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Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage–myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF. Migrasomes drive fibrosis in sepsis-associated lung damage Sepsis is a severe response to infection that can lead to lung damage, including pulmonary fibrosis. Researchers found that fibroblasts release small particles called migrasomes, which contain mitochondrial DNA (mtDNA) when exposed to lipopolysaccharide, a bacterial component. These migrasomes can be taken up by macrophages, causing them to transform into myofibroblasts (cells that contribute to fibrosis). The study used single-cell RNA sequencing (a method to analyze gene expression in individual cells) and other techniques to observe these changes. They discovered that activating a protein called PGC-1α in fibroblasts can reduce the release of mtDNA migrasomes, thereby decreasing fibrosis. This suggests that targeting PGC-1α could be a potential treatment for sepsis-related lung fibrosis. Future research may focus on understanding the detailed mechanisms of mtDNA’s role in fibrosis and developing therapies based on these findings. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Coal and gas outburst is a dynamic phenomenon in underground mining engineering that is often accompanied by the throwing and breakage of large amounts of coal. To study the crushing effect and its evolution during outbursts, coal samples with different initial particle sizes were evaluated using a coal and gas outburst testing device. Three basic particle sizes, 5–10 mesh, 10–40 mesh, and 40–80 mesh, as well as some mixed particle size coal samples were used in tests. The coal particles were pre-compacted at a pressure of 4 MPa before the tests. The vertical ground stress (4 MPa) and the horizontal ground stress (2.4 MPa) were initially simulated by the hydraulic system and maintained throughout. During the tests, the samples were first placed in a vacuum for 3 h, and the coal was filled with gas (CH 4 ) for an adsorption time of approximately 5 h. Finally, the gas valve was shut off and the coal and gas outburst was induced by quickly opening the outburst hole. The coal particles that were thrown out by the outburst test device were collected and screened based on the particle size. The results show the following. (1) Smaller particle sizes have a worse crushing effect than larger sizes. Furthermore, the well-graded coal particles are weakly broken during the outburst process. (2) As the number of repeated tests increases, the relative breakage index grows; however, the increment of growth decreases after each test, showing that further fragmentation becomes increasingly difficult.

Background Histone lactylation and N6-methyladenosine (m6A) alteration are epigenetic modifications that have a crucial function in controlling gene expression throughout fibroblast activation and organ fibrosis. However, their roles in sepsis-associated pulmonary fibrosis (SAPF) remain unclear. Methods This study established a mouse and cell model induced by lipopolysaccharides (LPS) to investigate the possible mechanisms of lactylation and METTL3-mediated m6A RNA modification in pulmonary fibroblast activation and sepsis-associated PF. The gene expression of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model was examined using scRNA-Seq. Moreover, METTL3 short hairpin RNA (shRNA) and adeno-associated virus (AAV) were employed to knockdown METTL3 expression, and the glycolysis inhibitor Oxamate was utilized to attenuate lactate production and histone lactylation. Furthermore, to confirm the target gene controlled by m6A and H3K18 lactylation (H3K18la), ChIP-qPCR and RNA pulldown investigations were carried out. Results Single-cell RNA-sequencing unveiled the promotion of m6A modification and lactylation in pulmonary fibroblasts of LPS-induced PF mouse model. Furthermore, the induction of LPS resulted in an elevation of H3K18la lactylation and METTL3 concentrations, a reduction in PGC-1α levels, and the onset of mitochondrial dysfunction, all of which contribute to the activation of lung fibroblasts and the development of pulmonary fibrosis. Therapeutic effectiveness was observed in both in vitro and in vivo settings through focused rectification of abnormal histone lactylation or by reducing the expression of METTL3. Conclusion Our study demonstrates, LPS-induced histone lactylation contributes to sepsis-induced pulmonary fibrosis by upregulating METTL3 expression. Additionally, METTL3 recognizes m6A-modified PGC-1α mRNAs, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving pulmonary fibrosis. METTL3-mediated m6A modification potently degraded PGC-1α, leading to mitochondrial dysfunction and accelerated fibroblast activation, ultimately driving Sepsis-Associated PF. This suggests that the presence of histone lactylation in the fibrotic microenvironment associated with sepsis plays a crucial role in triggering the expression and activity of the RNA methyltransferase METTL3.

