Search

Men and women differ in their lipid biology. Here, the authors identify NCOA1 as a female-specific regulator that promotes the conversion of white fat into energy-burning fat, protecting women from obesity and metabolic disease by enhancing thermogenic activity in subcutaneous fat.

Interleukin (IL)-1β has been shown to promote tumour growth in non-small cell lung cancer (NSCLC). Here the authors show using chemo-immunotherapy resistant mouse tumour models that IL-1β improves CD8 T cell recruitment in a CXCL10-dependent manner and IL-1β therapy could be a useful adjunct to chemotherapy and anti-PD-1.

CRISPR-Cas9 technology holds the potential to treat a wide spectrum of genetic diseases. Here, the authors describe a modular platform for extracellular vesicle-based Cas9 delivery, using MS2-based RNA-binding domains and UV-cleavable linkers, suitable for various Cas9-based moieties.

Strategies for HIV prevention besides high manufacturing cost neutralizing antibody requires further investigation. Here the authors develop vaginal tissue deliverable mRNA-based antibody approaches, which demonstrate protection of rhesus macaque vaginal tissues against multiple HIV strains with favorable tolerability and prevention efficacy.

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.

Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.

Mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA–processing complex, cause an autoinflammatory syndrome due to enhanced interferon signaling mediated by the cGAS–STING pathway, showing an essential role for nuclear histones in suppressing the immunogenicity of self-DNA.

Exploring the molecular mechanisms by which the blood-borne factor osteocalcin promotes cognitive resilience, Rivagorda, Romeo-Guitart et al. identify a primary cilia axis through which osteocalcin promotes autophagy in neurons.

Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. François Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4⁺ T cells, which can promote tumor growth.

Ewing sarcoma (ES) is characterized by EWSR1/ETS gene rearrangements with unknown cellular origin. Here, authors show that expressing the EWS::FLI1 oncogene in human embryonic mesenchymal stem cells induces an Ewing sarcoma-like transcriptome and forms tumors in mice.

JNJ-A07 is a highly potent pan-serotype dengue virus inhibitor but the mechanism is not fully understood. Here, the authors show that JNJ-A07 blocks interaction between the viral protease/helicase complex NS2B/NS3 and the viral NS4A-2K-NS4B precursor, which then prevents formation of membranous replication organelles.

Sperm chromatin retains post-translationally modified histones whose function, after delivery to egg, is unclear. Using H2AK119Ub1 edited sperm the authors show that a sperm derived epigenetic cue is necessary for frog embryo development.

Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate T_H9 homeostasis and antitumour immunity.

A search for analogues of the human SAMD9/9L antiviral genes identifies convergent evolution of this gene family in the bacterial and animal kingdoms, with species-specific and recent genomic signatures indicative of adaptations resulting from evolutionary arms races with viruses.

This study shows that Crimean-Congo hemorrhagic fever virus (CCHFV) recruits apoE, an exchangeable apolipoprotein that mediates LDL/LDL-R interaction, to promote virion entry via the LDLR. Molecules that down-regulate LDL-R inhibit CCHFV infection.

Lipid droplets (LD) accumulation correlates with colorectal cancer (CRC) relapse. Here the authors show that chemotherapy induces LD synthesis via acyltransferase LPCAT2 which, in turn, promotes chemoresistance via LD accumulation both in vitro and in vivo by blocking chemotherapy-induced ER stress.

Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.

Argonaute proteins are key effectors in the microRNA pathway. Here, the authors show that the conserved peptidase DPF-3 regulates Argonautes in C. elegans, and that loss of dpf-3 restores function and fitness in animals lacking the microRNA Argonaute ALG-1.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Phosphorylation of residues in the N-terminal tail of histone H3 signals different biological outcomes. High-resolution NMR analyses now reveal a mechanistic hierarchy of H3 phosphorylation events, whereby phosphorylation of Ser10 impedes the phosphorylation of Thr6 and Thr11 by PKC and Chk1, respectively. Because both enzymes also target Ser10, this establishes an autoinhibitory feedback loop on H3 tails.

Here they show that SSUP-72/PINN-1 regulates Pol II 3′ pausing and transcription termination in C. elegans. Its loss bypasses the need for CDK-12 during development, uncovering a novel mechanism that coordinates operonic gene expression and ensures proper growth.

Blood vessel integrity is critical to maintain brain health. Here, the authors show that both the liver and the muscles secrete HFE2, a protein that promotes blood vessel integrity in healthy animals and in an animal model for multiple sclerosis.

Defects in non-canonical Wnt/planar cell polarity signalling have recently been linked to breast cancer aggressiveness. Puvirajesinghe et al. identify VANGL2, p62/SQSTM1 and JNK as important players in this pathway which may be amenable to therapeutic intervention in breast cancer.

RNA G-quadruplexes (RG4s) have been functionally linked to cancer gene expression. Here, Herviou, Le Bras et al. have identified the protein machinery modulating RG4s and reveal the role and mechanism of hnRNP H/F and DHX36 in RG4-mediated translational regulation affecting cancer treatment in glioblastoma.

Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease

Steatosis is characterized by initial accumulation of lipids, followed by inflammation and ultimately fibrosis. Here the authors show that the histone demethylase Plant Homeodomain Finger 2 protects liver form steatosis progression by acting as a co-activator of ChREBP, thus, favouring lipid accumulation without inflammation.

BamA is the catalytic core of the BAM complex, which inserts proteins into bacterial outer membranes. Here, the authors show that hinge flexibility between BamA’s β-barrel and POTRA domains is vital, demonstrating how evolution has fine-tuned the BamA sequence and structure for function.

Hepatitis D virus (HDV) relies on a helper virus to package and transmit its ribonucleoprotein (RNP). Here, Perez-Vargas et al. show that HDV can use envelope proteins from HBV-unrelated viruses, including HCV and flaviviruses, to propagate in vitro and in humanized mice.

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.

In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.

Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

An oligodendrocyte-specific genomic silencer element determines the cell type specificity for a fatal neurological disorder caused by a widely expressed nuclear protein (Lamin B1) and suggests a role for silencer elements in disease causation.

The histone variant, H2A.Z is known to regulate gene expression and cell proliferation. Here the authors show that H2A.Z has a central role in the control of intestinal epithelial homeostasis in mice, by preventing terminal differentiation of intestinal progenitors.

Ribosome biogenesis is influenced by the rate of RNAPI progression. Yet, mechanisms that control RNAPI elongation have remained elusive. Here, the authors show that the conserved protein Seb1 promotes cotranscriptional rRNA processing by controlling RNAPI progression.

Cachexia, or muscle-wasting syndrome, is often observed in patients with cancer or sepsis, and no specific treatment of cachexia is currently available. In this study, Di Marcoet al.show that low doses of pateamine A, an inhibitor of translation initiation, prevent cachexia in a mouse model of the disease.

Using complementary cryo-electron microscopy and functional studies, the authors demonstrate that botulinum neurotoxins exploit the accompanying nontoxic bacterial proteins, OrfXs and P47, activated by host digestive proteases, to greatly enhance their oral toxicity.

Inflammation is a component of Parkinson’s disease. Here the authors show that activation of Toll-like receptor 9 controlled by microglial glucocorticoid receptor signaling, contributes to dopamine neuron loss in a model of Parkinson’s disease.