CircTMTC1 Mediates Nucleo-cytoplasmic Translocation of DDX3X to Regulate Osteogenic Differentiation of Human Ligamentum Flavum Cells.

OBJECTIVE: This study was aimed to investigate the potential roles of circTMTC1 in the underlying pathophysiological mechanisms of ossification of the ligamentum flavum (OLF). SUMMARY OF BACKGROUND DATA: OLF is the primary contributor to thoracic spinal stenosis, which may cause severe neurological symptoms. There is a lack of effective medical therapy for OLF available so far because the exact underlying mechanism of OLF has not been fully elucidated. CircRNAs are a special class of non-coding RNAs and have attracted a growing interest of research in various human diseases recently. Therefore, we explored the potential roles of circRNAs in the underlying pathophysiological mechanisms of OLF. METHODS: We performed RNA-seq analysis to investigate the differentially expression profile of circRNAs in osteogenic differentiation of human LF cells, and identified a key circular RNA circTMTC1 functioned in OLF. Subsequently, we performed a series of experiments to investigate the exact molecular and cellular mechanisms in osteogenic differentiation of human ligamentum flavum cells. RESULTS: CircTMTC1 is significantly up-regulated during osteogenic differentiation of human LF cells. Mechanistically, we found that circTMTC1 could interact with the RNA binding protein DDX3X and enhance its nucleo-cytoplasmic translocation. An increased cytoplasmic level of DDX3X activated the NLRP3 inflammasome pathway and thus promoted osteogenic differentiation of human ligamentum flavum cells. CONCLUSION: Our findings suggested the circTMTC1-DDX3X-NLRP3 inflammasome signaling plays a pivotal role in osteogenic differentiation of human ligamentum flavum cells, which may provide novel diagnostic and therapeutic strategies for OLF.

N-Doped Porous Carbon Based on Anion and Cation Storage Chemistry for High-Energy and Power-Density Zinc Ion Capacitor.

Zinc ion hybrid capacitors (ZIHCs) show promise for large-scale energy storage because of their low cost, highly intrinsic safety, and eco-friendliness. However, their energy density has been limited by the lack of advanced cathodes. Herein, a high-capacity cathode material named N-doped porous carbon (CFeN-2) is introduced for ZIHCs. CFeN-2, synthesized through the annealing of coal pitch with FeCl3·6H2O as a catalytic activator and melamine as a nitrogen source, exhibits significant N content (10.95 wt%), a large surface area (1037.66 m2 g-1), abundant lattice defects and ultrahigh microporosity. These characteristics, validated through theoretical simulations and experimental tests, enable a dual-ion energy storage mechanism involving Zn2+ ions and CF3SO3 - anions for CFeN-2. When used as a cathode in ZIHCs, CFeN-2 achieves a high-energy density of 142.5 W h kg-1 and a high-power density of 9500.1 W kg-1. Furthermore, using CFeN-2 ZIHCs demonstrate exceptional performance with 77% capacity retention and nearly 100% coulombic efficiency after 10 000 cycles at 10 A g-1, showcasing substantially superior performance to current ZIHCs. This study offers a pathway for developing high-energy and high-power cathodes derived from coal pitch carbon for ZIHC applications.

[Research progress on the changes of blood-brain barrier in sepsis-associated encephalopathy].

Sepsis-associated encephalopathy (SAE) is the most common neurological complication of sepsis, with an incidence of up to 70% in sepsis, and contributes to the increased mortality and disability in sepsis. To date, the exact pathogenesis of SAE is not clear. Most of current researches indicated that blood-brain barrier (BBB) dysfunction, active neuroinflammation, glial cell over activation as well as cerebral microcirculation dysfunction contributed to the pathophysiology of SAE. BBB, as a complex cellular structure between the central nervous system and the peripheral system, strictly controls the entrance and discharge of substances and plays an important role in maintaining the balance between biochemical system and immune system of central system. During the progress of sepsis, inflammatory cytokines and reactive oxygen species resulting from peripheral system directly or indirectly resulted in the damage to the integrity and structure of BBB, which helped above species easily enter into the central system. Above these damages caused glial cell activation (microglia and astrocyte), the imbalance of neurotransmitters, mitochondrial dysfunction and neural apoptosis, which also reversely contributed to the damage to the integrity and permeability of BBB via decreasing the expression of tight junctional protein between cells. Therefore, this review focuses on the structural and functional changes of BBB in SAE, and how these changes lead to the development of SAE, in order to seek a BBB-targeted therapy for SAE.

