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Abstract Atherosclerosis is a leading cause of cardiovascular diseases, characterized by endothelial dysfunction and lipid accumulation. Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell behavior. This study aimed to investigate the role of lncRNA NORAD in endothelial cell proliferation and as a potential therapeutic target for atherosclerosis. A total of 75 CAD patients and 76 controls were recruited, and plasma NORAD levels were measured using qRT-PCR. HUVECs were transfected with si-NORAD to evaluate its effects on cell cycle, proliferation, migration, and apoptosis. Plasma NORAD levels were significantly elevated in CAD patients. The NORAD-miRNA-mRNA ceRNA regulatory network was constructed based on GEO database, and G1/S-specific cyclin-D1 (CCND1) was identified as one of the hub factors. NORAD deficiency suppressed cell migration and induced G1 cell cycle arrest in HUVECs by downregulating CCND1 in vitro. NORAD upregulated CCND1 in HUVECs via sponging miR-106a that inhibited cell migration. The dual-luciferase assay confirmed the direct targeting of miR-106a by NORAD, and overexpression of miR-106a inhibited HUVEC proliferation and migration. Si-NORAD transfection resulted in induced early apoptosis, increased intracellular ROS levels, decreased GSH levels, and reduced mitochondrial membrane potential. Additionally, si-NORAD decreased the expression of GPX4, FTH1, KEAP1, NCOA4, and Nrf2, while increasing Xct levels, confirming the involvement of ferroptosis. Our findings reveal that NORAD plays a critical role in endothelial cell proliferation, migration, and apoptosis, and its silencing induces ferroptosis. The regulatory network involving NORAD, miR-106a, and their target genes provides a potential therapeutic avenue for atherosclerosis.

Abstract Objective To investigate the status quo of nursing practices, job burnout and social support among private hospitals in Dazhou, Sichuan Province, and perform correlational analysis. Methods A cross-sectional study was conducted. A total of 244 nurses were surveyed via convenience sampling from 7 private hospitals, which were randomly selected from Dazhou city. A self-designed demographic sociology questionnaire was applied, and the Chinese versions of the Maslach Burnout Scale and the Social Support scale administered from September to November 2022. Results The investigated nurses were relatively young (26.84 ± 4.90 years), had a short duration of service, a low academic background, a low professional title and a low income; however, they were highly satisfied with their working environment and had a low level of burnout, and their level of personal achievement was low. Overtime work, education level and number of children had significant impacts on the level of nurse burnout. The level of social support was high, and various dimensions were negatively correlated with the emotional exhaustion and depersonalization dimensions of burnout (r=-0.438, P

Abstract The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic.

Ferroptosis is a unique modality of regulated cell death that is driven by iron-dependent phospholipid peroxidation. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. However, it remains elusive whether m6A reader Fragile X Mental Retardation Protein (FMRP) are involved in the modulation of ferroptosis in breast cancer (BC). In this study, we found that FMRP expression was elevated and associated with poor prognosis and pathological stage in BC patients. Overexpression of FMRP induced ferroptosis resistance and exerted oncogenic roles by positively regulating a critical ferroptosis defense gene SLC7A11. Mechanistically, upregulated FMRP catalyzes m6A modification of SLC7A11 mRNA and further influences the SLC7A11 translation through METTL3-dependent manner. Further studies revealed that FMRP interacts with splicing factor hnRNPM to recognize the splice site and then modulated the exon skip splicing event of SLC7A11 transcript. Interestingly, SLC7A11-S splicing variant can effectively promote FMRP overexpression-induced ferroptosis resistance in BC cells. Moreover, our clinical data suggested that FMRP/hnRNPM/SLC7A11 expression were significantly increased in the tumor tissues, and this signal axis was important evaluation factors closely related to the worse survival and prognosis of BC patients. Overall, our results uncovered a novel regulatory mechanism by which high FMRP expression protects BC cells from undergoing ferroptosis. Targeting the FMRP–SLC7A11 axis has a dual effect of inhibiting ferroptosis resistance and tumor growth, which could be a promising therapeutic target for treating BC.

Protein hydrolysates have attracted much attention for their high biological activity and are a crucial product form for the utilization of foxtail millet bran by-products. In this study, changes in the structure, functionality, activity and peptide profile of foxtail millet bran protein hydrolysates (FMBPHs) at different ultrasound powers (0 – 600 W) were investigated. The results showed that ultrasound promoted the transformation of α-helix and β-sheet to random coils and β-turn, and the exposure of hydrophobic groups and sulfhydryl groups in FMBPHs. The average particle size of the samples decreased, and the absolute value of the ζ-potential increased significantly. Simultaneously, smaller porous particles and loose fragments appeared on the surface of FMBPHs when the ultrasonic power was increased to 450 W. Additionally, 450 W ultrasound treatment improved solubility, foaming properties, emulsifying properties, thermal stability of FMBPHs. The DPPH, ABTS and hydroxyl radical scavenging ability (IC50, 2.65, 1.06 and 3.02 mg/mL), Fe2+ chelating activity (IC50, 2.62 mg/mL), and reducing power of the samples were also enhanced. The peptidomics results demonstrated that ultrasonication increased the number of active peptides in the hydrolysate, and the relative abundance of 17 active peptides was obviously elevated at 450 W. Peptide map analysis showed that ultrasound-induced structural modifications affected the peptide profiles of Ubiquitin-like domain-containing protein, Cupin type-1 domain-containing protein, 40S ribosomal protein S19, and Oleosin 1, showing changes in the abundance of certain peptides, which may be related to changes in the characterization of FMBPHs.