Background Pulmonary fibrosis (PF) severely impacts both the survival and quality of life of patients with acute respiratory distress syndrome (ARDS) and remains a leading cause of late-stage ARDS-related mortality. The role of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) is pivotal in the development of PF. Methods This study explored the modulation of mitochondrial dynamics and the induction of EMT by pyruvate kinase M2 (PKM2) in AECs, aiming to identify new strategies for the prevention and treatment of sepsis-associated PF. Results The results demonstrated that exposure to LPS increased the levels of PKM2 and the mitochondrial fission marker dynamin-related protein-1 (DRP1), while reducing the levels of the mitochondrial fusion marker mitofusin-2 (MFN2) and the epithelial marker E-cadherin. Moreover, the mesenchymal markers α-SMA and vimentin were upregulated. Treatment with shikonin effectively reversed these alterations, restoring the balance of mitochondrial dynamics, reversing EMT markers, and alleviating the severity of sepsis-associated PF. Conclusions This study identified PKM2 as a crucial regulator of mitochondrial dynamics and EMT in AECs during sepsis-associated PF. Targeting PKM2 activity offers a promising strategy for developing treatments to mitigate the progression of sepsis-associated PF.

Background Ultrasound-guided parasternal intercostal nerve block is rarely used for postoperative analgesia, and its value remains unclear. This study aimed to evaluate the effectiveness of ultrasound-guided parasternal intercostal nerve block for postoperative analgesia in patients undergoing median sternotomy for mediastinal mass resection. Methods This randomized, double-blind, placebo-controlled trial performed in Renmin Hospital, Wuhan University, enrolled 41 participants aged 18–65 years. The patients scheduled for mediastinal mass resection by median sternotomy were randomly assigned were randomized into 2 groups, and preoperatively administered 2 injections of ropivacaine (PSI) and saline (control) groups, respectively, in the 3rd and 5th parasternal intercostal spaces with ultrasound-guided (USG) bilateral parasternal intercostal nerve block. Sufentanil via patient-controlled intravenous analgesia (PCIA) was administered to all participants postoperatively. Pain score, total sufentanil consumption, and postoperative adverse events were recorded within the first 24 h. Results There were 20 and 21 patients in the PSI and control group, respectively. The PSI group required 20% less PCIA-sufentanil compared with the control group (54.05 ± 11.14 μg vs. 67.67 ± 8.92 μg, P  < 0.001). In addition, pain numerical rating scale (NRS) scores were significantly lower in the PSI group compared with control patients, both at rest and upon coughing within 24 postoperative hours. Postoperative adverse events were generally reduced in the PSI group compared with controls. Conclusions USG bilateral parasternal intercostal nerve block effectively reduces postoperative pain and adjuvant analgesic requirement, with good patient satisfaction, therefore constituting a good option for mediastinal mass resection by median sternotomy.

Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.

Along with the rapid development of urbanization and industrialization, the carrying capacity of territorial space has been confronted with a serious crisis. Faced with many uncertain risks and unknown disruptions, it is important to proactively address the uncertainty of future developments in planning and to improve territorial spatial resilience (TSR). Based on the connotation of TSR, we build an assessment framework for TSR containing urban, agricultural and ecological space from three dimensions, including element, structure and function. Using a variety of methods such as the source-sink landscape index, land suitability assessment, and cropland pressure index, we assessed the TSR of the Yangtze River Economic Belt (YREB) from 2000 to 2020 and comprehensively analysed its spatial and temporal evolutionary characteristics. Through data analysis, we observe that the urban spatial resilience (RU) decreases and then increases, while the agricultural spatial resilience (RA) and the ecological spatial resilience (RE) show an increasing trend. The spatial clustering in TSR is apparent, and the distribution of hot and cold spots in RA and RE is reversed in the east–west direction. The changes in TSR are influenced by a combination of RU, RA and RE, which show unique geographical characteristics. Based on the average level and overall evolution of TSR, we divided the study area into five type zones and proposed development strategies for each of them.

