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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.

In severe autism, deleterious variants at conserved residues are enriched in patients arising from female-enriched multiplex families, enhancing the detection of key autism genes in modest numbers of cases.

Photonic methods can be greatly improved by metal nanoparticles, but biological targets such as cells prevent spatial control of particles, excluding key regions of interest. Here, the authors show laser light can control nanoparticle growth locations in the cell, and probe intracellular molecules.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Ji et al. identify an idiopathic generalised epilepsy network that links heterogeneously distributed brain abnormalities to a common brain network and deep brain stimulation sites which reduce generalised seizures.

Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.

Vanessa Wong and colleagues report whole-genome sequencing of 1,832 Salmonella enterica serovar Typhi isolates from 63 endemic countries. They identify mutations that define the multidrug resistant (MDR) H58 lineage and report numerous inter- and intracontinental transmissions of this lineage as well as an ongoing MDR typhoid epidemic in Africa.

Here the authors identify two zinc/cobalt responsive proteins (ZCRPs) in marine diatoms, determining their functional roles in trace metal transport and homeostasis, as well as their application as an indicator of oceanic Zn stress.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Biocatalytic methods are lacking in current computer-aided synthesis planning tools. Now, RetroBioCat allows computer-aided design of biocatalytic cascades for organic synthesis and synthetic biology. The program was validated using reported cascades and is freely available at retrobiocat.com.

Circulating tumor DNA (ctDNA) may provide a prediction of treatment response, but could be impacted by tumor heterogeneity. Here, the authors investigate ctDNA in CDK4/6 inhibitor treatment in advanced breast cancer, finding ctDNA levels predict progression-free survival and anticipate clonal selection.

An enzyme (AspRedAm) capable of coupling carbonyls with a variety of amines in a reductive amination has now been discovered. Kinetic studies revealed that the enzyme catalysed both the imine formation step, as well as the reduction step. Structure and mutagenesis studies have highlighted essential catalytic residues and preparative scale examples have demonstrated total turnover numbers of up to 32,000.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

The authors determine the synaptic wiring diagram of a vertebrate circuit and reveal behaviorally associated modules. A model based on this connectome predicts neural coding and dynamics that are verified with calcium imaging data.

While CDK4/6 inhibitors (CDK4/6i) have improved outcomes for breast cancer patients, estrogen receptor (ER + ) breast cancers often develop resistance, and triple negative breast cancer (TNBC) show poor sensitivity. Here, the authors identify a vulnerability of CDK4/6i treated ER+ and TNBC on ferroptosis and identify the combination of CDK4/6i and GPX4 inhibition as synergistic.

Biocatalytic methods to access thioesters, such as acyl-coenzyme A, from carboxylic acids are underdeveloped. Now, it is shown that the adenylation domain of a carboxylic acid reductase enzyme can be exploited as a promiscuous thioester synthetase and combination with acyltransferases facilitates the synthesis of amides and peptide labelling.

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.

High-throughput biocatalytic screening and metagenomics have been used to discover over 300 imine reductases (IREDs) and subsequently produce a sequence-diverse panel of IREDs suitable for optimizing the synthesis of chiral amines. Additional characterization identified biocatalysts that accommodate structurally demanding amines and ketones for enzymatic reductive aminations.

The Vertebrate Genome Project has used an optimized pipeline to generate high-quality genome assemblies for sixteen species (representing all major vertebrate classes), which have led to new biological insights.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Building on their previous observation that neuronal calcium spike activity can drive neurotransmitter specification during development, these authors report that cJun phosphorylation integrates activity-dependent and intrinsic transmitter specification through the regulation of tlx3 transcription in Xenopus sensory neurons.

Defects in homologous recombination (HR) are found in some triple negative breast cancers, suggesting they may be sensitive to PARP inhibitors. In this phase II clinical trial of the PARP inhibitor rucaparib, changes in Ki67 levels did not correlate with markers of HR deficiency but HR deficiency was detected in 69% of tumours, indicating that PARP inhibitors may be a useful treatment.

Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.

Smith and colleagues find that a multivariate signature of unresolved inflammation and altered iron homeostasis detected beyond 2 weeks following acute COVID-19 onset was the strongest early differentiator of those who report long COVID symptoms at 3–10 months.

The spike protein of the Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 than Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic and vaccine-elicited neutralizing antibodies.

Efficient statistical emulation of melting land ice under various climate scenarios to 2100 indicates a contribution from melting land ice to sea level increase of at least 13 centimetres sea level equivalent.

Here authors show that machine learning derives the degree of background retinal pigmentation with more nuance than self-described ethnicity. Retinal pigment scores are associated with genes linked to melanin and may improve algorithmic fairness.

Single-nucleus ATAC-seq characterization of chromatin accessibility in human coronary artery disease samples identifies cell-type- and state-specific regulatory mechanisms underlying disease risk, highlighting the roles of TBX2 and PRDM16.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

Navigating the complex structure of the brain poses a challenge to neuroscientists. Here, the authors have trained an AI (DeepSlice) that can automatically register brain images with speed and accuracy, thus simplifying this process.

Mokry et al. performed bulk RNA sequencing of 654 advanced human carotid plaques from the Athero-Express biobank and 162 coronary samples, and they show that unsupervised clustering defines plaque types corresponding to different cell compositions and clinical presentations. Circulating biomarkers can be potentially used to mark the different transcriptomic-defined plaque phenotypes.

The late-stage functionalization of unactivated carbon–hydrogen bonds is a difficult but important task, which has been met with promising but limited success through synthetic organic chemistry. Here the authors use machine learning to engineer WelO5* halogenase variants, which led to regioselective chlorination of inert C–H bonds on a representative polyketide that is a non-natural substrate for the enzyme.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Aardvark Weather, an end-to-end machine learning model, replaces the entire numerical weather prediction pipeline with a machine learning model, by producing accurate global and local forecasts without relying on numerical solvers, revolutionizing weather prediction with improved speed, accuracy and customization capabilities.

A catalogue of the vascular flora of New Guinea indicates that this island is the most floristically diverse in the world, and that 68% of the species identified are endemic to New Guinea.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Catalysts working in pairs can promote more-effective reactions than can the same catalysts used sequentially. The coupling of an enzyme with a light-activated catalyst offers great potential for organic synthesis.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Breast cancer leptomeningeal metastasis is difficult to assess due to the site. Here, the authors assess cerebrospinal fluid cell-free DNA to show specific mutations present in leptomeningeal metastasis, and develop organoids of the disease.

Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.