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Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

A spatial and single-cell transcriptomics study across multiple mammalian species identifies epidermal BMP signalling as a functional requirement for rete ridge formation, providing insight into mechanisms underlying hair density loss and wound healing.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

The role of metabolic processes in endoderm differentiation remains elusive. Here, the authors discover that oxidative stress and GPX2 determine whether human stem cells differentiate into pancreatic or liver tissue. This finding could improve cell-based therapies for diabetes and liver diseases.

Expanded FMR1 CGG repeats drive toxic FMRpolyG in premutation disorders. Here, the authors show that IGF2BP3 binds the FMR1 5’UTR to promote non-AUG translation of FMRpolyG and that its loss reduces toxicity.

Despite high morbidity and mortality, there are currently no approved vaccines for protection against Middle East respiratory syndrome (MERS) coronavirus. Here the authors develop a ferritin nanoparticle-based MERS-CoV vaccine that elicits high levels of neutralizing antibodies in mice, non-human primates, and alpacas and prevents infection in an alpaca challenge model.

Barnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.

A CRISPR screen reveals that loss of structural components of the SAGA complex derails hematopoiesis by decoupling epigenetic control. This halts stem cell maturation, triggers a pathogenic interferon program and boosts human MDS-L cell growth.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Symbiotic bacteria can have exceedingly small genomes. This study finds that ancient bacterial symbionts of planthoppers have repeatedly evolved the smallest known genomes, losing most biosynthetic functions, revealing how extreme genome reduction shapes life at the edge of cellular complexity.

Sabatino and colleagues examine expanded CD8⁺ T cell clonotypes from a small cohort of multiple sclerosis patients. They identified several cognate peptide epitopes that derive from Epstein–Barr virus, suggesting EBV reactivation may drive pathogenesis in these patients.

Here authors show loss of AKAP11, a strong genetic risk factor for bipolar disorder and schizophrenia, disrupts PKA proteostasis and signaling, leading to widespread transcriptomic alterations across the brain, particularly in striatal neurons, as well as altered behavior.

This study provides new insights into the role of endoglin (ENG) as a co-receptor in endothelial cells and addresses a gap-in-knowledge on how ENG could be involved in both TGF-β and BMP9 signalling. Such knowledge greatly facilitates therapeutic targeting of ENG-related pathways.

Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.

Targeting FSP1 in lymph nodes has considerable potential for blocking melanoma progression.

Symmetry breaking is key to tissue formation. Now it is shown that symmetry breaking of epithelial spheroids is controlled by an interplay of collective migration with curvature and matrix remodelling.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Recently published results from a Phase I trial showed the blood brain barrier could be transiently opened in glioblastoma patients using low-intensity ultrasound and microbubbles. Here, the authors develop a microfluidic chip to capture tumour-derived extracellular vesicles and particles in response to paclitaxel treatment.

Vestibular schwannomas that are caused by genetic mutations in the NF2 gene are hard to treat and lead to hearing loss. Here authors show in a mouse model that faithfully represents the human condition that combination therapy with anti-PD-1 and anti-VEGF inhibits tumor growth via normalizing the tumor vasculature and enhances T and NK cell antitumor cytotoxicity via upregulation of NKG2D.

In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Splice-site targeting antisense oligonucleotides can increase the expression of host gene intron-embedded microRNA and affect axonal development in zebrafish.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

Here, they show that Very-long-chain 1-deoxyceramides impair mitochondrial function and cause toxicity. Inhibiting ELOVL1 prevents these effects, suggesting a therapeutic strategy for disorders linked to elevated 1-deoxysphingolipid levels.

Stem cell interactions involve biochemical and biophysical cues, but the transcriptional control of biophysical traits is unclear. This study identifies ETVs as regulators of adhesion in hPSCs and pancreatic progenitors, shaping lineage decisions.

A multiancestry phenome-wide analysis of copy number variants in the UK Biobank genomes increases power to detect genetic associations with complex traits across human populations.

Kozai, Fernandez-Martinez et al. use high-speed atomic force microscopy to study the permeability barrier of yeast nuclear pore complexes. They show that karyopherins remodel a central plug that shapes barrier dynamics and disorder within the pore.

Nonninger et al. identify the TFEB–TGFβ signaling axis as a regulator of stem cell resilience that protects against a senescence-like state during the adult diapause in Caenorhabditis elegans, a mechanism conserved in vertebrate aging and mammalian cancer.

McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.

Cellular Z-RNAs generated during active virus infections are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.

Reovirus mRNAs lack polyadenylated tails yet are efficiently translated. Here, the authors identify host protein ataxin-2-like (ATXN2L) as a mediator of reovirus nonpolyadenylated mRNA translation.

There are limited data on mpox immunity in West Africa. In this study, authors present serological and genomic evidence of residual smallpox vaccination immunity and possibly unrecognized mpox exposure among ostensibly healthy Nigerian adults.

The low-density lipoprotein receptor family members LRP1, LRP4 and VLDLR are entry receptors for yellow fever virus.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Despite extensive structural studies elucidating how antigens are anchored to antigen-presenting molecules and presented to T cells, little is known about the display mechanism of the lipid-antigen-presenting molecule CD1c. Here, by combining structural immunology, lipidomics, and biophysical analysis, the authors reveal that the CD1c binding cleft accommodates two different lipids, one of them with a bulky headgroup positioned sideways for display to T cells, rather than upwards, different from the conventional upright antigen-presentation mode

Sznajder et al. identified a molecular link between autism and myotonic dystrophy, showing that a tandem repeat mutation in a single gene can disrupt splicing of multiple autism-related genes during brain development, leading to autism-like traits.

The cytoplasm can be partitioned into distinct compartments by microtubule structures, which can be stabilized by distinct mechanisms in different species.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Cryo-EM structures of the stabilized prefusion conformation of the glycoprotein B ectodomain—the HSV-1 entry machine—identify a prefusion-specific neutralizing antibody and reveal how prefusion glycoprotein B may evade antibody-mediated neutralization.

This study reveals that transcription factors DAF-16/FOXO and HLH-30/TFEB promote healthy aging in C. elegans, in part, by activating lipid metabolism genes that remodel lysosomes into tubular networks.

ATP synthase powers cells by converting proton translocation into energy. Here, authors reveal distinct structural features of the P. aeruginosa ATP synthase that regulate activity and may serve as targets for new antimicrobial therapies.

The direct contribution of aberrant epithelial cells to lung fibrosis is largely unknown. The authors use murine and human systems to identify how these cells activate fibroblasts, and how reciprocal signals cause them to enter a profibrotic state.

A fresh approach to protein design that incorporates excited intermediate states enables precise control over the lifetime of protein interactions, with potential applications in cell-signalling modulation and in biosensors and synthetic circuits.

The role of rare pathogenic/likely pathogenic (P/LP) germline variants in pediatric central nervous system (CNS) tumour development remains poorly understood. Here, the authors investigate the prevalence and clinical significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumour patients.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

How inflammation spreads from the skin to the joints in psoriatic disease is unclear. Here, the authors show that joint-resident fibroblasts can control differentiation of infiltrating skin-derived myeloid precursors that can become inflammatory macrophages.