Search

Newly developed mouse models that enable cell-specific analyses of proteostasis dynamics across the lifespan of the mice reveal key aspects of neuronal proteostasis with ageing.

Schizophrenia is a complex brain disorder with its underlying protein changes generally not well understood. Here, authors show widespread alterations in the prefrontal cortex, marked by reduced energy production and disrupted synaptic function.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

This study finds stem-like endothelial cells in the optic nerve that supply and repair retinal blood vessels after injury, revealing a hierarchical repair system that may enable new treatments for blinding vascular eye diseases.

The anterior cingulate cortex encodes affective pain behaviours modulated by opioids; targeting opioid-sensitive neurons through a new chemogenetic gene therapy replicates the analgesic effects of morphine, providing precise chronic pain relief without affecting sensory detection.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Achieving tight Cas9 regulation without sacrificing activity remains difficult. Here, the authors design multi-level circuits combining anti-CRISPRs, splice sites, chemical induction, and degron control to enable ultra-high dynamic range and precise, on-demand genome editing across contexts.

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.

Genetic mapping in mice identified Homer1a as a key modifier of attention. Developmental downregulation in the prefrontal cortex enhances inhibitory tone, neural signal to noise and adult attentional performance, revealing a new control mechanism and target.

Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

Clade 2.3.4.4b highly pathogenic H5N1 is currently causing a panzootic and has the potential to become a pandemic. Here, Peña Alzua and colleagues develop specific monoclonal antibodies against this virus that could be used to prevent or treat human infections.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

One of three back-to-back papers to show dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance chimeric antigen receptor T cell therapies for cancer.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

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.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

MYC-driven medulloblastoma is highly aggressive and associated with poor survival. Here, the authors perform single nuclei multi-omic analysis of matched primary and recurrent tumours and identify potential resistance mechanisms and targetable pathways.

Mutations in GJB2 cause DFNB1, the most common hereditary deafness. ATAC-seq identification of gene regulatory elements enables targeted GJB2 delivery to cochlear cells, preventing hearing loss in mouse models.

The existence of phosphatases specialized in regulating the axon initial segment (AIS) was unclear. Here, the authors show that a PP2A-B55 subunit is selectively enriched at the AIS and contributes to its local phospho-regulation.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

There are limited vaccines available for Ebola virus and none for broad protection from filoviruses. Here, the authors rationally design vaccines using nanoparticles and stabilized Ebola virus and other filovirus glycoproteins, characterize antibody epitopes and profile lymph node and antibody responses in mice.

Myotonic dystrophy type 1 affects both muscle and neuronal function, but its synaptic pathology is poorly understood. Here, the authors show that upregulation of FasII (NCAM1) in both pre- and postsynaptic cells synergistically drives neuropathological and behavioral DM1 phenotypes, which can be rescued by FasII knockdown or specific isoform modulation.

Jonaitis et al demonstrate that serotonin differentially modulates feedforward inhibitory neurons in the olfactory system of Drosophila which likely reflects odor categorization in higher order brain regions.

Variation in SARS-CoV-2 viruses results in newly emergent virus lineages. Here, the authors characterize the BNT162b2 mRNA vaccines, adapted to two SARS-CoV-2 lineages, JN.1 and KP.2, measure responses elicited by these vaccines against contemporary and older SARS-CoV-2 variants in naive and antigen experienced animal models and describe the biophysical and structural properties of the spike proteins expressed by these vaccines.

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.

An understanding of the molecular mechanisms promoting the generation of immunoregulatory and tumour-promoting monocytes and macrophages is key to breaking the cycle of tumour myelopoiesis and developing more effective myeloid-targeting therapies.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

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.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

The extent of the hierarchical relationship between premotor and primary motor cortices has been contested. Here, the authors show that hierarchical interactions between analogous brain regions and forelimb musculature vary substantially between two motor behaviors in mice.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Here the authors show that lab mice have retained ancient gut bacterial symbionts that diversified in parallel with rodent species, but the genomes of these gut bugs have accumulated mutational burdens over the past ~ 120 years of inbreeding in captivity.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate. Through integrated laboratory and clinical studies, the authors identify significant ERBB2 (the gene that encodes the HER2 protein) mutational heterogeneity in patients with urothelial cancer and co-mutation and amplification of ERBB2 as a potential biomarker of exceptional response to T-DXd.

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.

Koh, Ma et al. show that during climbing, mouse motor cortex instructs limb muscle activity patterns primarily by selectively activating certain muscles at certain activity states, via neural activity patterns distinct from those previously described.

Fidler et al. show that anti-IL-1β treatment of atherosclerotic Ldlr-null mice with clonal expansion of Tet2-null or Jak2^VF hematopoietic stem cells promotes the recruitment of fibroblast-like cells to the plaque fibrous cap, leading to cap thickening and increased plaque stability. Conversely, the removal of fibroblast-like cells during atherosclerosis progression results in reduced fibrous cap formation in mice receiving anti-IL-1β antibody treatment.

Malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division.

Silk fibres derive their exceptional properties from hierarchical protein organisation, but the underlying molecular pathways remain underexplored. Here, the authors combine time-resolved small-angle neutron scattering, pH and turbidity measurements, and fluorescence emission to identify a stepwise assembly pathway comprising nanoscale clustering, domain growth within clusters, and mesoscale network formation.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.