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Z. Liu, Y. Liu and Z. Yu et al. discovered a subtype of valve interstitial cells underneath the valve endothelial cells sensing unidirectional flow. These cells express high levels of APOE, which is responsible for JAG1–NOTCH2-mediated fetal elastogenesis.

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

Beck et al. conducted single-cell and spatial profiling of embryonal tumors with multilayered rosettes, finding that malignant cellular hierarchies are driven by developmental programs and specific members of the chromosome 19 microRNA cluster.

Human and natural systems are inextricably intertwined, co-evolving systems. The study presents a new conservation framework incorporating the different roles people can play in ecosystem health, through land stewardship.

Cancer cells that have undergone whole-genome doubling are more reliant than their near-diploid counterparts on DNA-replication factors, the spindle-assembly checkpoint and a mitotic kinesin protein, KIF18A.

Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (mHtt) protein. Here the authors suggest that mHtt promotes ribosome stalling and inhibits protein synthesis.

The functional relevance of epigenetic modifications on transcription regulation has been an important question since their discovery. Here, the authors investigate the effect of DNA methylation on Pioneer Transcription Factor (PF) binding and distinguish between PFs that protect their binding sites from methylation and those that bind to methylated DNA and induce DNA demethylation.

Exhausted CD8⁺ T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

MxB is an interferon-induced GTPase that inhibits HIV replication. Here, Crameri et al. show that MxB restricts replication of herpesviruses by inhibiting delivery of incoming viral DNA into the nucleus, and this antiviral activity depends on MxB’s GTPase activity.

Asymmetrical cell division helps to maintain cellular heterogeneity in the T cell compartment. Here the authors examine the differential immune responses built by naive and virtual memory T cells from young and aged individuals, and explore the effect of mTOR inhibition on asymmetrical cell division and memory formation.

Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.

Quiescent CD4 T cells in lymphoid tissues are shown to die after HIV-1 infection by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death; caspase 1 inhibitors, which are safe for human use, can rescue the cell death in vitro raising the possibility of new therapeutics targeting the host instead of the virus.

Voltage-driven and enzyme-regulated control allows precise ratcheting of a DNA strand in and out of a nanopore.

The molecular mechanisms regulating remyelination are unclear. Here, the authors show that promoting deacetylation of eEF1A1 prevents the translocation of Sox10 outside the nucleus, contributing to maintaining the expression of Sox10 target genes and increasing remyelination efficiency.

Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.

In mice, persistent activation of mitochondrial cannabinoid receptors in astroglia impairs cellular glucose metabolism and lactate production, leading to an increase in redox stress in neurons and altered behavioural responses.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

PPAR-δ activity is impaired by mutant huntingtin, and a PPAR-δ agonist attenuates disease in a mouse model of Huntington's disease.

A large proportion of basal cell carcinomas develop resistance independently of the canonical mutations in genes encoding hedgehog pathway components. An unbiased analysis investigating alternative pathways of resistance uncovers the role of cytoskeletal signaling in driving noncanonical activation of hedgehog signaling through nuclear translocation of SRF and MKL1. These results advance understanding of the mechanisms underlying drug resistance and provide new actionable insights for clinical translation.

Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion.

Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.

Here the authors identify GPATCH11 variants responsible for retinal dystrophy with neurological impairment and facial dysmorphy. They explore its function using a mouse model and demonstrate GPATCH11’s involvement in RNA regulation and splicing.

Miz1 is a binding partner of the transcription factor c-Myc and a regulator of cell cycle progression. Wolf et al. show that inactivation of Miz1 in the mouse central nervous system results in neurodegeneration, and find that Miz1 is essential for the transcriptional regulation of autophagic flux.

Beta-arrestins have key roles in development and metabolic functions as euglycaemic control and insulin sentitivity. Here Zhuet al. show that beta-arrestin-2 regulates insulin secretion and glucose tolerance in mice by promoting CAMKII functions in beta cells.

Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.

Mechanical and electrical activity in the heart is propagated through unique cardiomyocyte membrane structures, the intercalated discs (ID). Sharma et al.identify a novel ID protein, Tmem65, that controls Ca2+ signalling and electrical coupling by interacting with and functionally regulating the gap junction protein Cx43.

Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.

AUF1 is an RNA-binding protein believed to function mostly by regulating the decay of its target transcripts. Here, Yoon et al.systematically identify the targets of AUF1 and provide insights into how AUF1 functions to regulate various cellular processes by enhancing the decay, stability or translation of specific RNAs.

Competition for glutamine between type-1 conventional dendritic cells and tumour cells has a central role in tuning the anti-tumour immune response and in immune evasion by cancer cells.

ASCC3 is a multi-functional helicase that contains two consecutive Ski2-like helicase units. Here, the authors show that ASCC3 can unwind DNA by threading one strand of a substrate duplex through both helicase units, supported by the TRIP4 protein.

VDAC2 deficiency elicits uncontrolled IFNγ-induced BAK activation and mitochondrial damage for improved cancer therapy.

B cells are thought to divide asymmetrically to generate distinct lineages required for adaptive immunity. Hawkins et al. find that surprisingly, mice lacking components of a complex required for asymmetric cell division display normal responses to vaccination and viral infection.

Single-cell transcriptomics and protein expression analyses of salivary glands and gingiva, along with the detection of infectious virus and virus-specific antibodies in saliva from SARS-CoV-2-infected individuals, support a potential role for the oral cavity in COVID-19 pathogenesis.

Human activities affect marine predators in complex ways, yet we lack spatial understanding of cumulative impacts across key habitats. Here the authors analyse distribution and movements of eight marine predators, and find that species and human impacts vary across space and overlap within marine sanctuaries.

Blood supply to the heart is crucial for cardiac function. Here, the authors show that the mitochondrial tryptophanyl-tRNA synthetase, WARS2, drives blood vessel generation in zebrafish and rats and that inhibition of Wars2 diminishes blood vessel growth both within and outside in the heart, suggesting a new target for manipulating angiogenesis.

A comprehensive analysis of the cell-specific molecular regulatory mechanisms underlying post-traumatic stress disorder in the human prefrontal cortex.

Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.

Here, the authors reveal using single-cell RNA sequencing that Parkinson’s disease (PD) patient-derived neuronal cells show altered primary cilia morphology and signaling suggesting cilia dysfunction may underlie PD pathogenesis.

Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

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.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

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.

Selective neurodegeneration is a critical causal factor in Alzheimer’s disease. Zalocusky et al. demonstrate a causal chain linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

Müller-Tidow and colleagues demonstrate that hotspot DNMT3A mutations found in clonal hematopoiesis and acute myeloid leukemia render cancer cells sensitive to the DNMT1 inhibitor azacitidine through focal DNA demethylation, viral mimicry and interferon activation.

Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.

Arabidopsis plants can produce 4-hydroxyindole-3-carbonitrile (4OH-ICN) upon pathogen infection. Here, the authors show that EPCOT3, a retrotransposonderived enhancer, mediates WRKY33-binding, pathogen-responsive transcription of CYP82C2, and synthesis of 4OH-ICN.