Search

Here the authors perform longitudinal sampling of lymphoid organs along with fate mapping and matched single-cell RNA sequencing and TCR sequencing to define the developmental dynamics of follicular regulatory T (T_FR) cells. They find that T_FR cells undergo clonal expansion and progressive differentiation in a process that requires follicular helper T cells.

Genome-wide CRISPRi screens for modulators of androgen receptor (AR) protein levels using live-cell quantitative endogenous AR fluorescence reporters identify PTGES3 as a new regulator of AR stability and function in prostate cancer.

Microhomology-mediated end joining (MMEJ) and mitotic DNA synthesis (MiDAS) are critical DNA repair pathways in mitosis. Here the authors show that CIP2A–TOPBP1 coordinate mitotic DNA repair through the regulation of factors required for MiDAS and MMEJ.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

Upon infection with HIV-1 and proviral integration, the host enzyme PADI4 citrullinates histone H3 at the integration site, leading to non-repressed HIV-1 transcription. This explains how a few reservoir cells remain active despite antiviral therapy.

The authors previously pinpointed OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. Here, the authors identify increased IL-18Rα expression on CD8⁺ T cells, which acquire a reduced cytotoxic signature, correlates with severe respiratory viral infection of influenza A virus, RSV and COVID-19.

In JAK2V617F mutant myeloproliferative neoplasms (MPN), inflammation impacts clinical outcomes. This study uncovers that the NLRP3 inflammasome drives thrombocytosis, granulocytosis, HSPC expansion, splenomegaly, and bone marrow fibrosis in MPN

With whole-genome screens using a bivalent MHC class I gene expression readout, Sparbier et al. identify opposing roles for Menin and KMT2A/B in modulating activating H3K4me3 versus repressive H3K27me3 at bivalent promoters to regulate gene activation.

Horizontally transferred genes must be integrated into host biology. Here, the authors show that the domestication of bacterial hopanoid synthesis has rewired lipid metabolism of a eukaryote leading to changes in membrane structure and physiology.

Activity recognition in live-cell imaging is laborious. Here, authors present, IVEA, a fully automated AI ImageJ plugin, that efficiently detects and classifies exocytosis events, from synaptic transmission to single-vesicle fusion, across cell types and imaging setups.

Rettkowski, Romero-Mulero et al. show that myocardial infarction impacts bone marrow haematopoietic stem cells and leads to inflammatory myelopoiesis, which can be dampened by treatment with 4-oxo-retinoic acid, promoting cardiac recovery.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

Centrosome dynamics play a central role in immune regulation. Here, the authors demonstrate that centrosome integrity as well as centriole numbers and spatial organisation emerge as critical determinants of effective T cell responses.

Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.

In bacteria Zn2+-dependent deacylases are underexplored. Here, the authors identify bacterial deacylases, providing systemic structure-function analyses to reveal the basis of substrate specificity, acyl-chain preference and inhibition.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Viral proteins can achieve high multifunctionality, but mechanisms are poorly understood. This study shows structural flexibility of rabies virus P protein enables RNA binding and phase separation to expand functions by infiltrating host condensates.

Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). Here the authors show the Rio1 kinase limits cenRNA production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5’− 3’exoribonuclease Rat1.

Dalit, Tan and colleagues provide a multiomic profile of T follicular helper (T_FH) cells responses to diverse pathogens, revealing a blueprint for transcriptional flexibility and new tools to interrogate T_FH heterogeneity in mice and humans.

Álvarez-Cubela et al. show that a BMP-7-like peptide induces β-cell regeneration and lowers hyperglycemia in diabetic mice, and reveal the transition of ductal cells into insulin-expressing cells. These results have potential therapeutic implications

Immunization via the respiratory route is predicted to increase the effectiveness of SARS-CoV-2 vaccines. Here, Kaiser et al. describe a murine pneumonia virus vectored vaccine expressing spike protein, and show that intranasal immunization of male rhesus macaques provides good mucosal and systemic immunogenicity and efficacy.

Dysregulated protein degradation drives diseases like cancer. Here, authors use protein language models to design target-binding peptides, which are subsequently attached to the catalytic domain of the OTUB1 deubiquitinase, generating “deubiquibodies” (duAbs). duAbs restore tumor suppressors and fusion oncoproteins, offering a programmable strategy for protein stabilization.

3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.

Whole-genome sequencing of polioviruses in Uganda following nOPV2 use showed high genetic stability and no sustained transmission, even though a rare double recombinant strain regained virulence, but did not spread due to high vaccination coverage.

Glioblastoma is divided into four subtypes based on molecular profiling at the methylome and transcriptome level. Here the authors perform an integrative analysis of these subtypes resulting in the identification of SOX10 whose loss induces a mesenchymal phenotype and promotes tumour progression.

Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals, suggesting that a tailored therapeutic strategy is needed to target each subset.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Although FZDs are promising drug targets, so far no small molecules targeting them were described. Here, the authors report the a FZD7 core-targeting small molecule negative allosteric modulators of WNT-induced signaling, confirmed by pharmacology, structure determination and MD simulations.

Single-cell genomic and transcriptomic analyses of longitudinal samples of patients with Richter syndrome reveal the presence and dynamics of clones driving transformation from chronic lymphocytic leukemia years before clinical manifestation

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.

Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

Here the authors connect inherited Apolipoprotein E genotype with the risk of developing Alzheimer’s disease by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Amyloid-beta.

The transfer of nuclear chromatin to the cytoplasm drives the pro-aging inflammatory phenotype of senescent cells. Here, Miller et al. show that this process is suppressed by p53 and that activation of p53 reverses some features of aging in vivo.

CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.

The underlying mechanism of acquired resistance to targeted therapy in cancer remains to be explored. Here, the authors show that upregulation of the FOSL1 transcription factor restores YAP/TEAD occupancy on chromatin to drive resistance to GNE-7883, an allosteric TEAD inhibitor.

Developing treatments that withstand viral evolution is difficult. Here, the authors design ReconnAb-multimers: broad, highly potent therapeutics linking a non-neutralizing antibody, ACE2, and a multimerization domain to prepare for future pandemics.

Exhausted T cells arise when chronic activation triggers functional defects. Here the authors show that chronic antigenic stimulation in both tumour and infection models induces the expression of EGR2, which drives and stabilises exhausted cell epigenetic and transcriptional identity.

Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.

Mitochondrial respiration provides reducing power to the electron transport chain (ETC), driving proton pumping and ATP synthesis required for T cell activation and differentiation. Here, the authors use alternative oxidase (AOX) as a mechanistic probe to bypass cytochrome c oxidase deficiency and thereby isolate the role of respiration and demonstrate that intact mitochondrial respiration is important for T cell proliferation, effector function, memory formation, and regulation of apoptotic and metabolic signaling pathways.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Loss of MEN1 affects tumor growth, varing with the components of the tumor microenvironment. These tumors show redistribution of MLL1 on chromatin and the activation of a viral mimicry response.

IRE1α plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1α is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

LINE-1 retrotransposons are a type of mobile DNA element normally repressed in the body. Here the authors show that LINE-1 sequences can jump in mouse parvalbumin interneurons and also promote the transcription of key parvalbumin interneuron genes.