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Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

Using advanced imaging techniques and computer modelling, the authors were able to create a detailed structural model of a nuclear pore complex from a seed plant.

Cocaine chemogenetics in rats is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine.

A re-assessment of the global carbon budget shows the natural land sink is substantially smaller than previously estimated, indicating emerging impacts of climate change on the evolution of the carbon sinks.

The iron–sulphur enzyme IspH catalyses the final step of the methylerythritol phosphate isoprenoid biosynthesis pathway. Spanet al. report that IspH can hydrate acetylenes to aldehydes and ketones, in addition to its role as a 2H⁺/2e⁻reductase.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Although metabolic reprogramming within the tumour microenvironment (TME) has been reported in breast cancer, whether and how this evolves during treatment remains unclear. Here, the authors use multiple ‘omic’ analyses to examine this question in patients with breast cancer undergoing neoadjuvant chemotherapy.

A transition from carbon sink to source for the aboveground woody biomass of moist tropical Australian forests has occurred, driven by increasingly extreme climate anomalies.

Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Neuropathy leads to sensory loss and increased risk of fall. Here, the authors design a wearable non-invasive neuroprosthesis that restores lost sensations and improves gait.

Loss-of-function variants in thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder. Here the authors identify genotype-phenotype relationships, advance insights in MCT8 (dys)function and create a pathogenicity-severity variant classifier.

The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.

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).

Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Two ‘outrigger’ telescopes were added to CHIME, leading to the localization at detection of FRB 20210603A. The burst originated from deep within the star-forming disk of its host galaxy.

For T cells, functional antigen receptors are selected in the thymus from a pre-selection repertoire by interaction with self MHCs. Here the authors show that specific, non-germline coded features located in the complementarity determining region 3 of the pre-selection antigen receptors are essential for the selection of MHC-restricted repertoire.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

The key to a strong grant application is a well-considered and detailed outline of expenses, says grant director Ingrid Eisenstadter.

Endothelial cells play a critical role in the adaptation of tissues to injury and show a remarkable plasticity. Here the authors show, using single cell sequencing, that endothelial cells acquire a transient mesenchymal state associated with metabolic adaptation after myocardial infarction.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Ing et al. develop a method of establishing direct relationships between psychiatric symptoms and neuroimaging measures of brain structure and function and use it to stratify adolescent psychopathology on the basis of underlying biology. They replicate their results in independent clinical samples.

Start and finish early, seek feedback and file before deadline, says Ingrid Eisenstadter.

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS).  Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.

Robust quantification of carbon dioxide fluxes from land use is critical for guiding climate change mitigation efforts and for improved understanding of the global carbon cycle. This Perspective explores the origins of uncertainties and discrepancies in established estimation approaches and considers strategies to improve, translate and harmonize flux estimates.

Analysis of time-series abundance trends from more than a thousand local populations across Europe reveals a consistent impact of temperature on terrestrial communities, but variable impacts on freshwater and marine realms.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Skyrmions and anti-skyrmions are magnetic textures that have garnered much interest due to their stability. Here, Jena et al demonstrate the existence of fractional spin textures at the edges of Heusler alloy sample, which can have continuous variable topological charges.

UBE2W catalyzes the ubiquitination of protein N-termini but its substrate spectrum is largely unknown. Here, the authors discover mAbs selective for peptides derived from N-terminally ubiquitinated proteins, solve the structure of a peptide-bound mAb and apply the mAbs to map endogenous UBE2W substrates by proteomics.

A large integrated genome and transcriptome analysis of colorectal cancer identifies prognostic mutations and expression subtypes.

Aberrant changes in DNA methylation have been implicated in various neurodevelopmental disorders but remain under studied in developmental and epileptic encephalopathies. Here, the authors demonstrate the diagnostic utility of genome-wide DNA methylation analyses toward identifying molecular etiologies in developmental and epileptic encephalopathies.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

This study identifies distinct genetic-epigenetictranscriptional interplay at the 1q21.1 locus in relation to neuronal deficits in primary progressive multiple sclerosis (PPMS).

The authors here show that two completely different classes of spinal premotor interneurons drive motoneurons during slow and fast swimming of zebrafish larvae. As the fish accelerate, the 'slow' interneurons are progressively silenced, while the 'fast' interneurons take over, and vice versa.

Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.

Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes.

Synapse loss is prominent in the cortex in multiple sclerosis (MS). In a cortical MS model, Jafari et al. show that phagocytes remove synapses by engulfment, which is triggered by local calcium accumulations and prevented by blocking colony-stimulating factor 1 signaling.

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.

Efficient deconvolution of antibody targets is needed for phenotype-based discovery. Here, the authors investigate a deconvolution approach based on pooled CRISPR Cas9 to achieve 97% deconvolution success rate.