Abemaciclib increases the risk of venous thromboembolism in breast cancer: Integrate meta-analysis, pharmacovigilance database analysis, and in vitro validation.

BACKGROUND: Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro. METHODS: PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test. FINDINGS: A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration. INTERPRETATION: Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.

Genome-wide analysis of the AP2/ERF gene family in Pennisetum glaucum and the negative role of PgRAV_01 in drought tolerance.

APETALA2/ethylene-responsive (AP2/ERF) plays crucial roles in resisting diverse stresses and in regulating plant growth and development. However, little is known regarding the structure and function of the AP2/ERF genes in pearl millet (Pennisetum glaucum). The AP2/ERF gene family may be involved in the development and maintenance of P. glaucum resilience to abiotic stresses, central to its role as a vital forage and cereal crop. In this study, PgAP2/ERF family members were identified and comprehensive bioinformatics analyses were performed, including determination of phylogenetic relationships, gene structures, conserved motifs, chromosomal localization, gene duplication, expression pattern, protein interaction network, and functional characterization of PgRAV_01 (Related to ABI3/VP1). In total, 78 PgAP2/ERF members were identified in the P. glaucum genome and classified into five subfamilies: AP2, ERF, DREB, RAV, and soloist. Members within the same clade of the PgAP2/ERF family showed similar gene structures and motif compositions. Six duplication events were identified in the PgAP2/ERF family; calculation of Ka/Ks values showed that purification selection dominated the evolution of PgAP2/ERFs. Subsequently, a potential interaction network of PgAP2/ERFs was generated to predict the interaction relationships. Additionally, abiotic stress expression analysis showed that most PgAP2/ERFs were induced in response to drought and heat stresses. Furthermore, overexpression of PgRAV_01 negatively regulated drought tolerance in Nicotiana benthamiana by reducing its antioxidant capacity and osmotic adjustment. Taken together, these results provide valuable insights into the characteristics and functions of PgAP2/ERF genes, with implications for abiotic stress tolerance, and will ultimately contribute to the genetic improvement of cereal crop breeding.

High-Sensitivity Enzyme-Free Fluorescence Probe Based on CRISPR/Cas13 and the Isothermal Amplification Strategy for Axl Sensing.

Axl is an important receptor tyrosine protein kinase that plays a key role in the development and progression of various diseases, such as cancer and inflammation. Developing a highly sensitive Axl detection method can help improve accuracy, better address-specific clinical needs, and guide personalized treatment. In this study, a CHA-CRISPR/Cas13 fluorescence probe was established using Axl-specific aptamers as a mediator to displace the polynucleotide chain (TA). Through TA construction, an entropy-driven nucleotide catalytic hairpin assembly system was created to cyclically release RNA that activates clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13 activity, triggering its cleavage activity. The activated CRISPR/Cas13 system cleaves the reporter labeled with BHQ1 and FAM at both ends, leading to the recovery of FAM fluorescence. Based on the optimization design using the free energy (△G) and secondary structure software simulation results of the nucleic acid sequence, the fluorescence intensity of the probe is proportional to the concentration of Axl. Results showed a good linear relationship between fluorescence intensity increment and log CAxl (CAxl in the range of 3.33-667 pM, r = 0.9907). The probe exhibited ultrahigh sensitivity with a detection limit of 0.84 pM. It was successfully applied in the detection of human serum samples, showing a higher Axl level in cervical cancer patients compared to breast cancer patients. The probe was also successfully applied in the imaging of various tumor cells, consistent with serum detection results. In conclusion, this probe represents an effective new method for detecting Axl, demonstrating outstanding specificity and sensitivity. It provides technological support for tumor diagnosis and shows the potential for detecting circulating tumor cells in blood through cell imaging.

Chinese Medicine in Colorectal Cancer Treatment: From Potential Targets and Mechanisms to Clinical Application.