Summary: Background: Microplastics are environmental pollutants detected in various human organs and tissues. These particles originate from multiple sources including the degradation of larger plastic items and the intentional inclusion in consumer goods. Potential risks for human health resulting from microplastics exposure have also been reported. However, the distribution in the male reproductive system and its effect remains largely unknown. This study aims to investigate the presence of multiple microplastics in human semen and urine and their association with sperm quality in a multi-site study across China. Methods: We conducted a cross-sectional study involving 113 male participants from three regions in China. Semen and urine samples were collected and analysed using Raman microscopy to detect eight types of microplastics: polystyrene (PS), polypropylene (PP), polycarbonate (PC), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), and acrylonitrile butadiene styrene (ABS). Semen quality parameters, including total sperm count, concentration, motility, and morphology, were assessed. Statistical analyses, including single and multi-variable models, were used to evaluate the relationship between microplastic exposure and semen quality, with a focus on PTFE, after adjusting confounding factors of age, body mass index (BMI), smoking, alcohol drinking, and sites. Findings: Microplastics were detected in all semen and urine samples, with participants typically exposed to 3–5 different types. The detection rates of PS, PP and PE were the highest. Notably, PTFE exposure was significantly associated with decreased semen quality. Participants exposed to PTFE showed reductions in total sperm count [188.90 ± 163.71 vs. 207.67 ± 132.36 million, p = 0.091], sperm concentration [52.13 ± 47.47 vs. 58.32 ± 37.26 million/mL, p = 0.041], and progressive motility [40.29% ± 19.06 vs. 34.11% ± 17.02, p = 0.083]. The multi-linear regression analysis indicated that each additional type of microplastic exposure was associated with a significant decrease in total sperm number [β = −15.4 (95% CI: −25.6, −5.2)], sperm concentration [β = −7.2 (95% CI: −12.4, −2.0)], and progressive motility [β = −8.3 (95% CI: −13.5, −3.1)]. Latent category analysis further refined these groups by types of microplastic exposure, highlighting specific types more strongly associated with decreased semen quality (OR = 3.5, 95% CI: 1.8, 6.9, p

Abstract Benign prostatic hyperplasia (BPH) is a multifactorial disease in which abnormal growth factor activation and embryonic reawakening are considered important factors. Here we demonstrated that the aberrant activation of transforming growth factor β (TGF-β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. When TGF-β/ROCK1 is abnormally activated, MSCs are recruited and differentiate into fibroblasts/myofibroblasts, leading to prostate stromal hyperplasia. Further research showed that inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation. Collectively, our findings suggest that abnormal activation of TGF-β/ROCK1 regulates stem cell lineage specificity, and the small molecule inhibitor GSK269962A could target ROCK1 and may be a potential treatment for BPH. Graphical Abstract

Abstract Background LncRNA PCED1B-AS1 is abnormally expressed in multiple cancers and has been confirmed as an oncogene. Our study aimed to investigate the regulatory mechanism of lncRNA PCED1B-AS1 in gastric cancer. Methods TCGA database was used to analyze the abnormal expression of lncRNA PCED1B-AS1 in gastric cancer. By database prediction and mass spectrometric analysis, miR-3681-3p and MAP2K7 are potential downstream target molecules of lncRNA PCED1B-AS1 and verified by dual-luciferase report assay. RT-qPCR analysis and western blot were performed to detect the expressions of PCED1B-AS1 and MAP2K7 in gastric cancer cell lines and tissues. CCK-8 kit was applied to measure the cell viability. Wound healing and Transwell experiment were used to detect the migration and invasion. Western blot and immunohistochemical staining were performed to detect the expressions of EMT-related proteins in tissues. The changes of tumor proliferation were detected by xenograft experiment in nude mice. Results PCED1B-AS1 expression was higher but miR-3681-3 expression was lower in gastric cancer cell lines or tissues, compared to normal group. Function analysis verified PCED1B-AS1 promoted cell proliferation and inhibited cell apoptosis in gastric cancer cells in vitro and in vivo. LncRNA PCED1B-AS1 could bind directly to miR-3681-3p, and MAP2K7 was found to be a downstream target of miR-3681-3p. MiR-3681-3p mimics or si-MAP2K7 could partly reverse the effect of PCED1B-AS1 on gastric cancer cells. Conclusion PCED1B-AS1 accelerated cell proliferation and inhibited cell apoptosis through sponging miR-3681-3p to upregulate MAP2K7 expression in gastric cancer, which indicated PCED1B-AS1/miR-3681-3p/MAP2K7 axis may serve as a potential therapeutic target for gastric cancer.

Abstract Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3′-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

Abstract Background Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. Results Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. Conclusions Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis. Graphical abstract

The water-soluble nido-carborane was prepared by alkali treatment of o-carborane. A polymer PInd containing a polyindole structure was synthesized and employed to label the modified o-carborane. Subsequently, four polymeric nanomaterials were synthesized with the objective of encapsulating them in order to enhance its bioavailability. The experimental results showed that the fluorescent complex encapsulated by the pH-sensitive polymer A had the best UV absorption and fluorescence intensity, and thus A-PInd-C was chosen for subsequent experiments. The Transmission electron microscopy images revealed that the compounds exhibited a rounded internal morphology, with the layers exhibiting a tightly stacked arrangement. The AFM imaging revealed that the surface of the sample exhibited a relatively uniform and smooth appearance. In vitro release experiments conducted under acidic conditions demonstrated that A-PInd-C was released in a predominantly linear manner, with a maximum release rate of 80% observed within 48 h. Cellular imaging experiments showed that the compound could enter HeLa and HCT-116 cells and was mainly distributed around the nucleus, especially in the acidic environment. The results of the cell proliferation toxicity experiments demonstrated that A-PInd-C exhibited inhibitory effects on HeLa, PC-3 and L02 cells. Among these, the inhibitory effect on PC-3 cells was the most pronounced, reaching up to 70%. In conclusion, this paper solves the problem of poor bioavailability of carborane by improving the boron containing compounds and also makes the system have potential for Boron neutron capture therapy.

