Communications Biology最新文献

Ulcerative colitis (UC) is a debilitating, immune-mediated inflammatory disorder of the gastrointestinal (GI) tract with far-reaching consequences on distal organs, including the bone marrow. Here, we describe the molecular mechanisms that contribute to UC-induced abnormal hematopoiesis. We show that chronic UC drives HSPC differentiation toward myelopoiesis in an APE1/Ref-1/HIF-1α/IL-1r1-dependent manner. Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory milieu of UC, including suppression of pro-inflammatory Ly6C^hi monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop.

Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is no effective treatment available. Various modalities of magnetic stimulation have emerged for recovery from spinal cord injuries; however, the underlying mechanisms remain unclear, significantly hindering the application of magnetic stimulation technologies in treating such injuries. This study aims to elucidate these relevant mechanisms by establishing a simulated closed-loop magnetic stimulation system. In this study, we established a right hemisection model at T8 in mice and administered continuous simulated closed-loop magnetic stimulation targeting the left motor cortex and right L5 nerve root over six weeks. We subsequently utilized a spinal cord dorsal hemisection model to examine regeneration of the corticospinal tract (CST). Motor-evoked potential assessments and calcium imaging techniques were employed to explore neural circuit repair. Additionally, we integrated transcriptomics, proteomics, and metabolomics approaches to investigate related mechanisms. The findings indicate that simulated closed-loop magnetic stimulation effectively restores motor function in the hind limbs, promotes the regeneration of corticospinal tracts in mice with spinal cord injuries, and facilitates the reconstruction of sensorimotor circuits and functions within the spinal cord. Simulated closed-loop magnetic stimulation significantly enhances axonal regeneration of the CST following SCI. This effect may be mediated through the activation of the AMPK-CREB-BDNF signaling pathway, which promotes neurotrophic factor secretion and subsequently induces nerve axon regeneration. This study suggests that simulated closed-loop magnetic stimulation represents a promising therapeutic approach for the treatment for impaired gait following SCI.

Polystyrene microplastics (PSs), pervasive environmental contaminants found in food and human tissues, pose an emerging threat to reproductive health. Elucidating the mechanisms underlying PS-induced toxicity and identifying effective interventions to mitigate adverse effects are therefore critically important. Here, our findings demonstrated that PS exposure in 5-week-old female SPF Kunming mice leads to decreased serum hormone levels and reduced transzonal projections. Furthermore, this study revealed that PS-induced ferroptosis in ovarian granulosa cells. Mechanistically, ERα-mediated PS internalization led to activation of the YAP1-ACSL4 signalling and subsequent lipid peroxidation. Moreover, we demonstrated that glycine effectively alleviate PS-induced ferroptosis by modulating lysosome-dependent ferritin degradation in a PAT1-dependent manner, thereby restoring iron homeostasis. Taken together, these findings revealed that PS exposure triggers ACSL4 overexpression and iron overload in ovarian granulosa cells, whereas glycine restored iron homeostasis via lysosome-mediated ferritinophagy. This study provides critical insights into the reproductive health risks of PS exposure and offers a potential intervention strategy.

Due to their essentiality, studying proteins involved in fundamental processes in vivo is challenging. PROTAC-based systems offer time-controlled protein depletion, but their characterization in vivo remains limited. Here, with an efficient direct zygote editing protocol, we generate degron-tag models (dTAG/FKBP or BromoTag) for seven genes involved in therapeutic and endogenous mRNA metabolism (Cnot1, Pan2, Tent5a, Tent4b, Dcp2, Rnasel, Tsg101). Degron tags occasionally cause phenotypes that can be mitigated by tag position or tagging system change. In cells, both approaches yield rapid and sustained degradation. In mice, dTAG depletion is effective but varies by protein and administration route, whereas BromoTag shows no in vivo activity. We showcase the utility of these models through an analysis of CNOT1's roles in cell division, immunity, and poly(A) tail maintenance. We present a valuable toolbox for studying mRNA metabolism in mammalian models, while providing a benchmark for applying degron-tag models to study other biological processes.

Acinetobacter baumannii produces outer membrane vesicles (OMVs) to alleviate envelope stress, though the mechanisms remain poorly understood. To induce periplasmic accumulation of misfolded proteins and trigger stress, a degP mutant is exposed to elevated temperatures. Periplasmic crowding-induced OMV production is demonstrated using fluorescence recovery after photobleaching, where green fluorescent protein is targeted to the periplasm via the DegP signal peptide. OMV proteomics and western blotting reveal accumulation of OmpA and LPS in OMVs. Quantification using lipophilic dye and electron microscopy shows increased OMV production and larger vesicle sizes in degP mutants at elevated temperatures, despite normal growth. Deletion of the lytic transglycosylase mltB abolishes OMV formation in the degP mutant. Interestingly, the surA mutant, characterized by increased outer membrane permeability but impaired OMV production, exhibits enhanced OMV protrusions upon mltB overexpression. These results indicate that peptidoglycan hydrolysis is a key step in OMV biogenesis under periplasmic crowding stress, linking cell wall remodeling to vesicle formation.

