Cells最新文献

Chromosomal inversions and copy-number variants (CNVs) drive genomic and phenotypic diversification in birds by reshaping recombination, gene expression, and genome architecture. Here, we report a complex structural polymorphism on great tit (Parus major) chromosome 1A that occurs in the Siberian population with a 19% heterozygote frequency. Using cytogenetic and genomic approaches, we show that this rearrangement combines a ~55 Mb paracentric inversion in the long arm with a dramatic (>30 Mb) expansion of the short arm driven by extensive amplification of multiple genomic loci. These include a region homologous to the poorly characterized FAM118A gene, whose paralog FAM118B has been recently shown to play a pivotal role in innate immune activation. This region is missing from the current reference genome assembly while present in ~20 copies on wild-type 1A chromosome and nearly twentyfold amplified in the rearranged variant. It contains a nested 630 bp tandem repeat, encompassing the entire exon 3, which has burst to a total of ~50,000 copies in the rearranged chromosome. While functional analyses are required to uncover the biological effects of the genomic features linked to this rearrangement, our results offer a unique framework for studying how complex structural polymorphisms drive genome innovation and adaptive diversity.

Cellular senescence, a hallmark of aging, involves irreversible growth arrest and an enhanced senescence-associated secretory phenotype (SASP). It is often accompanied by mitochondrial dysfunction and altered inter-organelle communication. Using a chronic oxidative stress model in AML12 hepatocytes, we confirmed senescence by canonical assays (e.g., SA β-gal positivity and proliferation arrest) and observed a decline in the RNA-binding protein AUF1 (hnRNP D). AUF1 knockdown further amplified senescent phenotypes, including elongation of mitochondrial network, loss of mitochondrial membrane potential, reduced ATP level, and elevated mitochondrial reactive oxygen species (ROS). In addition, AUF1 knockdown weakened mitochondria-endoplasmic reticulum coupling and reduced mitochondrial Ca²⁺ load. At the molecular level, AUF1 binds to the 3' untranslated regions (3'UTRs) of Opa1 and Mfn2 and limits their abundance, thereby coupling post-transcriptional control to mitochondrial dynamics. In gain-of-function experiments, ectopic expression of AUF1 attenuated Opa1/Mfn2 induction, restored mitochondrial network architecture, and preserved bioenergetic function under pro-senescent stimuli. Collectively, these findings support a model in which AUF1 preserves mitochondrial homeostasis and thereby restrains the mitochondria-senescence axis in hepatocytes.

This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

Mechanobiology plays a pivotal role in skeletal development and bone remodeling. Mechanical signals such as matrix stiffness, fluid shear stress, and hydrostatic pressure activate the Runt-related transcription factor 2 (RUNX2) bone-specific transcription factor through pathways including the mitogen-activated protein kinase (MAPK) signaling cascade and yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) effectors. RUNX2 itself affects chromatin remodeling and nuclear architecture via Lamin A/C and Nesprin 1, thereby directing osteogenic differentiation. Thus, RUNX2 acts both as a mechanosensor and mechanoregulator, whereas RUNX2's mechanosensitivity has been leveraged as a target to achieve bone regeneration. Notably, post-translational modifications and epigenetic alterations can orchestrate this regulation, integrating metabolic and circadian signals. However, due to RUNX2's nuclear localization, its targeting remains a challenging issue. To this end, indirect targeting, through mammalian/mechanistic target of rapamycin complex 1 (mTORC1) or microRNAs (miRNAs), offers new strategies to employ biomechanics in an attempt to intervene with bone diseases driven by mechanical cues or degeneration, and ultimately repair and regenerate the damaged tissues. Herein we critically elaborate upon molecular aspects of RUNX2 regulation towards exploitation at the clinical level.

Cell-cell communication (CCC) is essential for multicellular organisms, enabling different cell types to coordinate their activities in both physiological and pathological contexts, such as cell growth, proliferation, tumorigenesis, and immune responses. Metabolites represent an important class of signaling molecules, though their signaling roles were long underappreciated. Growing evidence has highlighted the critical involvement of metabolites in CCC, and the advent of single-cell RNA sequencing (scRNA-seq) has enabled high-resolution exploration of CCC events. This review summarizes existing metabolite-sensor databases and computational tools developed to identify metabolite-mediated CCC using scRNA-seq data. Nonetheless, these databases exhibit considerable variability due to lack of unified collection standards. Most computational tools were adapted from methods used for general CCC inference and often estimate metabolite abundance based on the expression of one or several related genes. Therefore, such approaches are not fully suited to capturing metabolite-mediated CCC due to the complexity of interaction mechanisms between metabolites and their sensors. To address these challenges, improved computational methods and refined databases are needed for the reliable inference of metabolite-mediated CCC. This review discusses the current limitations in database construction and method development, and highlights potential directions for future improvement, including the incorporation of spatial omics and artificial intelligence (AI) approaches. Furthermore, the systematic inference and validation of metabolite-mediated CCC will pave the way for the discovery of novel drugs and therapeutic targets.