Summary: Background: Gastrointestinal stromal tumors (GISTs) represent the most prevalent type of subepithelial lesions (SELs) with malignant potential. Current imaging tools struggle to differentiate GISTs from leiomyomas. This study aimed to create and assess a real-time artificial intelligence (AI) system using endoscopic ultrasonography (EUS) images to differentiate between GISTs and leiomyomas. Methods: The AI system underwent development and evaluation using EUS images from 5 endoscopic centers in China between January 2020 and August 2023. EUS images of 1101 participants with SELs were retrospectively collected for AI system development. A cohort of 241 participants with SELs was recruited for external AI system evaluation. Another cohort of 59 participants with SELs was prospectively enrolled to assess the real-time clinical application of the AI system. The AI system's performance was compared to that of endoscopists. This study is registered with Chictr.org.cn, Number ChiCT2000035787. Findings: The AI system displayed an area under the curve (AUC) of 0.948 (95% CI: 0.921–0.969) for discriminating GISTs and leiomyomas. The AI system's accuracy (ACC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) reached 91.7% (95% CI 87.5%–94.6%), 90.3% (95% CI 83.4%–94.5%), 93.0% (95% CI 87.2%–96.3%), 91.9% (95% CI 85.3%–95.7%), and 91.5% (95% CI 85.5%–95.2%), respectively. Moreover, the AI system exhibited excellent performance in diagnosing ≤20 mm SELs (ACC 93.5%, 95% CI 0.900–0.969). In a prospective real-time clinical application trial, the AI system achieved an AUC of 0.865 (95% CI 0.764–0.966) and 0.864 (95% CI 0.762–0.966) for GISTs and leiomyomas diagnosis, respectively, markedly surpassing endoscopists [AUC 0.698 (95% CI 0.562–0.834) for GISTs and AUC 0.695 (95% CI 0.546–0.825) for leiomyomas]. Interpretation: We successfully developed a real-time AI-assisted EUS diagnostic system. The incorporation of the real-time AI system during EUS examinations can assist endoscopists in rapidly and accurately differentiating various types of SELs in clinical practice, facilitating improved diagnostic and therapeutic decision-making. Funding: Science and Technology Commission Foundation of Shanghai Municipality, Science and Technology Commission Foundation of the Xuhui District, the Interdisciplinary Program of Shanghai Jiao Tong University and the Research Funds of Shanghai Sixth people’s Hospital.

Polystyrene nanoplastics (PS-NPs) have been reported to accumulate in the testes and constitute a new threat to reproductive health. However, the exact effects of PS-NPs exposure on testicular cells and the underlying mechanisms remain largely unknown. The C57BL/6 male mice were orally administered with PS-NPs (80 nm) at different dosages (0, 10, and 40 mg/kg/day) for 60 days, and GC-1 cells were treated with PS-NPs in this study. Enlarged seminiferous tubule lumens and a loose and vacuolated layer of spermatogenic cells were observed in PS-NPs-exposed mice. Spermatogenic cells which may be one of the target cells for this reproductive damage, were decreased in the mice from PS-NPs group. PS-NPs caused spermatogenic cells to undergo senescence, manifested as elevated SA-β-galactosidase activity and activated senescence-related signaling p53-p21/Rb-p16 pathways, and induced cell cycle arrest. Mechanistically, Gene Ontology (GO) enrichment suggested the key role of reactive oxygen species (ROS) in PS-NPs-induced spermatogenic cell senescence, and this result was confirmed by measuring ROS levels. Moreover, ROS inhibition partially attenuated the senescence phenotype of spermatogenic cells and DNA damage. Using the male health atlas (MHA) database, Sirt1 was filtrated as the critical molecule in the regulation of testicular senescence. PS-NPs induced overexpression of the main ROS generator Nox2, downregulated Sirt1, increased p53 and acetylated p53 in vivo and in vitro, whereas these disturbances were partially restored by pterostilbene. In addition, pterostilbene intervention significantly alleviated the PS-NPs-induced spermatogenic cell senescence and attenuated ROS burst. Collectively, our study reveals that PS-NPs exposure can trigger spermatogenic cell senescence mediated by p53-p21/Rb-p16 signaling by regulating the Sirt1/ROS axis. Importantly, pterostilbene intervention may be a promising strategy to alleviate this damage.

Background: Esophageal gastrointestinal stromal tumors (E-GISTs) are highly uncommon and have not been thoroughly examined. Objectives: The objective of this multi-center study was to assess the viability of endoscopic resection (ER) in the treatment of E-GISTs and to explore its clinical implications. Design: This was a multi-center retrospective study. Consecutive patients referred to the four participating centers. Methods: E-GISTs among the consecutive subepithelial tumors (SETs) treated by ER methods were enrolled from April 2019 to August 2022. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. Results: A total of 23 patients with E-GISTs were included for analysis, accounting for 1.9% of all the esophageal SETs (1243 patients). The average size of the tumor lesions was 2.3 cm (range 1.0–4.0 cm). We observed that tumors larger than 2.0 cm were more likely to grow deeper, with a statistically significant difference ( p

Abstract Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5 + BMSCs and Tek + BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5 + BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.

Abstract Background Helicobacter pylori (H.pylori, HP) is one of the main causes of gastric cancer (GC). CircRNAs have been reported to play a crucial role in developing many types of cancer. However, the role of circRNAs in the development and progression of HP infected-GC has not been studied. Methods The location of circRNA_15430 in GC cells were detected by nuclear and cytoplasmic RNA fractionation and RNA fluorescence in situ hybridization analysis (FISH) assays, and circRNA_15430, miR-382-5p and ZCCHC14 expression in GC cell lines and tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The function of circRNA_15430 in GC cells were examined by using colony formation, cell counting kit-8 (CCK-8) and Transwell assays, flow cytometry and laser scanning confocal microscopy. The protein levels were detected by Western blotting. Whether circRNA_15430 sponges miR-382-5p was monitored with a dual-luciferase reporter assay. Furthermore, circRNA_15430 was analyzed in vivo in tumor growth with nude mice. Results CircRNA_15430 is primarily localized in the cytoplasm of GC cells, and downregulated in the GC cell lines and tissues, and is negatively correlated with the tumor size. Downregulation of circRNA_15430 promotes proliferation, migration and suppresses cell apoptosis and autophagy in GC cells. Mechanically, circRNA_15430 acts as a miR-382-5p sponge, alleviating the inhibitory effect of miR-382-5p on its target ZCCHC14. Knockdown circRNA_15430 enhances tumor growth in vivo. In addition, circRNA_15430 was reduced in HP + gastritis tissues and HP-infected MGC-803 cells, reversing the pro-HP effect on autophagy. Additionally, miR-382-5p was increased in HP + gastritis tissue and HP-infected MGC-803 cells while ZCCHC14 decreased in HP-infected MGC-803 cells. MiR-382-5p reverses the effect of si-ZCCHC14 on autophagosome numbers in MGC-803 cells. Conclusions Therefore, circRNA_15430 plays an inhibitory role in GC and regulates the progression of HP infection-related GC, providing a novel molecular marker for GC therapy.

Abstract Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.