Colorectal cancer (CRC) is a global health challenge necessitating innovative therapeutic strategies. There is an increasing trend toward the clinical application of integrative Chinese medicine (CM) and Western medicine approaches. Chinese herbal monomers and formulations exert enhanced antitumor effects by modulating multiple signaling pathways in tumor cells, including inhibiting cell proliferation, inducing apoptosis, suppressing angiogenesis, reversing multidrug resistance, inhibiting metastasis, and regulating immunity. The synergistic effects of CM with chemotherapy, targeted therapy, immunotherapy, and nanovectors provide a comprehensive framework for CRC treatment. CM can mitigate drug toxicity, improve immune function, control tumor progression, alleviate clinical symptoms, and improve patients' survival and quality of life. This review summarizes the key mechanisms and therapeutic strategies of CM in CRC, highlighting its clinical significance. The potential for CM and combination with conventional treatment modalities is emphasized, providing valuable insights for future research and clinical practice.

Polymer-Supported Pd Nanoparticles for Solvent-Free Hydrogenation.

Breaking the trade-off between activity and stability of supported metal catalysts has been a long-standing challenge in catalysis, especially for metal nanoparticles (NPs) with high hydrogenation activity but poor stability. Herein, we report a porous poly(divinylbenzene) polymer-supported Pd NP catalyst (Pd/PDVB) with both high activity and excellent stability for the solvent-free hydrogenation of nitrobenzene, even at ambient temperature (25 °C) and H2 pressure (0.1 MPa). Pd/PDVB gave a turnover frequency as high as 22,632 h-1 at 70 °C and 0.4 MPa, exceeding 5556 h-1 of the classical Pd/C catalyst under equivalent conditions. Mechanistic studies reveal that the polymer support benefits the desorption of the aniline product from the Pd surface, which is crucial for rapid hydrogenation under solvent-free conditions. In addition, the polymer support in Pd/PDVB efficiently hindered Pd leaching, resulting in good stability.

Efficient elimination of antibiotics and antibiotic resistance genes in hyperthermophilic sludge composting.

Composting is widely applied in recycling ever-increasing sewage sludge. However, the insufficient elimination of antibiotics and antibiotic resistance genes (ARGs) in conventional compost fertilizer poses considerable threat to agriculture safety and human health. Here we investigated the efficacy and potential mechanisms in the removal of antibiotics and ARGs from sludge in hyperthermophilic composting (HTC) plant. Our results demonstrated that the HTC product was of high maturity. HTC led to complete elimination of antibiotics and potential pathogens, as well as removal of 98.8 % of ARGs and 88.1 % of mobile genetic elements (MGEs). The enrichment of antibiotic-degrading candidates and related metabolic functions during HTC suggested that biodegradation played a crucial role in antibiotic removal. Redundancy analysis (RDA) and structural equation modelling (SEM) revealed that the reduction of ARGs was attributed to the decline of ARG-associated bacteria, mainly due to the high-temperature selection. These findings highlight the feasibility of HTC in sludge recycling and provide a deeper understanding of its mechanism in simultaneous removal of antibiotics and ARGs.

Tackling the plastisphere: the single-cell Raman spectroscopy framework.

Conventional bulk molecular approaches, often limited by their destructive nature and low spatial resolution, face challenges when probing the intricate dynamics of the plastisphere. Here, we outline a framework employing Raman spectroscopy combined with stable isotope profiling (SIP) to interrogate the physiological function of the plastisphere microbiome and track its evolutionary trajectories.

Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration.

Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value.Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/ß-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

Engineered probiotic ameliorates ulcerative colitis by restoring gut microbiota and redox homeostasis.

Probiotics are potential treatments for ulcerative colitis (UC), but their efficacy is frequently compromised by gastrointestinal conditions that limit adhesion and activity. Here, we use machine learning and bioinformatics to confirm that patients with UC have decreased prevalence of Lactobacillus genus and increased oxidative stress, which correlate with inflammation severity. Accordingly, we developed a probiotic-based therapeutic that synergistically restores intestinal redox and microbiota homeostasis. Lactobacillus casei (Lac) were induced to form a pericellular film, providing a polysaccharide network for spatially confined crystallization of ultrasmall but highly active selenium dots (Se-Lac). Upon oral administration, the selenium dot-embedded pericellular film efficiently enhanced gastric acid resistance and intestinal mucoadhesion of Lac cells. At the lesion site, the selenium dots scavenged reactive oxygen species, while Lac modulated the gut microbiota. In multiple mouse models and non-human primates, this therapeutic effectively relieved inflammation and reduced colonic damage, thus showing promise as a UC treatment.