Many cellular processes, including gene expression regulation, DNA replication and repair, as well as proper condensation and segregation of chromosomes, require highly coordinated remodeling of chromatin. Cohesin and condensins, the structural maintenance of chromosomes (SMC) protein complexes that function as ATP-powered loop extrusion motors, are key determinants of chromatin structure. The genetic loss of their function is lethal, whereas inducible degradation approaches enable rapid, robust analysis of the depletion phenotype. In this review, we discuss new insights into chromatin folding through each cell cycle phase from the auxin-inducible degradation (AID) system. We review the mechanisms by which condensins and cohesins contribute to the helical organization of mitotic chromosomes and to the maintenance of chromosome territories in interphase. Additionally, we discuss studies examining the roles of TOP2A, KIF4A, and SRBD during mitosis using the AID system. We then outline emerging principles of the mitotic-to-interphase transition and how targeted degradation of chromatin proteins reshapes this process. Finally, we highlight and discuss new advances in understanding interphase chromatin organization revealed by AID-based studies.

Therapeutic antibodies have revolutionized hematology, offering targeted and effective treatments for both malignant and non-malignant diseases. In hematologic malignancies, anti-CD20, anti-CD19, anti-CD38, and anti-B-cell maturation antigen (BCMA) antibodies have markedly improved survival outcomes, whereas antibody-drug conjugates and bispecific antibodies continue to expand therapeutic possibilities. Besides cancer, complement inhibitors such as eculizumab, ravulizumab, and the recently approved crovalimab have redefined paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome management, and the bispecific antibody emicizumab has transformed prophylaxis in hemophilia A. Furthermore, novel antibody formats such as the trifunctional anti-CD38 × CD3 antibody (Tri-31C2) exhibit enhanced anti-myeloma activity compared to chimeric CD38 antibodies, underscoring the future potential of T-cell-redirecting designs. This review summarizes key developments in therapeutic antibodies for hematological disorders, their action mechanisms, and emerging strategies to further optimize their efficacy and safety.

The mucus layer covering the gastrointestinal tract forms a specialised interface where mucins, microbes, and extracellular vesicles create a dynamic, self-regulating ecosystem. Here, we introduce the concept of the muco-microbiotic layer as an integrated eco-physiological system that maintains mucosal homeostasis through coordinated structural, metabolic, and immune functions. The MuMi layer varies regionally in its biochemical composition, microbial inhabitants, and environmental parameters-from the acidic stomach to the anaerobic colon-thereby generating distinct niches for microbial colonisation and metabolite production. We summarise current evidence on how mucin glycans, mucus-associated microbiota, and vesicle-mediated signalling sustain barrier integrity, nutrient flux, and immune tolerance. Perturbations in any of these components lead to barrier failure, microbial encroachment, and inflammation, contributing to a broad spectrum of disorders, including gastritis, inflammatory bowel disease, colorectal cancer, and metabolic syndrome. Methodological advances such as organoid and mucus-on-chip models, spatial multi-omics, and vesiculomics are now enabling site-specific analyses of this complex system. Conceptually, defining the mucus, microbiota, and vesicular compartments as a single MuMi layer provides a new framework for understanding mucosal physiology and pathophysiology, emphasising the interdependence between structure and function. Integrating this perspective into experimental and clinical research may open new avenues for diagnostics and therapies targeting mucosal health.

Non-motor symptoms (NMSs) of Parkinson's disease (PD) were recognized by James Parkinson himself about 200 years ago and are now considered to be an integral part of PD, significantly contributing to the deterioration of patients' quality of life. Although awareness of NMSs is growing, and several scientific societies now have dedicated non-motor study groups, the NMS burden is still the hidden face of PD and in most cases, clinicians' views are focused on the motor symptoms alone. The literature was reviewed using several databases and scientific journals; this review provides a comprehensive description of the most common NMSs in PD, their clinical phenotype, social impact, diagnosis, and therapeutic management. Early recognition of these features may lead to more prompt and effective treatment and may help to better understand patients' needs.

The acute gouty arthritis (AGA) to chronic gouty arthritis (CGA) transition is a critical phase leading to irreversible joint damage and systemic complications. However, current molecular mechanism investigations have remained limited to single-omics approaches that lack comprehensive multi-omics explorations. We integrate high-depth data-independent acquisition (DIA) proteomics and untargeted metabolomics to analyze serum samples from healthy controls (n =28), AGA (n = 31), and CGA (n = 14) patients to address this gap. Through differential expression analysis, we identified nine persistently dysregulated pivotal proteins with robust discriminative capacity, including the urate excretion regulator ZBTB20 and inflammation/immune-related proteins (GUCY1A2, CNDP1, LYZ, SERPINA5, GSN). Additionally, 11 consistently altered core metabolites with diagnostic potential were detected, indicating perturbations in sex hormones, thyroid hormones, gut microbiota-derived metabolites, environmental exposures, and nutritional factors. Multi-omics KEGG enrichment analysis highlighted thyroid hormone synthesis, AMPK signaling pathway, and taurine and hypotaurine metabolism as central pathways. Correlation network analysis further revealed significant immune dysregulation, illustrating an evolution from acute immune activation to chronic inflammation during AGA-to-CGA progression. Our study establishes that a coordinated disruption of the thyroid hormone-AMPK-taurine metabolic axis and concomitant immune microenvironment remodeling is associated with chronic gout development. These findings provide critical targets for developing early diagnostic indicators and targeted interventions for CGA.