Background: In recent years, fracture liaison services (FLS) have been applied for hip fractures; however, their effectiveness remains uncertain. Objective: To evaluate the effectiveness of FLS in patients with hip fractures. Design: A systematic review and meta-analysis of randomized controlled trials. Data sources: Embase, PubMed, Cochrane Library, Ebsco, Ovid, Web of Science, Medline, CNKI, Wangfang, and Vip were searched from their date of inception to March 2023. Two researchers screened the literature based on the inclusion and exclusion criteria, evaluated the quality, extracted data, and conducted a meta-analysis using ReviewManager 5.4. Results: After screening, 12 randomised controlled trials (RCT) including 2136 patients were used in the meta-analysis. The primary outcomes were hip function rate of recurrent fracture, medication adherence, and degree of weakness. FLS improved hip function in patients with hip fractures [MD = 9.37, 95 % CI (7.69, 11.06), P

Abstract CircRNAs have critical effects on tumor development and progression. However, circPGD effect on gastric cancer (GC) is still elusive. Nuclear and cytoplasmic RNA fractionation, and RNA-FISH assay examined the localization of circPGD in MGC-803 cells. qRT-PCR was conducted to detect the expression and prognostic significance of circPGD, miR-16-5p, and ABL2 within GC tissues. Meanwhile, qRT-PCR, luciferase reporter assays, rescue, and western blotting assays confirmed the interactions between circPGD, miR-16-5p, and ABL2. Transwell, wound healing, and colony-formation assays, as well as CCK-8 and cell apoptosis assays, analyzed the functions of circPGD, miR-16-5p, ABL2, as well as PGD-219aa within GC cells. Western blotting and cell immunofluorescence experiments detected the differences in the expression of the related proteins. Finally, xenograft and metastatic mouse models were used to investigate circPGD function in vivo. Mass spectrometry was used to detect the existence of PGD-219aa in MGC-803 cells. CircPGD was localized in the cytoplasm and nucleus of MGC-803 cells. Compared with the control, circPGD and ABL2 expression increased within GC tissues and cells, and the miR-16-5p level was decreased. Functionally, circPGD promoted cell proliferation, migration and suppressed apoptosis in vitro. Mechanistically, circPGD sponged miR-16-5p for relieving miR-16-5p suppression on the corresponding target ABL2 via the SMAD2/3 and YAP signaling pathways. In addition, circPGD encodes a novel PGD-219aa protein that can enhance the growth and migration of GC cells, while inhibiting GC cells apoptosis via the SMAD2/3 and YAP signaling pathways. Furthermore, circPGD overexpression enhanced tumor aggressiveness, while circPGD knockdown inhibited tumor growth. Overall, circPGD has a novel oncogenic effect on GC cells, indicating the potential of circPGD as the tumorigenic factor and a promising diagnostic marker for GC.

Face generation and manipulation techniques based on deep learning have enabled the creation of sophisticated forged facial videos, which are indistinguishable by human eyes. However, the illegal use of deep fake technology will have a serious impact on social stability, personal reputation, and even national security. Therefore, the detection technology of fake facial videos is of great significance to protect national security and maintain social order. Although the existing video-based fake face video detection technology has achieved good detection performance on the public fake face video database, there are still the following problems: (1) the existing technology uses a 2D attention mechanism to obtain local region features from face images and lacks a 3D attention mechanism to obtain local area features from face videos; (2) after obtaining local area features, the existing technology is directly used to classify or only model the inter-regional relationship of images without modeling the temporal relationship between regions of the video. This paper proposes a fake facial video detection framework based on multi-region temporal relationship features, including designing a three-dimensional attention mechanism to extract local features of multiple regions of the face from the video. In order to model the time series relationship between different face areas, a time series graph convolution neural network is also introduced to extract the time series relationship features between multiple areas. In order to model the time sequence relationship between different face regions, the convolution neural network of a time sequence diagram is also introduced to extract the characteristics of the time sequence relationship between multiple regions. Through the change characteristics of the time sequence relationship between face regions, the timing inconsistency of the face video is detected so as to determine whether the face has been deeply forged. Through experiments on multiple datasets, the experimental results of the model accuracy test show that the method proposed in the present invention achieves the highest detection accuracy, and the accuracy in the FaceForensics++ (low definition) dataset is 18.19% higher than that of the benchmark method. The experimental results of the generalization ability test show that the method proposed in the present invention achieves the highest generalization performance, and the detection accuracy in the Celeb-DF dataset is 11.92% higher than that of the benchmark method.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive. Objectives: This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms. Methods: The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders. Results: The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling. Conclusion: Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.

Background: N6-methyladenosine (m6A) modification is a common epigenetic methylation modification of RNA, which plays an important role in gastric carcinogenesis and progression by regulating long non-coding RNA (lncRNA). This study is aimed to investigate the potential prognostic signatures of m6A -related lncRNAs in STAD.Methods: The m6A-related lncRNAs with the most significant impact on gastric cancer prognosis in the TCGA database were identified by bioinformatics and machine learning methods. The m6A-related lncRNA prognostic model (m6A-LPS) and nomogram was constructed by Cox regression analysis with the minimum absolute contraction and selection operator (LASSO) algorithm. The functional enrichment analysis of m6A-related lncRNAs was also investigated. The miRTarBase, miRDB and TargetScan databases were utilized to establish a prognosis-related network of competing endogenous RNA (ceRNA) by bioinformatics methods. The correlation of AL391152.1 expressions and cell cycle were experimentally testified by qRT-PCR and flow cytometry.Results: In total, 697 lncRNAs that were identified as m6A-related lncRNAs in GC samples. The survival analysis showed that 18 lncRNAs demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of GC patients. Cox regression analysis and ROC curve indicated that this lncRNA prediction model was an independent risk factor for survival rates. Functional enrichment analysis and ceRNA network revealed that the nomogram was notably associated with cell cycle. qRT-PCR and flow cytometry revealed that downregulation of GC m6A-related lncRNA AL391152.1 could decrease cyclins expression in SGC7901 cells.Conclusion: A m6A-related lncRNAs prognostic model was established in this study, which can be applied to predict prognosis and cell cycle in gastric cancer.

