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Different types of SETBP1 variants cause variable developmental syndromes with only partial clinical and functional overlaps. Here, the authors report that SETBP1 variants outside the degron region impair DNA-binding, transcription, and neuronal differentiation capacity and morphologies.

Here the authors develop a novel statistical method for quantifying mutation burden from whole genome sequencing data and use it to discover the genetic, genomic, and phenotypic correlates of clonal hematopoiesis without known driver genetic lesions.

How neurons form synapses is central to brain development. Here, the authors show that astrocytes can limit neuronal morphogenesis by secreting S100A6, which reduces protein turnover in neurons through calcyclin-binding protein mediated signaling.

BPTF is known to regulate chromatin accessibility and self-renewal in mammary epithelial stem cells. Here, the authors discover that BPTF inhibition delays tumor formation, re-activates ERα expression, increases sensitivity to tamoxifen treatment, and inhibits metastatic development.

Joint injury and disease are leading causes of disability, with mammalian joints exhibiting poor regenerative capacity. Here the authors showed that after loss of a whole joint, adult zebrafish regenerate de novo articular cartilage, ligament, and synovium into a complex joint organ.

Capillary-associated macrophages are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice.

Inhibition of ELOVL6, a fatty acid elongation enzyme, selectively degrades mutant KRAS, disrupts its membrane localization and suppresses tumor growth, revealing a novel vulnerability in KRAS-driven cancers.

Intratumoral hypoxia promotes cancer progression. Here, authors show that hypoxia upregulates RNA Polymerase I activity and ribosome biogenesis in breast cancer cells and targeting RNA Polymerase I with BMH-21 reduces tumor growth and metastasis in murine models.

Mellor et al. report that deficiency of GABARAPL1, an ATG8-specific linking protein, impairs diastolic function in diabetic mice. This effect can be reversed by gene delivery of the gene encoding GABARAPL1 in diabetic mice and a human organoid model of type 2 diabetes.

Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism

Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity drives proliferation of small lung cell cancer via paracrine interactions and through synapses formed with tumour cells.

Xu et al. perform a whole-genome CRISPR-Cas9 knockout screen using directed differentiation systems. They find that MEN1 and SUZ12 modulate human developmental timing by epigenetically controlling bivalent promoters of developmental genes.

The placenta plays vital roles in supporting fetal development. Here, Richards et al. develop a high-throughput bioprinted trophoblast organoid model to recapitulate the microenvironment of the early placenta, enabling investigation of placenta development and evaluation of therapeutics for placenta dysfunction disorders.

Opposing forces generated by exopolysaccharide trail binding versus type IV pilus retraction generate a high cyclic diGMP–high cyclic AMP state in Pseudomonas aeruginosa that promotes social motility.

Using a new analytical method for tracking gamma band events in mouse visual cortex, flexible encoding of visual information according to behavioural context is shown.

This prospective cohort study of patients with cancer incorporated antemortem follow-up visits and rapid autopsy analyses, and reports that spikes—rapidly increasing levels—of circulating tumor cell clusters, observed immediately before and at the time of death, along with tumor masses infiltrating large vessels, were cancer-related events associated with patient mortality.

During chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy through WSTF interaction with ATG8 in the nucleus, leading to WSTF nuclear export and its subsequent degradation.

Here the authors show how the DNA-sensing cGAS–STING pathway activates NF-κB and inflammatory gene expression with delayed kinetics via post-Golgi endolysosomal signaling.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with anti-inflammatory interventions.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Bioactivity-guided isolation of specialized metabolites is an iterative process. Here, the authors demonstrate a native metabolomics approach that allows for fast screening of complex metabolite extracts against a protein of interest and simultaneous structure annotation.

Small cell lung cancer cells form functional synapses with glutamatergic neurons, receiving synaptic transmissions and deriving a proliferative advantage from these interactions.

CAR-T cells have been found to be less effective as treatment for solid tumours. Here the authors, utilising B7H3 as an antigen, consider how changes in B7H3 binders lead to functional changes of CAR-T cells and differences in tumour outcomes in humanised mouse tumour models.

Cryogenic electron microscopy structures and functional analyses reveal that NCLX functions as a H⁺/Ca²⁺ rather than a Na⁺/Ca²⁺ exchanger, and uncover its transport mechanism with implications for therapies treating cardiac and neurodegenerative disorders related to abnormal mitochondrial Ca²⁺.

The broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, the authors established a generalizable re-engineering framework to narrow the activity windows of diverse base editors, streamlining the development of therapeutic base editing.

Spatial transcriptomic studies and lineage tracing reveal that, after brain injury, transient profibrotic fibroblasts develop from existing brain fibroblasts, infiltrate lesions, regulate the local immune response and lead to beneficial scar tissue formation.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

Here, the authors develop pluripotent stem cell-derived kidney organoids by mimicking in vivo proximal differentiation, providing a model to study nephron development, injury responses, and a platform for therapeutic discovery.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Regulation of gene expression is a facet of human brain specialization. Here, the authors show that human-like expression of the CLOCK gene in the mouse neocortex enhances cognitive flexibility and neural connectivity, suggesting an evolutionary gain of function that may have contributed to human cognitive specialization.

The developing heart integrates several progenitor cell types. Here they show that the pericardium enveloping the heart develops among cells that form the mesothelium around inner organs and body cavities, distinct from the classic heart field.

Lee et al. show that the circadian clock protein REV-ERBα controls brain NAD⁺ levels by regulating the NAD⁺-consuming enzyme CD38. Global or astrocytic REV-ERBα deletion or pharmacologic REV-ERB inhibition protects against tau pathology in mice.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the functional loss of the tumor suppressor gene neurofibromin, that can lead to the development of benign and malignant tumors. Here the authors describe the development of an adeno-associated virus vector for NF1 gene replacement therapy of NF1 related tumors, showing tropism and anti-tumor activity in preclinical models

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

Understanding how community-based initiatives work is crucial for effective environmental management, but causal evaluations of these efforts are rare. This study presents a national-scale evaluation of a locally managed network of marine areas in Fiji and examines whether the expected mechanisms deliver conservation outcomes.

IP6 is a critical host cofactor for HIV-1 assembly and infectivity. In this study, the authors uncover the structural basis by which HIV-1 adapts to a deficiency in IP6 packaging through a G225R mutation at the C-terminus of the capsid protein.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

Myocardial contractile force and intracardiac hemodynamic shear stress coordinate the initiation of trabeculation in heart development. Here, the authors report that radially aligned myocardial strain activates snai1b⁺/Notch⁻ cardiomyocytes, initiating delamination for trabeculation.

In this work, the authors investigate the activation mechanism of proprotein convertases (PC) based on the PC1/3-prodomain and the PC furin. They engineer a prodomain-nanobody fusion protein that effectively blocks propagation of a H7N7 bird flu virus.

Zaman, Yang and Huang et al. demonstrate MDK’s suppressive effect on amyloid-β and its impact on amyloid burden and microglial activation in Alzheimer disease mice, highlighting its protective role in pathogenesis.

Here they perform a systematic dissection of OCT4 and reveal how intrinsically disordered regions can be used to serve specific functions during reprogramming and embryonic development. This can be exploited to engineer more efficient and specific reprogramming factors.

Current treatment options for ovarian cancer are limited to surgery and chemotherapy, but most patients experience recurrent metastatic diseases. Here, the authors develop an antigen–adjuvant combination immunotherapy for ovarian cancer by coupling tumor antigen loaded liposomes with plant virus adjuvant as a vaccine platform to prevent cancer recurrence and metastatic diseases.

Head motion is an artifact in structural and functional MRI signals, and some traits or groups are more strongly correlated with motion than others. Here the authors describe a method to attribute a motion impact score to specific trait-functional connectivity relationships.

Shallow seawater during the Great Oxidation Event contained abundant phosphite, comprising 5–88% of total dissolved phosphorus. Preferential phosphate removal by ferric oxides and microbial competition may have promoted its biological usage.

The relative contribution of intrinsic and extrinsic factors to astrocyte heterogeneity is unknown. Using heterotropic transplantation of septal astrocytes with distinct lineage origins, we show that local factors specify their ultimate identities.

Here, the authors show that MacroD1 is important for mitochondrial integrity and function. Lack of MacroD1 resulted in impaired cellular respiration which was particularly detrimental for cells and organs with high energetic requirements, such as skeletal muscle.

This study introduces the Cattle Cell Atlas, a single-cell expression resource including 1,793,854 cells from 59 tissues. Integrative analyses leveraging this atlas provide insights into the biology underlying bovine monogenic and complex traits.