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Asymmetric cyanosilyation is a powerful method to convert carbonyls to chiral, configurationally stable cyanohydrins. Here, the authors report a catalyst capable of carrying out this reaction on large scales with extremely low catalyst loading, and also identify and explain a dormant period in the cycle.

Dietary interventions have been proposed as potential therapeutic strategies in cancer. Here, the authors report a feasibility randomized clinical trial comparing standard diet with a very lowcarbohydrate ketogenic diet (VLCD) in treatment-naive women with endometrial cancer and obesity or overweight.

The metabolite αKG promotes carnitine synthesis and increases site-specific histone acetylation, thereby promoting homologous recombination-mediated DNA repair, which has potential implications for chemoresistant cancers.

Two-dimensional transition metal carbides and nitrides, known as MXenes, are currently considered as energy storage materials. A generic Lewis acidic etching route for preparing high-rate negative-electrode MXenes with enhanced electrochemical performance in non-aqueous electrolyte is now proposed.

Here, in a large-scale study of over 900 companion dogs, the authors examine how the gut microbiome varies as dogs age, identifying consistent microbial shifts associated with age, as well as associations with diet, behavior, and health.

Utilizing the electrophilicity of ambiphilic silyl nitronates in asymmetric synthesis has remained elusive. Now, silylium-based Lewis acids are used for their activation, achieving the catalytic asymmetric nucleophilic addition of silyl ketene acetals to silyl nitronates for the synthesis of β³-amino acids.

Post-translational site-selective formation of boronoalanine in proteins enables applications of boron for binding partner capture, footprinting of interactions with reactive oxygen species, proteolytic control and mapping of transient structures.

This study describes a novel mechanism of calcium control of metabolism found in the mitochondrial intermembrane space that is entirely independent of matrix Ca²⁺ uptake.

This study found COVID-19 vaccination offers added protection against reinfection in children and adolescents with prior infection but variable effectiveness across variants. Findings support vaccination benefits beyond infection-acquired immunity.

Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.

INSTALL overcomes fundamental challenges for DNA delivery and integration methods by synergizing immune-stealth nucleic acids with recombinases to enable kilobase-scale integration strategies without viral vectors.

Catalytic asymmetric synthesis of stable, acyclic N-stereogenic amines by the addition of enol silanes to nitronium ions that ion pair to a confined chiral anion is described.

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.

Element-element bonded multiply charged cationic species are well known as dimers or small cyclic oligomers in the condensed phase but the smallest acyclic version, a trinuclear unit possessing greater than a monocationic charge, has remained elusive. Here the authors report a bis(phosphine) supported low valent triantimony-based tricationic compound.

Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

An effective CRISPR RNA occlusion strategy enhances mismatch detection when using Cas13.

An unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses the selective conversion of neral to (1R,6S)-trans-isopiperitenol, enabling sustainable routes to menthol and cannabinoids.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Magrinelli et al. link biallelic PSMF1 variants to phenotypes from parkinsonism to perinatal lethality, implicating proteasomal and mitochondrial dysfunction. PI31 loss in fly and mouse models causes age-dependent motor deficits and neurodegeneration.

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).

Increased effectiveness of anti-cancer chimeric antigen receptor T cell therapy is associated with a stem-like phenotype through increased expression of FOXO1.

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.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The authors present a deep learning approach to uncover complex genetic effects on circulating protein levels. They reveal new interactions and dominance patterns using UK Biobank proteomics data.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

In vivo regulation of neuronal lipid droplet formation mediates whole-body energy homeostasis in a sex-specific manner in Drosophila and mice.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Here the authors analyse genetic data for over 400,000 British and Irish people, showing that the frequency of the major genetic risk factor for haemochromatosis varies from a low of 1/212 in Southern England to 1/62-1/54 in Outer Hebrideans and Northwest Irish. Clinically diagnosed haemochromatosis varies 11- fold in frequency across England, emphasising the uneven risk landscape.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Carta leverages lineage tracing data to infer the optimal trajectory of cell differentiation.

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.

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 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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.