ABSTRACT: Magnolol (MAG) is a multifunctional plant polyphenol with anti-inflammatory, antibacterial, antioxidant and antitumor properties. In poultry, it has been shown to improve growth performance, antioxidant, immune functions and intestinal health. However, its applications are limited by poor solubility and low oral bioavailability. This study aimed at improving the water solubility of MAG through solid dispersion and investigating its effects in Arbor Acre (AA) broilers. Hydroxypropyl methylcellulose succinic acid (HPMCAS) was used as a carrier to prepare magnolol solid dispersions (MAG-HPMCAS SD) via antisolvent coprecipitation, which were characterized thereafter. Optimal formulation proportions for SD were screened by in vitro dissolution assays, while its effects on improving absorption were investigated via in vivo pharmacokinetic assays. In addition, we evaluated the effects of MAG-HPMCAS SD on growth performance, antioxidant status, and gut microbiota in AA broilers. The powder samples prepared via antisolvent coprecipitation did not exhibit a crystal diffraction peak of MAG in powder X-ray diffractions or melting point peak in differential scanning calorimetry, proving the successful preparation of an amorphous solid dispersion system. The in vitro dissolution assay showed that the cumulative dissolution rate of MAG-HPMCAS(LF) SD (2:8, w/w) was 100%. Pharmacokinetic analyses revealed that the peak concentration (Cmax) of MAG-HPMCAS SD was 5.07 ± 0.73 μg/mL, which was 1.76 times greater than that of MAG. In addition, AUC0–48 and t1/2 of MAG-HPMCAS SD were 40.49 ± 6.29 g·h/mL and 9.15 ± 3.23 h, respectively, which were 2.17 and 2.56 times higher than those of MAG. Supplementation of MAG-HPMCAS SD in AA broilers significantly increased ADG (7–14 d and 15–21 d) and reduced feed conversion ratio (15–21 d) (P < 0.05). Bacterial diversity in the MAG-HPMCAS SD-supplemented group was greater than in the Control and MAG-supplemented group. Supplementation of MAG-HPMCAS SD stimulated the proliferation of beneficial bacteria, such as Lactobacillaceae and Bifidobacteriaceae. In conclusion, the MAG-HPMCAS SD prepared by coprecipitation improved the dissolution rate, the bioavailability of MAG, growth promotion, antioxidant effects and gut health in broilers.

The tail rotor of a helicopter, a crucial component, traditionally relies on a complex drive mode involving reducers and transmission gears. This conventional setup, with its lengthy transmission chain and numerous components, hinders miniaturization efforts. In response to this challenge, our paper presents a novel piezoelectric drive approach. Our objective was to suggest an innovative design capable of minimizing the components involved in the tail rotor drive. This design can be adjusted in size according to specific requirements and is effective up to a specified speed. Moreover, it facilitates the process of miniaturization and integration. The piezoelectric actuator’s stator comprises an ultrasonic amplitude transformer, a ring, and three drive teeth. Utilizing the rod-like structure of the tail brace, the actuator is simplified by adhering ceramic sheets to it. The rotary piezoelectric actuator combines the first longitudinal mode of a rod with torus bending modes. The drive teeth then amplify the ring’s displacement, facilitating rotor rotation. The resonant frequency and modal shape of the actuator were determined using the finite element method. Furthermore, an investigation was conducted to analyze the influence of the drive teeth positioning on the motion trajectory at the contact point. Theoretically, we infer that the declination angle of the drive tooth is a crucial parameter for achieving high speeds. To test our idea, we built three prototype stators with different drive tooth declination angles. Our actuator stands out for its cost-effectiveness, structural simplicity, compatibility with harmonic signals, and ease of miniaturization. It can be considered for the drive of the tail rotor of a microhelicopter.

Emerging research findings suggest that airborne particulate matter might be a risk factor for gestational diabetes mellitus (GDM). However, the concentration–response relationships and the susceptible time windows for different types of particulate matter may vary. In this retrospective analysis, we employ a novel robust approach to assess the crucial time windows regarding the prevalence of GDM and to distinguish the susceptibility of three GDM subtypes to air pollution exposure. This study included 16,303 pregnant women who received routine antenatal care in 2018–2021 at the Maternal and Child Health Hospital in Chongqing, China. In total, 2482 women (15.2%) were diagnosed with GDM. We assessed the individual daily average exposure to air pollution, including PM2.5, PM10, O3, NO2, SO2, and CO based on the volunteers’ addresses. We used high-accuracy gridded air pollution data generated by machine learning models to assess particulate matter per maternal exposure levels. We further analyzed the association of pre-pregnancy, early, and mid-pregnancy exposure to environmental pollutants using a generalized additive model (GAM) and distributed lag nonlinear models (DLNMs) to analyze the association between exposure at specific gestational weeks and the risk of GDM. We observed that, during the first trimester, per IQR increases for PM10 and PM2.5 exposure were associated with increased GDM risk (PM10: OR = 1.19, 95%CI: 1.07~1.33; PM2.5: OR = 1.32, 95%CI: 1.15~1.50) and isolated post-load hyperglycemia (GDM-IPH) risk (PM10: OR = 1.23, 95%CI: 1.09~1.39; PM2.5: OR = 1.38, 95%CI: 1.18~1.61). Second-trimester O3 exposure was positively correlated with the associated risk of GDM, while pre-pregnancy and first-trimester exposure was negatively associated with the risk of GDM-IPH. Exposure to SO2 in the second trimester was negatively associated with the risk of GDM-IPH. However, there were no observed associations between NO2 and CO exposure and the risk of GDM and its subgroups. Our results suggest that maternal exposure to particulate matter during early pregnancy and exposure to O3 in the second trimester might increase the risk of GDM, and GDM-IPH is the susceptible GDM subtype to airborne particulate matter exposure.