Calcium is a key component in the shell and skeleton structure, serving as a second messenger for regulating biomineralization across many species. Ocean acidification (OA) is well-studied for causing shell dissolution in marine bivalve species by disordering calcium deposition. However, the regulatory pathway of calcification affected by OA remains unclear. This study assessed eastern oyster (Crassostrea virginica) to determine how calcium signaling responds to elevated pCO₂ and influences shell formation. Under elevated pCO₂, increased calcium influx was found in mantle epithelial cells, followed by the upregulation of calmodulin, a primary sensor of intracellular calcium. Expression levels of shell matrix proteins (SMPs), representing shell construction conditions, were significantly upregulated in the CO₂-induced mantle cells. Larval C. virginica exhibited developmental stage-dependent alterations in calcium signaling and SMPs disarrangement stimulated by pCO₂. Pharmaceutical blockage of the calcium binding on calmodulin induced abnormal expression of downstream genes and shell matrix changes consistent with those caused by elevated pCO₂. Restored SMPs expressions in CO₂-treated mantle cells were achieved by rescuing the level of calcineurin, a downstream effector of calmodulin. These findings suggest that shell deformities under OA are primarily caused by the disruption of the calcium-calmodulin signaling pathway in mantle epithelial cells.

The mitotic spindle is a microtubule-based apparatus that is responsible for accurate segregation of chromosomes into two daughter cells. In this study, we show that the DNA damage kinase Chk1 is required for optimal density and efficient nucleation of spindle microtubules during unperturbed mitosis in vertebrate cells. Chk1 phosphorylates β-tubulin at the identified conserved site threonine-285 (T285) in vitro, and at mitotic centrosomes in prometaphase and metaphase. Impaired β-tubulin-T285 phosphorylation correlates with improper spindles, delayed anaphase onset, erroneous chromosome alignment and segregation, unequal daughter cell-size and reduced cell proliferation. The ATR-interacting protein ATRIP promotes localization of ATR kinase and the mediator protein TopBP1 to mitotic centrosomes; furthermore, interaction of ATRIP with ATR and TopBP1 is required for Chk1 activation and β-tubulin-T285 phosphorylation. These results identify a signaling pathway that promotes spindle maturation and function in human cells, through Chk1-mediated β-tubulin-T285 phosphorylation.

Activation of free fatty acid receptor 2 (FFAR2) on enteroendocrine L-cells mediates secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), key regulators of central appetite control with therapeutic relevance to obesity. Here, we show that butyrate, a metabolite derived from fermentation of dietary fibre and an FFAR2 agonist, stimulates a PYY-biased profile in a human L-cell model at the transcriptional, morphological and secretory level via an FFAR2-Gαi axis that does not require dynamin-dependent receptor internalisation. We observe that butyrate modulates active Notch cascades within a Hes1-GFP mouse organoid model, which are antagonistic to secretory differentiation, and identify butyrate-dependent regulation of late-stage human enteroendocrine maturation markers, NeuroD1 and Pax6. Butyrate-mediated upregulation of Pyy and Pax6 is enhanced by the FFAR2-selective Gαi biased allosteric agonist AZ-1729. Our study reveals functions of spatiotemporally regulated butyrate-activated FFAR2 signalling mechanisms that could be pharmacologically amplified to fine-tune L-cell populations in the human colon.

Cells and organs constantly experience mechanical forces. Neurons, in particular, are exposed to such stimuli during development, aging, disease, and normal activities like movement and homeostasis. Recent studies highlight the key role of microtubules (MTs) in mechanotransduction, adjusting cytoskeletal dynamics in response to mechanical cues. While the effects of acute forces on MTs are known, the impact of repetitive mechanical stimuli over time remains unclear. In this study, we applied repetitive mechanical motion to neurons from the dorsal root ganglia and analyzed responses at varying strain levels. A 10% strain caused MT and organelle damage, leading to cell death. In contrast, a 2.5% strain did not harm cells and instead stabilized MTs. A 5% strain caused damage to the MT structure and leads to MT destabilization, but neurons activate a molecular response to counteract and recover from this damage, suggesting the involvement of the Ras pathway in response to injury. These findings suggest that neurons can adapt to repetitive mechanical stress, maintaining homeostasis when strain is below a certain threshold. Our results improve understanding of how mechanical forces influence neuronal structure and function, and how cells respond to injury by initiating protective pathways.

Extending culture to blastocysts in vitro enhances embryo selection efficiency and implantation success in mammals, yet the epigenetic mechanisms underlying blastocyst formation remain unclear. Here, we investigate the role of histone acetyltransferase MOF-mediated H4K16ac during sheep blastocyst formation. We find dynamic changes in H4K16ac distribution during development, with a significant increase from the 8-cell stage to blastocyst and stage-specific enrichment in promoters. Inhibition of MOF activity reduces blastocyst formation and induces widespread transcriptional dysregulation and loss of H4K16ac at 3044 genomic peaks. Genes with these peaks are down-regulated and enriched for pathways critical to blastocyst formation. Notably, the lost H4K16ac peaks show reduced chromatin openness and lower RNA polymerase II (Pol2) enrichment, demonstrating the essential role of MOF in RNA Pol2 occupancy during blastocyst formation. Our findings indicate that MOF-mediated H4K16ac is critical for ovine blastocyst formation by promoting chromatin accessibility and RNA Pol2 occupancy at promoters, thereby facilitating appropriate transcriptional programs.