Search

An approach that tackles the underlying causes of coral-reef decline could be applied to other habitats, argue Tiffany H. Morrison, Terry P. Hughes and colleagues.

TGF-β is a latent complex (L-TGF-β). Latency is conferred by a homodimeric prodomain with a previously undefined domain architecture. Here we define the architecture of the prodomain as domain-swapped providing structural insights into the mechanism of activation of L-TGF-β.

Wang, Tang and colleagues develop the low-signal signed iterative random forest pipeline to investigate epistasis in the genetic control of cardiac hypertrophy, identifying epistatic variants near CCDC141, IGF1R, TTN and TNKS loci, and show that hypertrophy in induced pluripotent stem cell-derived cardiomyocytes is nonadditively influenced by interactions among CCDC141, TTN and IGF1R.

Oceans are on the front line of new planned climate actions, but understanding of novel marine-climate intervention development and deployment remains low. Here a survey among intervention practitioners allows identification of science and governance gaps for marine-climate interventions.

Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a truth set to understand the most fundamental processes underlying human genetic variation.

Engagement of T cell receptors (TCRs) induces the formation of microclusters that mediate the downstream signalling events. Here the authors show, using high resolution TIRF-SIM and live cell imaging, that ZAP70 and LAT are recruited to TCR with distinct kinetics, with the delayed ZAP70-TCR association modulated by TCR-induced calcium flux.

Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.

In Drosophila and mouse models of cancer cachexia, Liu et al. show that tumour-derived cytokines induce hepatic gluconeogenesis, which in turn leads to dysregulation of metabolism and drives cancer cachexia.

Howard Chang and colleagues identify a long noncoding RNA, DINO, that is transcribed upstream of CDKN1A and induced by p53 in response to DNA damage. They show that DINO binds to p53 protein and promotes its stabilization, producing a feedback loop that amplifies DNA damage signaling.

Controversy exists over the function of plasma membrane versus intracellular vesicular LAT in T-cell receptor signaling. Here the authors use high resolution imaging of the temporal dynamics of LAT involvement to show that both sources of LAT are required, but at distinct stages.

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.

Tumor–normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking ‘tumor-only’ or ‘matched tumor–normal’ analyses.

An optogenetic tool called Opto-OGT has been developed that enables researchers to probe pathways involving modifications with O-linked β-N-acetylglucosamine (O-GlcNAc) such as OGT, mTOR and AMPK signaling with high spatiotemporal precision. The method is based on fusing a photosensitive cryptochrome protein to an O-GlcNAc transferase and enables OGT to be reversibly activated with blue light.

Oceans are on the frontline of an array of new marine–climate actions that are both poorly understood and under-regulated. Development and deployment of these interventions is outpacing governance readiness to address risks and ensure responsible transformation and effective action.

The metabolic regulator protein family, mTOR, regulate natural killer (NK) cell development and function, but the underlying mechanism is unclear. Here, the authors show that Raptor/mTORC1 and Rictor/mTORC2 form a feedback crosstalk network to variegate cytokine and cellular signaling and modulate NK maturation and effector functions.

Distinct macrophage phenotypes are associated with their polarization to a proinflammatory or alternative state, but it is not well understood how metabolic status affects this process. Here, Byles et al.demonstrate that the mTOR metabolic pathway regulates macrophage differentiation.

Metabolically-mature human islet-like organoids generated from induced pluripotent stem cells are able to recapitulate insulin-responsive pancreatic islet function and avoid immunologic cell death in diabetic mouse transplantation models.

Single-cell chromatin profiling of different brain regions identifies cell-type-specific regulatory elements, and helps to predict functional SNPs for Alzheimer’s and Parkinson’s diseases.

Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Distinct clusters of inhibitory neurons in the mouse amygdala perform opposing roles in fear extinction.

By manipulating the rhythmicity of neural activity in entorhinal cortex and hippocampus, Quirk et al. show that memory is impaired by aberrant oscillatory activity during the encoding phase, but not during retention or retrieval phases.

Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

Richard Lifton and colleagues report a genomic analysis of cutaneous T cell lymphoma (CTCL). Their results implicate several pathways in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response.

The Rbfox family of developmentally important splicing factors controls alternative splicing in a tissue-specific manner. Genome-wide analyses now show that more than half of Rbfox-binding sites are located distally from exons, that these distal sites are conserved and functionally important, and that long-range RNA-RNA secondary structures mediate distal splicing regulation by Rbfox.

Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, developmental delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.

David Wong, Howard Chang and colleagues report the identification of long noncoding RNAs transcribed from the promoters of cell cycle genes. Many of these RNAs have periodic expression during the cell cycle and are regulated by oncogenic stimuli, stem cell differentiation or DNA damage.

In this study, the authors identify a population of deep dorsal horn interneurons that receive inputs from both sensory neurons and the descending motor tracts and that can evoke activity from functionally related motor pools. These cells may represent the central node for coordinating motor output programs in the spinal cord.

Grady, Bhattacharjee and Silva et al. examine the effects of COVID-19 vaccination on 16 vaccine-naive individuals with Long COVID, finding that 10 reported improvements, 3 had no change, and 3 experienced worse overall health post-vaccination. Specific immune signatures correlate with these health changes following vaccination.

The regulation of gene expression at the level of transcription is important for controlling inflammatory responses. Here, the authors describe the key factors and molecular mechanisms involved in this regulation in macrophages and explain how these factors and mechanisms mediate the distinct but coordinated regulation of the different components of the inflammatory response.

Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Here, the authors show that inhibition of PMIF may have translational benefits for managing malaria infections.

Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate T_H9 homeostasis and antitumour immunity.

Oncogenic Nras in mouse haematopoietic stem cells can increase the probability of cell division in some cells and decrease it in others; this bimodal activity explains how this single pre-leukaemic mutation can increase proliferation without reducing competitiveness by clonally expanding the rapidly dividing cell population and also promoting long-term self-renewal of stem cells.

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.

In this Perspective, the authors argue that radical, rather than conventional, interventions are necessary to address climate change. They discuss the definitions and interpretations of the term ‘radical’, and present a typology of radical intervention that addresses the root drivers of climate change.

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome. Here it is shown that lincRNAs in the HOX genetic loci are dysregulated during breast cancer progression in human cells, and that expression levels of the lincRNA called HOTAIR can predict whether a tumour will metastasize. Moreover, enforced expression of HOTAIR can lead to altered patterns of binding of the PRC2 protein to the genome.

Interaction between international organizations and national governments over 238 World Heritage ecosystems shows patterns of productive and counterproductive dynamics, which yield lessons to improve environmental governance.