Abstract Background Intrauterine adhesion (IUA) is a clinical disease characterized by the uterine cavity occlusion caused by the damage of the endometrial basal layer. Bone marrow mesenchymal stem cells (BMSCs) transplantation have the potential to promote endometrial regeneration mainly through paracrine ability. Estrogen is an indispensable and important factor in the repair of endometrial damage, which has been reported as a promising and adjunctive therapeutic application for stem cell transplantation therapy. This study aims to investigate the synergistic effect of BMSCs and estrogen on improving the endometrial regeneration and restoring the endometrium morphology in a dual damage model of IUA in rabbits and the underlying molecular mechanisms. Methods BMSCs were isolated and identified by adipogenic and osteogenic differentiation and flow cytometry assays. The rabbit IUA animal model was established by a dual damage method of mechanical curettage and lipopolysaccharide infection. Additionally, we investigated the therapeutic impact of both BMSCs and estrogen either separately or in combination in a rabbit model. The retention of PKH26-labeled BMSCs was observed by vivo fluorescence imaging.The number of endometrial glands and the degree of fibrosis were observed by H&E and Masson staining respectively. Western blotting, Immunohistochemistry and immunofluorescence staining were performed to detect biomarkers related to endometrial epithelium, endometrial fibrosis and EMT. Finally, the protein expression of core molecules of Wnt/β-catenin pathway was detected by Western blotting. Results PKH26-labeled fluorescence results revealed that BMSCs appeared and located in the endometrial glands and extracellular matrix area when orthotopic transplanted into the uterine cavity. Histological assays showed that remarkably increasing the number of endometrial glands and decreasing the area of endometrial fibrosis in the BMSCs combined with estrogen treatment group. Moreover, downregulated expression of fibrosis markers (fibronectin, CollagenI, a-SMA) and interstitial markers (ZEB1, Vimentin, N-cadherin), as well as upregulated E-cadherin expression were found in the combined group. Further study of in vivo staining revealed that fluorescence intensity of CK7 was stronger in the combined group than that of direct BMSCs intrauterine transplantation, while vimentin showed the opposite results. Moreover, the protein levels of β-catenin, Axin2, C-myc, CycinE of Wnt/β-catenin signaling pathway increased in the BMSCs combined with estrogen group than in the other treatment groups. Conclusion BMSCs combined with estrogen can promote the differentiation of stem cells into endometrial epithelial cells to facilitate the regeneration of damaged endometrium. The potential mechanism of the synergistic effect may inhibit the occurrence of EMT by activating the Wnt/β-catenin signaling pathway.

This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.

Abstract In the present work, two novel coordination polymers on the basis of Cu(II) are hydrothermally produced via utilizing 2,5‐dichloroterephthalic acid (H2DCTP), a halogenated linear ligand with the existence of diverse flexible nitrogen‐donor ligands of the 1,4‐bis(5,6‐dimethylbenzimidazol‐1‐yl)‐2‐butylene (L2) and the 1,1′‐(1,4‐butanediyl)bis‐1H‐benzimidazole (L1), and their chemical formulae are [Cu(L1)(DCTP)]n (1) and [Cu(L2)(DCTP)]n (2). The evaluation of two compounds’ treatment effect against the thyroid cancer was carried out, and meanwhile, their relevant mechanism was also studied. First of all, the cancer cells proliferation was detected through Cell Counting Kit‐8 (CCK‐8) detection kit. Furthermore, the JAK‐STAT signalling pathway activation has been assessed through employing real time RT‐PCR assay. Finally, the toxicity of the new compounds was evaluated with MTT assay.

Abstract It has been 40 years since the Chinese Environmental Mutagen Society (CEMS) was established in 1981. Now, it has grown a first-level national society in China, which has 15 professional committees and more than 5000 members. Over the past 40 years, the CEMS has been making many contributions to advance the research of environmental mutagens in China and cultivate professional talents in this field. In the twenty-first century, looking back on what the CEMS has gone through and accomplished, and in light of the major changes in our tasks and mission in the new era, we must plan well for the future, to overcome our shortcomings, to embrace greater development of the CEMS.

Overlapping community structures are universal in complex networks. Multi-label propagation approach, as a method for detecting overlapping community, has been received widespread attention for the near linear time complexity. In recent years, some algorithms based on multi-label propagation approach have been proposed, but there is still room to improve the accuracy of these algorithms to detect overlapping communities. In this paper, a double-layer filtering strategy is proposed to help nodes filter labels, and the node centrality of each node according to the number of its neighbors and the number of edges between its neighbors is used to fix the node update sequence. Then based on the double-layer filtering strategy, the new fixed node update sequence and the previous multi-label propagation algorithm, a new algorithm called MLPA-DF is proposed. Theory analysis shows that MLPA-DF still has the near linear time complexity. And experimental results on the synthetic and real-world networks show that MLPA-DF has better performance than previous multi-label propagation algorithms (COPRA, SLPA and LPANNI) in terms of the accuracy of detecting overlapping communities without reducing stability.

ObjectiveTo investigate the association between pre-pregnancy body mass index (BMI) and gestational depressive phenotypes.MethodsThe pregnant women receiving the first prenatal examination (4th –13th week of gestation) in Chongqing Health Center for Women and Children were recruited between February 2020 and September 2021. Depressive phenotypes was assessed by the Patient Health Questionnaire (PHQ-9) and the Symptom Checklist 90 (SCL-90) scale at recruitment. Pre-pregnancy weight and height were self-reported by the participants. Demographic and obstetric characteristics were obtained from the hospital information system. The association between pre-pregnancy BMI and the scores of PHQ-9 or SCL-90 scale was investigated by uni-variate analysis with Kruskal-Wallis test and by multi-variate analysis with linear regression model with adjustment of age, parity, smoking, alcohol consumption, and assisted reproduction. The association between pre-pregnancy BMI and PHQ-9 or SCL-90 diagnosed depressive phenotypes was analyzed by Chi-square test and logistic regression respectively.ResultsA total of 12,099 pregnant women were included, where 100% of them filled out the PHQ-9 scale and 99.6% filled out the SCL-90 scale, and 47.26% and 4.62% of the pregnant women had depressive phenotypes, respectively. Women with higher pre-pregnancy BMI had lower depressive phenotypes scores during pregnancy. Multivariable analysis of the PHQ-9 scale showed that overweight/obese subjects had a higher incidence of depressive phenotypes compared with subjects with normal BMI (OR=0.803, 95% CI [0.723, 0.892]). In a stratified analysis assessed by the PHQ-9, women who were overweight/obese prior to pregnancy were less likely to develop depressive phenotypes during pregnancy than women who were normal weight prior to pregnancy, regardless of whether they were nulliparous (OR=0.795, 95%CI[0.696,0.908]) or multiparous (OR=0.809, 95%CI[0.0.681,0.962]), while in the three age groups of 25-29 years, 30-34 years and ≥35 years, pre-pregnancy overweight/obesity were associated with lower risk of gestational depressive phenotypes. However, analysis of the SCL-90 scale showed no statistical association between depressive symptom and BMI. No substantial interaction was observed between BMI and parity or age.ConclusionsIncreased pre-pregnancy BMI may be associated with reduced risk of gestational depressive phenotypes in Chinese women. Independent studies are warranted to validate the findings of the present study.