Giant mucinous liposarcoma of the abdominal cavity: A case report.

RATIONALE: Mucinous liposarcoma myxoid liposarcoma is a malignant mucoid soft tissue tumor derived from undifferentiated stromal cells in perivascular, subbody cavity and intermuscular space, and composed of cells at different stages of differentiation from preadipocytes to mature cells. In rare cases, it may change from lipoma malignancy. The main manifestations is painless mass, relatively slow growth, the course can last decades, the prevalence of liposarcoma in the population is 14% to 18%, mainly in adults, male prevalence is higher than women, but not significant. The main good hair part is the thigh, have mucinous sex, high differentiation type, dedifferentiation type, polymorphic type. Clinical diagnosis is difficult, and there are no obvious symptoms in the early stage, so the diagnosis should be combined with B ultrasound, MRI, CT, and other auxiliary examinations. The gold standard is pathological examination. In December 2023, our department admitted a patient with a mucinous abdominal mass. The report is as follows. PATIENT CONCERNS: Does liposarcoma metastasize? Is any chemotherapy required after surgery? Will it ever relapse in the future? What is the survival period after surgery? DIAGNOSIS: Mucinous liposarcoma. INTERVENTIONS: Surgical resection of the sarcoma. RESULTS: The nodule sample was 33 * 28 * 13 cm, with complete capsule, gray and yellow sections, fine texture, soft, gray, red, grayish, and yellow mucoid nodules in some areas, and the maximum diameter of the nodules was 21cm. Immunohistochemistry was: CD34 (+), CDK 4 (+), CK (-), Desmin (weak +), Ki67 (index 5%), MDM 2 (-), p16 (weak +), S-100P (+), Vimentin (+), BCL-2 (+). He was also sent to the Department of Pathology of Peking Union Medical College Hospital for consultation with Professor Lu Zhaohui, whose consultation opinion was in line with myxoliposarcoma. CONCLUSION: Retroperitoneal liposarcoma is a common retroperitoneal tumor, but it is relatively rare in clinical practice; the overall morbidity is low, mainly manifested as abdominal pain and abdominal distension, abdominal distension, and a long course of disease; it is not sensitive to radiotherapy and chemotherapy, and should be closely follow up by CT examination to understand the recurrence and metastasis.

Comprehensive analysis of B3 family genes in pearl millet (Pennisetum glaucum) and the negative regulator role of PgRAV-04 in drought tolerance.

Introduction: Members of the plant-specific B3 transcription factor superfamily play crucial roles in various plant growth and developmental processes. Despite numerous valuable studies on B3 genes in other species, little is known about the B3 superfamily in pearl millet. Methods and results: Here, through comparative genomic analysis, we identified 70 B3 proteins in pearl millet and categorized them into four subfamilies based on phylogenetic affiliations: ARF, RAV, LAV, and REM. We also mapped the chromosomal locations of these proteins and analyzed their gene structures, conserved motifs, and gene duplication events, providing new insights into their potential functional interactions. Using transcriptomic sequencing and real-time quantitative PCR, we determined that most PgB3 genes exhibit upregulated expression under drought and high-temperature stresses, indicating their involvement in stress response regulation. To delve deeper into the abiotic stress roles of the B3 family, we focused on a specific gene within the RAV subfamily, PgRAV-04, cloning it and overexpressing it in tobacco. PgRAV-04 overexpression led to increased drought sensitivity in the transgenic plants due to decreased proline levels and peroxidase activity. Discussion: This study not only adds to the existing body of knowledge on the B3 family's characteristics but also advances our functional understanding of the PgB3 genes in pearl millet, reinforcing the significance of these factors in stress adaptation mechanisms.

Neuroprotective Effects of Phenolic Constituents from Drynariae Rhizoma.

