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Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

The CMS Collaboration reports the study of three simultaneous hard interactions between quarks and gluons in proton–proton collisions. This manifests through the concurrent production of three J/ψ mesons, which consist of a charm-quark–antiquark pair.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

The nuclear envelope tethers chromatin to the nuclear periphery to control genome architecture. Here, the authors show that Net39 preserves the integrity and gene expression of muscle nuclei in mice, and it may contribute to the pathogenesis of Emery–Dreifuss muscular dystrophy.

Here, single nucleotide variants within the LMO1 locus are shown to be associated with inherited susceptibility to neuroblastoma, a childhood cancer of the sympathetic nervous system. Acquired structural variation in the same locus was also frequently found in neuroblastoma patients, leading to the suggestion that loci identified through genome-wide association studies might be also prone to somatic alterations and therefore identify potential therapy targets and/or biomarkers of tumour aggressiveness.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Understanding and controlling the rheology of polymeric complex fluids is of fundamental importance in both industry and biology. Here, Michieletto et al. show how to achieve time-dependent rheology of DNA solutions via enzymatically-driven architectural alterations by restriction endonucleases.

The mechanisms underlying the emergence of novel morphological traits are largely unknown. Here, the authors show that cis-regulatory changes controlling the expression of the fhl2bpigmentation gene are associated with the evolution of egg-spots colour markings in the male fins of a group of cichlids.

It is unclear whether providing the results of abdominal aortic calcification imaging to patients improves diet parameters. This randomized trial shows that this intervention does not lead to improvements in fruit and vegetable intake, while showing an effect on some cardiovascular disease risk factors used as secondary outcomes.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Long-range looping of an enhancer to a promoter (E-P looping) is a key feature of gene activation; thus, regulation of E-P looping could serve as an effective strategy to precisely control gene expression. Here the authors propose the Drosophila chromatin insulator antagonist Shep represses expression of genes during neuronal maturation by preventing E-P looping.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

An assessment of variations in phytoplankton nutrient limitation in the tropical Pacific over the past two decades finds that phytoplankton iron limitation is more stable in response to ENSO dynamics than models predict.

Quach and Farrell et al. report single-cell transcriptomic analysis of over 150,000 cell from 19 human fetal lung tissues and describe the temporal and spatial dynamics of epithelial lineage development. These epithelial lineage trajectories were further identified in human pluripotent stem cell-based models of lung cell differentiation.

The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments. Here the authors report on the production of the ergot (fungus)-derived therapeutic precursor, D-lysergic acid (DLA), in baker’s yeast.

Structural analysis and spectroscopy elucidate how pairs of electrons are bifurcated in a flavoenzyme by generating an unstable flavin semiquinone, thus coupling exergonic and endergonic oxidation–reduction reactions.

Moro et al. discover an Argonaute 2 (Ago2)-dependent miRNA network that, in response to substrate stiffness, regulates genes involved in tissue mechanics, and show that Ago2 restrains stiffness and contributes to regeneration in the zebrafish fin fold.

The metabolic enzyme GAPDH exhibits oxidative inactivation in response to H₂O₂. A proton relay system was identified that enhances H₂O₂ sensitivity of GAPDH distinct from its catalytic activity, which ensures viability under oxidative stress.

Structural analysis of the human choline and ethanolamine transporters FLVCR1 and FLVCR2 clarifies the mechanisms of transport, the conformational dynamics of these proteins and the disease-associated mutations that interfere with these processes.

Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.

Cell shape provides a structural signature for the classification and investigation of the jamming of bronchial epithelial layers in asthma.

The degree of irreversibility of a dynamical system is commonly characterized by the total rate of entropy production. Seara et al. introduce a measure that quantifies irreversibility from data in broad classes of spatiotemporal non-equilibrium systems.

The oncogenic activation of TLX transcription factors demarcates a specific molecular subtype of T cell acute lymphoblastic leukemia (T-ALL). This study identifies aneuploidy induction as a molecular mechanism by which TLX1 transforms T cell progenitors and reveals new TLX1 transcriptional targets, including Bcl11b, a crucial factor in T cell progenitor differentiation and survival, and Chek1, a mitotic checkpoint regulator. The findings delineate the role of TLX1 in T-ALL initiation and maintenance.

Large sequences are integrated site specifically into the human genome without double-strand DNA cleavage.

Maps of protein-protein interactions (PPIs) help identify new components of pathways, complexes, and processes. In this work, state-of-the-art methods are used to identify binary Drosophila PPIs, generating broadly useful physical and data resources.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.

Distinct signatures of the airway microbiota associate with acute respiratory distress syndrome, hospital-acquired pneumonia and prolonged mechanical ventilation, and may help to inform clinical outcomes in critically ill patients.

The heart arises from distinct progenitor cells of both the first and second heart fields (FHF and SHF). Here, the authors generated precardiac organoids from mouse and human pluripotent cells and show that FHF and SHF cells form similarly to their in vivo counterparts in response to BMP and Wnt signalling, respectively.

Measurements of the inelastic cross section of anti-³He allow the estimation of the transparency of the Milky Way to the propagation of these light antinuclei produced in either cosmic-ray collisions or annihilation of dark-matter particles.

Studies of the confinement of filamentous hydrogels such as fibrin, a major component of blood clots, can shed light on the resistance of strained occlusive clots to lysis with therapeutic agents. Here, the authors show the mechanism of the response of fibrous hydrogels to confinement.

The molecular circuitry that drives dendrite formation during osteocytogenesis remains poorly understood. Here the authors show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites.

Several models have been proposed to explain the emergence of sex chromosomes. Here, through comparative genomics and mutant analysis, Harkess et al. show that linked but separate genes on the Y chromosome are responsible for sex determination in Asparagus, supporting a two-gene model for sex chromosome evolution.

Iron homoeostasis is tightly orchestrated to avoid toxic iron overload. Here Lim and colleagues show that iron excess activates Nrf2 via mitochondrial reactive oxygen species, enhancing the expression of Bmp6 in liver sinusoidal endothelial cells, which in turn promotes hepcidin expression by hepatocytes, decreasing systemic iron levels.

Climate feedbacks associated with wetland methane emissions and permafrost-thaw carbon release substantially reduce available carbon budgets to achieve temperature targets, suggest simulations with a climate–land-surface model system.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Biobased furans are important chemical building blocks for the development of materials, but selective, efficient, and cost-effective scalable conversion of biobased furans remains elusive. Here, the authors report a transaminase from Shimia marina (SMTA) that enables the scalable amination of biobased furanaldehydes with high activity and broad substrate specificity and provide structural and mechanistic insights into SMTA activity.

FGFR-1 upregulation has been associated with endocrine therapy resistance in breast cancer patients. Here the authors report the results of a phase IIa study to assess the safety and efficacy of AZD454, an inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases, in combination with anastrozole or letrozole, in estrogen receptor positive breast cancer patients.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

Single-unit ensemble activity recorded in unilateral human precentral gyrus reveals a wide range of gesture-related signals across both hands, providing an intuitive and diverse set of potential command signals for intracortical BCI use.