Abstract Objectives To explore the role of folate metabolism in 1,3-Butadiene (BD)'s genotoxicity, we conducted a match-up study in BD-exposed workers in China to analyze the associations between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the chromosomal damage induced by BD exposure, and culture-based experiments in TK-6 cells to examine the global DNA methylation levels and chromosomal damage when exposed both to BD’s genotoxic metabolite, 1,2:3,4-diepoxybutane (DEB), and MTHFR’s direct catalytic product, 5-methyltetrahydrofolate (5-MTHF). Methods Cytokinesis block micronucleus assay (CBMN) was used to examine the chromosomal damage induced by BD or DEB. Poisson regression models were produced to quantify the relationship of chromosomal damage and genetic polymorphisms in the BD-exposed workers. Global DNA methylation levels in TK6 cells were examined using DNA Methylation Quantification Kit. Results We found that BD-exposed workers carrying MTHFR C677T CC (2.00 ± 2.00‰) (FR = 0.36, 95%CI: 0.20–0.67, P

AimPublic concerns over the mental health problems of college students are rising. Previous research show that female tend to suffer more from mental health problems than males, with few studies focusing on males. This study sought to explore the association of lifestyle-related risk factors with the prevalence of mental health problems among male college students in China.MethodsThe lifestyle information and mental health status of 686 male college students from Chongqing, China, were assessed in 2014, and 582 of them were followed up a year later. Participants completed a questionnaire assessing demographic and lifestyle factors which include sleep quality, computer usage, sedentariness, physical activity, smoking, current alcohol, coke, coffee, and milk tea drinking, and current tea/fried food/baked food consumption. Mental health problems were measured using the Depression Anxiety Stress Scale-21 (DASS-21).ResultsUnivariate analyses indicated that age, sleep latency, sleep duration, computer usage time, milk tea drinking, and fried food consumption were potential risk factors for mental health problems (p's < 0.05). Multivariate analysis further revealed that, either at baseline or during follow-up, participants with (i) more computer usage time were at a higher risk of having depression symptoms (p's < 0.05) and (ii) a higher frequency of fried food consumption were associated with a higher risk of having depression, anxiety, and stress symptoms (p's < 0.05). Additionally, the cross-lagged analysis showed that (i) computer usage time in 2014 is positively correlated with depression status (β = 0.106, p < 0.05) but not anxiety (β = 0.047, p > 0.05) and stress (β = 0.019, p > 0.05) status a year later and (ii) fried food consumption in 2014 is positively correlated with depression (β = 0.129, p < 0.01), anxiety (β = 0.168, p < 0.001), and stress (β = 0.113, p < 0.01) status a year later.ConclusionsComputer usage time and fried food consumption were lifestyle-related risk factors for mental health problems in male college students in Chongqing, China. These results might emphasize further preventive strategies for mental health problems, especially in male college students.

The effects of ambient fine particles on male reproductive health have raised widespread concern. The particular underlying mechanisms of the damage remain largely unclear and demand more research in new directions. Previous research has revealed that DNA methylation plays an important role in male reproductive development and is also vulnerable to environmental influences. However, there hasn't been enough investigation into the involvement of DNA methylation in PM2.5-induced male reproductive toxicity. Here, we establish a real-time PM2.5 exposure model and revealed that PM2.5 exposure could lead to testicular dysfunction including spermatogenesis impairment and steroid hormone dysfunction. In particular, the decrease in the testicular global level of 5-methylcytosine (5mC) indicated a possible association of DNA methylation with testicular injury induced by PM2.5 exposure. Further genome-wide methylation analysis revealed genomic hypomethylation of testicular DNA and identified more than 1000 differentially methylated regions in both CAP and UA versus FA, indicating that PM2.5 exposure, even low-dose, could modulate the testicular methylome. Furthermore, integrated analysis of methylome and transcriptome identified some key methylated genes and networks, which may be involved in spermatogenesis and synthesis of steroid hormone. The testicular methylation levels of key genes especially Cyp11a1 and Pax8 raised, and their consequent reduced expression may impair the testosterone and sperm production process. Our research provides fundamental knowledge as well as novel insights into the possible involvement of DNA methylation in PM2.5-induced male reproductive harm.

This present work underlines the effect of pH-shifting at pH 2 and pH 12 individually or combined with ultrasound treatment to modify the molecular structure of β-conglycinin (7S) on its emulsifying properties and stability. Fourier transform infrared (FTIR) spectroscopy and intrinsic fluorescence spectroscopy showed that pH-shifting improves the molecular structure of 7S, while ultrasound further promotes structural changes. In particular, the pH-shifting at pH 12 combined with ultrasound treatment (U-7S-12) resulted in more significant changes than the pH-shifting at pH 2 combined with ultrasound (U-7S-2). U-7S-12 showed a significant reduction in protein particle size from 152 to 34.77 nm and a relatively smooth protein surface compared to 7S. The protein had the highest surface hydrophobicity and flexibility at 81,560.0 and 0.45, respectively, and the free sulfhydryl content from 1.57 to 2.02 μmol/g. In addition, we characterized the emulsions prepared after 7S treatment. The single or combined treatment increased the interfacial protein adsorption of the samples, which showed lower viscosity and shear stress compared to 7S. The U-7S-12 emulsion exhibited the highest emulsifying properties and was more stable than other emulsions under creaming, heating, and freeze–thaw conditions. In summary, the concerted action of pH-shifting and ultrasound can modify the structure, and combined alkaline pH-shifting and ultrasound treatment can further improve the emulsifying properties and stability of 7S.

Benzo[a]pyrene (B[a]P), a representative of polycyclic aromatic hydrocarbons (PAHs), is ubiquitously spread in the environment and showing deleterious impacts on male steroidogenesis, including testosterone synthesis disorder. However, the precise mechanisms involved in B[a]P-induced steroidogenesis perturbation remains obscure. In the present study, we integrated in vivo tests, transcriptome profiling, in vitro assays, and conjoint in silico toxicological approaches to delineate the detailed mechanisms. In mouse models, we observed that B[a]P administration remarkably inhibited testosterone synthesis accompanied by ultrastructural impairments of mitochondria and mitophagosome formation in mouse Leydig cells. Transcriptome profiling showed that B[a]P down-regulated the expression of Ndufa9, Ndufa6, Ndufa10, and Ndufa5 in mouse testes, which are identified as critical genes involved in the assembly and functionality of mitochondrial complex I. In the in vitro tests, the bioactive B[a]P metabolite BPDE induced perturbation of testosterone synthesis by NDUFA10-mediated mitochondrial impairment, which was further exacerbated by mitophagy in TM3 Leydig cells. The findings of in silico toxicological analyses were highly consistent with the experimental observations and further unveiled that B[a]P/BPDE-involved PPARα activation could serve as a molecular initiating event to trigger the decline in Ndufa10 expression and testosterone synthesis. Overall, we have shown the first evidence that mitochondrial compromise in Leydig cells is the extremely crucial target in B[a]P-induced steroidogenesis perturbation.