This study aimed to provide scientific data on the anti-Alzheimer's disease (AD) effects of phenolic compounds from Drynariae Rhizoma (DR) extract using a multi-component approach. Screening of DR extracts, fractions, and the ten phenolic compounds isolated from DR against the key AD-related enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), and monoamine oxidase-B (MAO-B) confirmed their significant inhibitory activities. The DR extract was confirmed to have BACE1-inhibitory activity, and the ethyl acetate and butanol fractions were found to inhibit all AD-related enzymes, including BACE1, AChE, BChE, and MAO-B. Among the isolated phenolic compounds, compounds (2) caffeic acid 4-O-ß-D-glucopyranoside, (6) kaempferol 3-O-rhamnoside 7-O-glucoside, (7) kaempferol 3-o-b-d-glucopyranoside-7-o-a-L-arabinofuranoside, (8) neoeriocitrin, (9) naringin, and (10) hesperidin significantly suppressed AD-related enzymes. Notably, compounds 2 and 8 reduced soluble Amyloid Precursor Protein ß (sAPPß) and ß-secretase expression by over 45% at a concentration of 1.0 µM. In the thioflavin T assay, compounds 6 and 7 decreased Aß aggregation by approximately 40% and 80%, respectively, and degraded preformed Aß aggregates. This study provides robust evidence regarding the potential of DR as a natural therapeutic agent for AD, highlighting specific compounds that may contribute to its efficacy.

Serum trace elements show association with thyroperoxidase autoantibodies in Thyroid Imaging Reporting and Data System (TI-RADS) 4 nodules.

Thyroid nodule (TN) has been becoming a great concern worldwide due to its high incidence. Although some studies have reported associations between trace elements exposure and the risk of TNs, the linkage was not inconclusive. The present study aimed to identify the association of selected serum trace elements (Ca, Mg, V, Fe, Co, Cu, Zn, Se, Mn and Mo) with TNs among general adults. A cross-sectional study was conducted in January 2021 in Chengdu, China. 1282 subjects completed the questionnaire and gave at least one human biological material after an overnight fast, venous blood, and urine, including 377 TN participants defined through ultrasound. Various trace elements in serum specimens were determined by inductively coupled plasma mass spectrometry. Thyroid functions were tested by chemiluminescent microparticle immunoassay (CMIA). The associations between trace elements levels and the risk of TNs were examined by restricted cubic splines (RCS) regression and bayesian kernel machine regression (BKMR) models. TNs were more common in females (P < 0.001) and in the elderly (P < 0.001) and that they were also frequently associated with fertility, marital status, annual household income, drinking, anxiety, vitamin supplement, tea consumption, hypertension and hyperlipidemia. After adjusting for confounders by a propensity score matching model, the association between trace elements concentrations and TNs risk was found to be statistically insignificant in the RCS (P for nonlinear > 0.05) and BKMR models. FT3 or T4 (total or free) increased significantly with increasing total trace elements mixture levels. In TI-RADS-4 TN subjects, TPO-Ab level increased significantly with increasing total trace elements mixture levels in the high-dose range. Ca, Zn, Mo at their 75th percentile showed positive individual effects on TPO-Ab, which was examined to be interactive. The detection of trace elements for TNs in general adults may be of no significance, but once individuals classified as TI-RADS-4 TNs are detected with abnormal TPO-Ab, Ca, Zn and Mo level are recommended to measure. The substantive association on it still needs to be continuously explored in the future.

Long-term exposure to ozone and sleep disorders in children: A multicity study in China.

Evidence regarding the link between long-term ambient ozone (O3) exposure and childhood sleep disorders is little. This study aims to examine the associations between long-term exposure to O3 and sleep disorders in children. We conducted a population-based cross-sectional survey, including 185,428 children aged 6-18 years in 173 schools across 14 Chinese cities during 2012 and 2018. Parents or guardians completed a checklist using Sleep Disturbance Scale for Children, and O3 exposure at residential and school addresses was estimated using a satellite-based spatiotemporal model. We used generalized linear mixed models to test the associations with adjustment for factors including socio-demographic variables, lifestyle, meteorology and multiple pollutants. Mean concentrations of O3, particulate matter with diameters ≤2.5 mm (PM2.5) and nitrogen dioxide (NO2) were 89.0 µg/m3, 42.5 µg/m3 and 34.4 µg/m3, respectively. O3 and NO2 concentrations were similar among provinces, while PM2.5 concentration varied significantly among provinces. Overall, 19.4% of children had at least one sleep disorder. Long-term exposure to O3 was positively associated with odds of sleep disorders for all subtypes. For example, each interquartile increment in home-school O3 concentrations was associated with a higher odds ratio for global sleep disorder, at 1.22 (95% confidence interval: 1.18, 1.26). Similar associations were observed for sleep disorder subtypes. The associations remained similar after adjustment for PM2.5 and NO2. Moreover, these associations were heterogeneous regionally, with more prominent associations among children residing in southeast region than in northeast and northwest regions in China. We concluded that long-term exposure to O3 is positively associated with risks of childhood sleep disorders. These associations varied by geographical region of China.

