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Divergent white matter metabolic patterns reveal a mechanistic basis for cognitive resilience and enhance prediction of future cognitive decline beyond established aging and dementia biomarkers.

Elevated levels of the oxidoreductase NQO1 in tumours are associated with poor prognosis but how this contributes to cancer is poorly understood. Here, the authors find that NQO1 competes with PHD proteins, resulting in the stabilization of the hypoxia induced transcription factor HIF-1α.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

Here, Lopaticki et al. show that Plasmodium falciparum expresses a Dpy19 C-mannosyltransferase in the endoplasmic reticulum that glycosylates TSR domains. Functional characterization shows that PfDpy19 plays a critical role in transmission through mosquitoes as PfDpy19-deficiency abolishes C-glycosylation and destabilizes proteins relevant for gametogenesis and oocyst formation.

Nickel(II) dihalide precatalysts with bidentate nitrogen ligands are widely used in cross-coupling reactions, notably in combination with photosensitizers, forming catalytic systems that currently drive major conceptual and synthetic thrusts within organic chemistry. Here the authors show a general mechanism by which these precatalysts are converted to the reduced, catalytically active species, using a range of characterization and spectroscopic techniques.

A large, open dataset containing parallel recordings from six visual cortical and two thalamic areas of the mouse brain is presented, from which the relative timing of activity in response to visual stimuli and behaviour is used to construct a hierarchy scheme that corresponds to anatomical connectivity data.

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.

Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

National implementation of a computed tomographic angiography and AI-diagnostic tool, CT-derived fractional flow reserve (FFR-CT), did not provide significant benefits in reducing mortality but led to fewer invasive coronary angiograms and downstream cardiac tests.

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.

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).

Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of hypertrophic cardiomyopathy. Here, the authors present an AAV9-based gene therapy system with an optimized expression cassette with minimal promoter and cis-regulatory elements that can ameliorate cardiac functions and prolong survival in a murine MYBPC3-deficient model.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

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.

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.

Development of BRET sensors for nearly all major G proteins show that GPCR–G-protein coupling ranges from promiscuous to extremely specific, Switch III is a novel site for G-protein engineering, and optimal donor–acceptor positioning is non-obvious.

Justin Rubio and colleagues report results of a genome-wide association study of multiple sclerosis using cases from Australia and New Zealand. Their findings confirm several published risk loci for MS and identify two new risk loci on chromosomes 12 and 20.

Singlet fission produces two low-energy triplet excitons that are difficult to dissociate into free charges. Now, separate optima in charge yield have been observed as a function of driving force for singlet and triplet excitons in pentacene. At optimal driving forces, the triplet-exciton dissociation rate is at least five orders of magnitude smaller than the singlet-exciton dissociation rate.

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.

An increase in wildfire extent and related greenhouse gas emissions can be linked to abrupt climatic changes during the last glacial period.

Perivascular and leptomeningeal macrophages, collectively termed here parenchymal border macrophages, are shown to regulate flow dynamics of cerebrospinal fluid, implicating this cell population as new therapeutic targets in neurological diseases such as Alzheimer’s.

Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

The small heat-shock protein HSP27 occurs predominantly in oligomeric forms, which makes its structural characterisation challenging. Here the authors employ CPMG and high-pressure NMR with native mass spectrometry and biophysical assays to show that the active monomeric form of HSP27 is substantially disordered and highly chaperone-active.

The role of O-glycosylation in the malaria life cycle is largely unknown. Here, the authors identify a Plasmodium protein O-fucosyltransferase and show that it is important for normal trafficking of a subset of surface proteins, particularly CSP and TRAP, and efficient infection of mosquito and vertebrate hosts.

Wiita and colleagues use cross-linking mass spectrometry and glycoprotein surface capture to identify an activated conformation of integrin β₂ present on AML cells and develop CAR T cells that target this conformation antigen in preclinical models.

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.

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.

Recent studies revealed that G protein-coupled receptors rapidly interconvert between multiple states. Here, authors use the kappa opioid receptor (KOR) and show how two state-dependent nanobodies provide real-time reporting of ligand stabilized states with KOR and other GPCRs.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

Thermostable enzymes are used for a range of industrial processes, including biofuel production. Berka et al. report the genome sequences of two thermophilic eukaryotic fungi with enzymes that operate at the elevated temperatures needed to digest biomass and prepare many biochemicals.

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.

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.

The predicted rise in CO₂ levels during this century is expected to stimulate crop yields, offsetting losses from greater drought. But this study, using free-air CO₂ enrichment, shows soybean yield gains dropping to zero as drought stress increased.

An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

Building crystal structures into the electron density is an important step in protein structure solution. Here, the authors recruit online game players, students, and experienced crystallographers to compete in a competition to solve a new structure, and find that crowdsourcing model-building works.

The National Cancer Institute (NCI) Genomic Data Commons (GDC) contains more than 2.9 petabytes of genomic and associated clinical data from more than 60 NCI-funded and other contributed cancer genomics research projects. The GDC consists of five applications over a common data model and a common application programming interface.

He et al. develop a network-based metric of amyloid-β burden by integrating individualized brain connectomes with amyloid-PET imaging. This approach improves prediction of future cognitive decline in older adults and may support earlier identification of individuals at risk of dementia.