Sepsis‐associated pulmonary fibrosis (SAPF) is a life‐threatening condition driven by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition. While metabolic reprogramming, profibrotic extracellular vesicles (EVs), and integrin activation are implicated in pulmonary fibrosis, their interplay remains unclear. This study reveals that succinic acid, a product of glycometabolic reprogramming, promotes macrophage‐mediated endocytosis, driving the release of profibrotic EVs. These EVs transfer integrin beta1 (ITGβ1) from macrophages to fibroblasts, activating fibroblasts and advancing SAPF. Through Single‐cell RNA sequencing (scRNA‐seq), proteomics, immunofluorescence, and electron microscopy, the critical role of EV‐mediated ITGβ1 transfer in macrophage‐fibroblast communication is identified. Knockdown of ITGβ1 or Alix, a mediator of multivesicular bodies (MVBs) biogenesis, inhibited profibrotic EVs formation and alleviated SAPF. These findings highlight a novel mechanism in that the transfer ITGβ1 via EVs plays a critical role in macrophage‐fibroblast communication, representing a novel mechanism underlying SAPF. Targeting EV‐mediated ITGβ1 transfer can provide a promising therapeutic strategy to alleviate the progression of SAPF. Lipopolysaccharide (LPS) stimulates the production of succinic acid in lung tissue, which promotes macrophages endocytosis and the formation of multivesicular bodies (MVBs). These MVBs release profibrotic extracellular vesicles (EVs), facilitating the transfer of integrin beta1 (ITGβ1) transfer and subsequently activating fibroblasts, thereby contributing to the development of sepsis‐associated pulmonary fibrosis (SAPF).

Morphine tolerance remains an intractable problem, which hinders its prolonged use in clinical practice. Endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer's disease, diabetes, atherosclerosis, cancer, etc. In this study, we provide the first direct evidence that ER stress may be a significant driver of morphine tolerance. Binding immunoglobulin protein (BiP), the ER stress marker, was significantly upregulated in neurons in spinal dorsal horn in rats being treated with morphine for 7 days. Additionally, chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. These findings implicate a potential clinical strategy for preventing morphine tolerance and may contribute to expanding the morphine usage in clinic.

Abstract PurposeTo investigate the genetic causes of polyspermy and total fertilization failure (TFF) in two independent male patients suffering from male infertility.MethodsImmunofluorescence (IF) staining was used to detect the localization of the PLCζ protein in sperm and the maternal pronucleus in the zygote. Genomic DNA samples were extracted from the peripheral blood of patients and their families. The ExAC database was used to identify the frequency of corresponding mutations. The PLCZ1 mutations were validated by Sanger sequencing. The pathogenicity of the identified mutations and their possible effects on the protein were assessed using in silico tools and molecular modeling.ResultsWe identified a reported homozygous mutation c.588C > A (p.Cys196Ter) and a compound heterozygous mutation c.2 T > C(p.Met1Thr)/c.590G > A (p.Arg197His) with one novel mutation in PLCZ1. The IF results showed that these multipronuclear zygotes formed as a result of polyspermy. In silico analysis predicted that the mutations result in disease-causing proteins. IF staining revealed that PLCζ is abnormally localized in the sperm samples from the two affected patients. Assisted oocyte activation (AOA) successfully rescued polyspermy and TFF and achieved pregnancy in two patients with the PLCZ1 mutation.ConclusionWe identified a homozygous mutation in PLCZ1 (c.588C > A [p.Cys196Ter]) in a male patient with polyspermy after in vitro fertilization (IVF) as well as a compound heterozygous mutation c.2 T > C(p.Met1Thr)/c.590G > A (p.Arg197His) with one novel mutation in a male patient with fertilization failure after intracytoplasmic sperm injection (ICSI), and we provide evidence that the homozygous mutation can cause polyspermy and the compound heterozygous mutation can cause fertilization failure.