional status and that it has a role in regulating organismal insulin sensitivity.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

TDP-43 controls an exon splicing event in UNC13A that results in the inclusion of a cryptic exon associated with frontotemporal dementia and amyotrophic lateral sclerosis.

The solved crystal structure of the GLP-1 receptor bound to a truncated agonist enables the design of synthetic agonists that exhibit potent activity in vivo.

Variant detection in problematic genes is facilitated with a curated benchmark.

Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.

Exposure to irreparable stresses induces transient ciliogenesis, enabling communication with PML-NBs via a FBF1 pathway to trigger senescence in mammalian cells. Fbf1 ablation reduces senescence and associated health decline in mice, highlighting cilia as a promising senotherapy target.

In this study, the authors report the small molecule inhibitor EDP-235 as a potent inhibitor of SARS-CoV-2 and show that it is effective against a range of variants and other coronaviruses and that it suppresses virus replication, reduces lung damage, and prevents transmission in small animal models.

The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

The nervous system utilizes adaptive strategies to mitigate trauma-induced neurodegeneration. Here, the authors report that a MAPK phosphatase VHP-1 is induced by trauma and regulates transcriptional responses to mechanical stress in a C. elegans model.

Spintronic nano-neurons and synapses can be connected by radiofrequency signals into neural networks that are capable of classifying real-world radiofrequency inputs without digitization at high speed and with low energy costs—an important step for artificial intelligence at the edge.

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.

Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.

Mg-protoporphyrin IX monomethyl ester cyclase catalyses the formation of the isocyclic ring in the synthesis of chlorophyll. Kinetic analyses and mass spectrometry identified intermediates in the reaction.

The integrator complex is required for the synthesis of protein coding and non-coding RNA and contains the protein INTS13. Here, the authors find germline mutations in INTS13 in two families with oral facial digital syndrome and show that the mutation affects the c-terminal domain of the protein and disrupts cilliogenesis.

The relationships that control seed production in trees are key to understand evolutionary pressures that have shaped forests. A global synthesis of fecundity data reveals that while seed production is not constrained by a strict size-number trade-off, it is influenced by taxonomy and nutrient allocation.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

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.

A systematic analysis reveals that acidic or phosphorylated residues upstream of the PDZ-binding motif contribute to efficient recognition of cargos by the SNX27 PDZ domain, thus leading to the identification of hundreds of potential new SNX27 ligands.

Distinct seasonality of export pathways from the different pumps in the Pacific Southern Ocean are revealed using year-round robotic profiler observations, contributing to understanding of particle export into the oceans’ interior.

Pallett et al. report that myeloid derived suppressor cells expand, home to the liver, and inhibit T cell-mediated liver damage in chronic hepatitis B virus infection.

Chinnaiyan and colleagues perform a high-throughput compound screen and identify PIKfyve inhibition as a therapeutic strategy to enhance immune checkpoint blockade responses in advanced prostate cancer.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

A comparative analysis of community metabolomics and herbivore-induced damage in tropical, subtropical and subalpine tree communities shows that both phytochemical diversity and herbivory were higher in tropical communities, providing support to the latitudinal biotic interactions hypothesis.

Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.

Mice possess neurons in the preoptic area of the hypothalamus that are sensitive to violet light; these deep brain neurons sense light via OPN5 and regulate adaptive thermogenesis in brown fat.

To better understand the impacts of marine heatwaves in coastal ecosystems, this study examined the responses of habitat-forming species (macroalgae, seagrass, and corals) to heatwave events in 1322 areas across 85 marine ecoregions. The results suggest marine heatwaves play a key role in the decline of habitat-forming species globally, although some areas exhibit a level of resilience.

Physical analysis of processes universal to raised peatlands produces an equation that explains their morphology and carbon storage across biomes, from Alaska to New Zealand.

The p97 unfoldase is an essential and abundant enzyme that segregates its substrates from macromolecular complexes and organelle membranes. Here, authors determined the structure of human p97 in the act of unfolding an authentic substrate.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

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.

Human populations in the southern Africa interior were collecting non-utilitarian objects at around 105,000 years ago, suggesting that the development of this innovative behaviour did not depend on exploiting coastal resources.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

A new method to quantify three masting components from individual tree-years has revealed that globally, masting is uncommon in tree species that depend on mutualist dispersers, with its distribution further mediated by climate and nutrient availability.

Plant biodiversity often has a positive influence on ecosystem functioning. Here Jinget al. show that belowground diversity can also significantly impact ecosystem multifunctionality, but its relative effect varies by regional-scale climate variation.

The insertion of magnesium into protoporphyrin starts the biosynthesis of chlorophyll. X-ray crystallography, computational modelling, mutagenesis and enzymology combined probe the magnesium chelatase complex’s structure and catalytic function.

Whole genome sequences enable discovery of rare variants which may help to explain the heritability of common diseases. Here the authors find that ultra-rare variants explain ~50% of coronary artery disease (CAD) heritability and highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Phase-resolved mid-infrared observations from JWST of the hot gas giant WASP-43b detect a day–night difference of 659 ± 19 K. Comparison with climate models shows that the observations are compatible with cloudy skies, at least on the nightside, and the lack of methane detection suggests the presence of disequilibrium chemistry.

The microbes responsible for releasing the potent greenhouse gas methane from thawing permafrost remain largely unknown. Mondav and Woodcroft et al. investigate methane flux across a thaw gradient in Sweden and recover a near-complete genome of the dominant methanogen Candidatus ‘Methanoflorens stordalenmirensis’.

The gut microbiota can alter the effects of anticancer fluoropyrimidines such as 5-fluorodeoxyuridine (FUdR) in the model organism C. elegans. Here, the authors show that these effects are further affected by diet, and dietary thymidine and serine increase FUdR toxicity in C. elegans via different mechanisms.

An atomistic structure of a toxic pre-fibrillar α-Synuclein intermediate is presented, highlighting structural changes that drive amyloid fibril formation.

The chronology and mode of parallel evolution remain unclear. Here, the authors compare mid-Holocene and contemporary bottlenose dolphin adaptations between pelagic and coastal ecosystems with paleogenomics, finding rapid adaptation to newly emerged habitat from standing genetic variation.