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ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

Neuroinflammation triggers DNA damage and subsequent parthanatos-mediated neuron death. Inhibiting parthanatos in a mouse model of autoimmune inflammation is neuroprotective and reduces disease-associated paralysis.

Kornfeld-Sylla et al reveal how alpha brainwaves are altered in children and adults with Fragile X Syndrome (FXS) and find parallel changes in alpha-like rhythms in juvenile and adult FXS model mice, showing their use for testing potential therapies.

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

Skin-targeted siRNA therapies require optimized delivery to achieve therapeutic efficacy. Here, authors show that increasing conjugate hydrophobicity enhances siRNA skin retention and gene silencing in porcine and human models while limiting systemic tissue exposure.

How microglia regulate adult hippocampal neurogenesis and cognitive and affective behavior remains poorly understood. Here, the authors show that TGF-β-deficient microglia increase adult neurogenesis in the subgranular zone and alter anxiety-like behavior in mice.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

The authors find that distinct radial glia subtypes generate and support midbrain dopaminergic neurons, revealing specialized function and lineage relationships among the diverse cell types that shape dopamine neuron development.

Crohn’s disease is associated with disturbances in the B-cell compartment and secreted antibodies. Here, the authors reveal impaired colonic dimeric IgA responses in patients with Crohn’s disease and verify this phenotype in murine models, demonstrating that mitochondrial dysfunction drives defective mucosal humoral immunity.

The ZFTA–RELA fusion, an oncogene for ependymomas, promotes the production of itaconate, and its dependence on this metabolite represents a new therapeutic target for this cancer.

Immunotherapies that employ engineered T cells rely on the selective and high expression of the targeted antigen in cancer cells and thus tumor heterogeneity compromises therapeutic success. Here authors generate an engineered T cell coreceptor that targets a secondary antigen and selectively enhances antigen receptor sensitivity in T cells.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

There is a lack of effective therapies for patients with non-V600E BRAF mutant cancer. Here, the authors report limited response in a phase II trial investigating the combination of binimetinib (MEK inhibitor) and encorafenib (BRAF inhibitor) for the treatment of non-V600E BRAF mutant cancer and subsequently investigate resistance mechanisms and combination therapeutic strategies in patient-derived models.

Becker et. al developed a proteomic proximity labeling platform named POCA, which makes use of a photosensitizer for singlet oxygen production and protein capture in the presence of amine, enabling profiling of interactomes of proteins and lipids in living cells.

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.

The authors uncover a direct, BAI1-dependent, role for C1q in the control of neural stem cell proliferation and quiescence via MDM2–p53 and p32, a complement cascade-independent mechanism of C1q action that has implications for central nervous system health and disease.

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.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.

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.

While the photoreceptor outer segments in the bird outer retina have access to oxygen, the inner retina operates under chronic anoxia, supported by anaerobic glycolysis in the retinal neurons.

A cortical premotor network in HVC, once initiated, can sustain and regulate the sequential production of zebra finch song syllables without major extrinsic inputs.

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.

The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

The authors present Gemini, their bifunctional replicon platform capable of functioning as either self-amplifying RNA (saRNA) or self-amplifying DNA (saDNA).

In this study, Weber et al., investigate the long-term survival and integration of human stem cell-derived neural progenitors into the stroke-injured mouse brains. They report grafted cells integrate into host circuits and mediate repair through graft-host crosstalk via neurexin, neuregulin, neural cell adhesion molecules, and SLIT signalling pathways.

Butyrophilin 2A2 is a member of the B7 costimulatory family that is expressed on antigen presenting cells and is linked to the regulation of T cells. Here the authors implicate butyrophilin 2A2 in enhancement of CD45 phosphatase activity within the immunological synapse during T cell activation, leading to expansion of regulatory T cells and reduction of proinflammatory Th17 CD4 T cells.

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.

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.

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.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

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.

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.

Biosynthesis of all androgens from cholesterol first requires cytochrome P450 (CYP) 11A1 for generation of pregnanes and then CYP17A1 for biosynthesis of androgens, but CYP17A1 inhibition cannot completely inhibit androgen biosynthesis in prostate cancer. Here, the authors identify a role for CYP51A1 in the biosynthesis of androgens that completely bypasses the requirement for CYP17A1 and demonstrate that CYP51A1 is essential for the biosynthesis of ¹³C-testosterone from ¹³C-cholesterol in prostate cancer cells.

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).

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease and scaffolding activities. However, a significant nonenzymatic IRE1 dependency has been shown in cancer. Here, the authors design a proteolysis-targeting chimera (PROTAC) to fully disrupt cellular IRE1 protein, selectively blocking growth of IRE1-dependent cancer cells.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

DEAD-box helicase 6 (DDX6), the regulator of P-body assembly, is essential for the survival of acute myeloid leukemia (AML) cells. Here the authors report that DDX6 undergoes phase separation to preserve mRNA subsets in P-bodies, promoting branched-chain amino acid metabolism and chemoresistance in AML.

NBCn1 plays an important role as a base loader allowing breast cancer cells to survive in an acidic environment. Here, Wang et al report its near atomic structure and transport cycle involving minimal structural changes associated with an exceptionally high turnover rate, enabling efficient cellular base loading and tumor survival

Affinity-proteomics platforms often yield poorly correlated measurements. Here, the authors show that protein-altering variants drive a portion of inter-platform inconsistency and that accounting for genetic variants can improve concordance of protein measures and phenotypic associations across ancestries.

Clear cell renal cell carcinoma (ccRCC) usually metastasizes to the lungs. Here, the authors discover that SWI/SNF ATPase subunit SMARCA4 silencing of HLF regulates ccRCC lung metastasis by modulating the integration of collagen's mechanical cues with the actin cytoskeleton through leupaxin.

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.

Mitochondrial diseases lead to chronic health impairment, aggravated by infections and other environmental exposures. Here authors show, in a mouse model of polymerase gamma (Polg)-related mitochondrial disease, that Pseudomonas aeruginosa infection prompts innate immune hyperreactivity via interferon-mediated upregulation of caspase11 and guanylate-binding proteins, leading to lung inflammation.

Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.

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.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

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