Revealing the novel metabolism-related genes in the ossification of the ligamentum flavum based on whole transcriptomic data.

Backgrounds: The ossification of the ligamentum flavum (OLF) is one of the major causes of thoracic myelopathy. Previous studies indicated there might be a potential link between metabolic disorder and pathogenesis of OLF. The aim of this study was to determine the potential role of metabolic disorder in the pathogenesis of OLF using the strict bioinformatic workflow for metabolism-related genes and experimental validation. Methods: A series of bioinformatic approaches based on metabolism-related genes were conducted to compare the metabolism score between OLF tissues and normal ligamentum flavum (LF) tissues using the single sample gene set enrichment analysis. The OLF-related and metabolism-related differentially expressed genes (OMDEGs) were screened out, and the biological functions of OMDEGs were explored, including the Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and protein-protein interaction. The competing endogenous RNA (ceRNA) network based on pairs of miRNA-hub OMDEGs was constructed. The correlation analysis was conducted to explore the potential relationship between metabolic disorder and immunity abnormality in OLF. In the end, the cell experiments were performed to validate the roles of GBE1 and TNF-α in the osteogenic differentiation of LF cells. Results: There was a significant difference of metabolism score between OLF tissues and normal LF tissues. Forty-nine OMDEGs were screened out and their biological functions were determined. The ceRNA network containing three hub OMDEGs and five differentially expressed miRNAs (DEmiRNAs) was built. The correlation analysis between hub OMDEGs and OLF-related infiltrating immune cells indicated that metabolic disorder might contribute to the OLF via altering the local immune status of LF tissues. The cell experiments determined the important roles of GBE1 expression and TNF-α in the osteogenic differentiation of LF cells. Conclusions: This research, for the first time, preliminarily illustrated the vital role of metabolic disorder in the pathogenesis of OLF using strict bioinformatic algorithms and experimental validation for metabolism-related genes, which could provide new insights for investigating disease mechanism and screening effective therapeutic targets of OLF in the future.

Host genetic variation and specialized metabolites from wheat leaves enriches for phyllosphere Pseudomonas spp. with enriched antibiotic resistomes.

Antibiotic resistance in plant-associated microbiomes poses significant risks for agricultural ecosystems and human health. Although accumulating evidence suggests a role for plant genotypes in shaping their microbiome, almost nothing is known about how the changes of plant genetic information affect the co-evolved plant microbiome carrying antibiotic resistance genes (ARGs). Here, we selected 16 wheat cultivars and experimentally explored the impact of host genetic variation on phyllosphere microbiome, ARGs, and metabolites. Our results demonstrated that host genetic variation significantly influenced the phyllosphere resistomes. Wheat genotypes exhibiting high phyllosphere ARGs were linked to elevated Pseudomonas populations, along with increased abundances of Pseudomonas aeruginosa biofilm formation genes. Further analysis of 350 Pseudomonas spp. genomes from diverse habitats at a global scale revealed that nearly all strains possess multiple ARGs, virulence factor genes (VFGs), and mobile genetic elements (MGEs) on their genomes, albeit with lower nucleotide diversity compared to other species. These findings suggested that the proliferation of Pseudomonas spp. in the phyllosphere significantly contributed to antibiotic resistance. We further observed direct links between the upregulated leaf metabolite DIMBOA-Glc, Pseudomonas spp., and enrichment of phyllosphere ARGs, which were corroborated by microcosm experiments demonstrating that DIMBOA-Glc significantly enhanced the relative abundance of Pseudomonas spp. Overall, alterations in leaf metabolites resulting from genetic variation throughout plant evolution may drive the development of highly specialized microbial communities capable of enriching phyllosphere ARGs. This study enhances our understanding of how plants actively shape microbial communities and clarifies the impact of host genetic variation on the plant resistomes.

GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress.

BACKGROUND: Acetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein-coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI). METHODS: GPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116△HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI. RESULTS: Intrahepatic GPR116 was upregulated in human and mice with AILI. GPR116△HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116△HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with ß-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model. CONCLUSIONS: Upregulation of GPR116 on hepatocytes inhibits ER stress by binding to ß-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.