Ga2O3-based solar-blind ultraviolet photodetectors (PDs) have stimulated extensive attention for covering both civilian and military applications. During the past decade, Ga2O3-based solar-blind PDs have made a great progress in key metrics such as responsivity, detectivity and gain. However, they still suffer from relatively slow response time, from milliseconds to seconds. The trapping states at the surface/interface are believed to contribute to the low response speed. Besides the intrinsic factors, external factors including the illumination and bias voltage also have an important influence on the photoresponse speed. However, there is no in-depth analysis of illumination and bias impact on the photoresponse properties. Herein, we present an experimental investigation on the illumination intensity and bias voltage modulating response speed in a typical Ga2O3-based photoconductive PD. The photoresponse time can be accelerated up to two orders by varying the illumination and bias. The superior photoresponse capabilities of the Ga2O3-based PDs can be ascribed to the light controllable trap/de-trap processes as well as electric field accelerated carrier transport. The study offers clear images of the charge diffusion and drift process in the photodetector upon external stimuli, which will aid to optimize the performance of Ga2O3-based PDs.

China, the largest hog producer and consumer globally, has long experienced significant fluctuations in hog prices, partly due to the lack of rational expectations for future hog spot prices. However, on 8 January 2021, China’s first futures in animal husbandry, the live hog futures, were listed on the Dalian Commodity Exchange. To investigate the forecasting performance of the new live hog futures on forthcoming hog spot prices, we developed six futures-based forecasting models and utilized data on daily hog spot and futures prices from January 2021 to March 2023. Our results show that all six models consistently generate more accurate forecasts than the no-change model across six prediction horizons and four accuracy measures, indicating that China’s new live hog futures prices help forecast forthcoming hog spot prices. Among the futures-based forecasting models, futures spread-based models generally produce the best forecasts for one-, two-, three-, and four-month-ahead forecasting, while the simple linear regression using both spot and futures prices is the best for five- and six-month-ahead forecasting. Our results suggest that live hog futures are a promising and practical tool for various stakeholders in China’s hog industry to develop rational expectations for future hog spot prices.

We propose an improved BM3D algorithm for block-matching based on UNet denoising network feature maps and structural similarity (SSIM). In response to the traditional BM3D algorithm that directly performs block-matching on a noisy image, without considering the deep-level features of the image, we propose a method that performs block-matching on the feature maps of the noisy image. In this method, we perform block-matching on multiple depth feature maps of a noisy image, and then determine the positions of the corresponding similar blocks in the noisy image based on the block-matching results, to obtain the set of similar blocks that take into account the deep-level features of the noisy image. In addition, we improve the similarity measure criterion for block-matching based on the Structural Similarity Index, which takes into account the pixel-by-pixel value differences in the image blocks while fully considering the structure, brightness, and contrast information of the image blocks. To verify the effectiveness of the proposed method, we conduct extensive comparative experiments. The experimental results demonstrate that the proposed method not only effectively enhances the denoising performance of the image, but also preserves the detailed features of the image and improves the visual quality of the denoised image.

Objective: The aim of the study was to evaluate the advantages of without enzyme isolating patellar fat pad-derived mesenchymal stem cells (IPFP-SCs) and the feasibility of cartilage repair.Methods: The IPFP-SCs were isolated using the without enzyme method and compared with the IPFP-SCs obtained by the traditional enzyme digestion method in terms of cell proliferation ability, characterization, and differentiation ability, and the differences in chondrogenic induction and differentiation between the two groups were compared. Twenty-four New Zealand rabbits were randomly divided into four groups (n = 6). After the articular cartilage defects were modeled, different preparations were injected into the joint cavity. The rabbits in the group A were injected with the mixture of IPFP-SCs and pure PRP (P-PRP), separated using the without enzyme method, while those in the group B were injected with the mixture of IPFP-SCs and P-PRP separated with the digestion method, while those in the group C were injected with SVF separated using the without enzyme method, and those in the group D were injected with normal saline. At 6 weeks and 12 weeks after operation, the cartilage repair of rabbit joint specimens was observed and evaluated by gross observation and histological staining, and the effects of different IPFP-SCs application forms in repairing cartilage defects were compared.Results: The time required to obtain IPFP-SCs by enzyme-free isolation was significantly less than that by enzyme digestion, while the acquisition rate of primary cells was significantly lower than that by enzyme digestion. After culture and amplification, the two IPFP-SCs from different sources did not show significant differences in cell proliferation, cell phenotype, and differentiation ability. In animal experiments, groups A and B had the best effect on the repair of cartilage defects, and there was no significant difference between the two groups. The repair effect in group C was weaker than that in the former two groups, but it was relatively better than that in group D.Conclusion: It is more time-saving to obtain IPFP-SCs by the without enzyme method than by enzymatic digestion, and there is no significant difference in cell identification and differentiation potential between the two methods. However, the rate of obtaining primary cells was significantly lower than that with the enzyme digestion method. IPFP-SCs showed good repair effect in the rabbit animal cartilage defect model, providing ideas and reference for the clinical application of stem cells in repairing articular cartilage.

Diuretics have been one of the well-known nephrotoxic drugs which can lead to acute kidney injury (AKI). However, there are few real-world studies on the incidence of AKI in hospitalized patients received diuretics. In the present study, a single-center retrospective study was conducted in our center. The clinical data of hospitalized patients received diuretics from January 2018 to December 2020 was retrospectively analyzed. Among the 18,148 hospitalized patients included in the study, 2,589 patients (14.26%) were judged as incidence with AKI, while only 252 patients were diagnosed with AKI in the medical record. Among diuretics drugs in the study, the incidence rate of AKI with torasemide was the highest with 21.62%, and hydrochlorothiazide had the lowest incidence rate (6.80%). The multiple logistic regression analysis suggested that complicated with hypertension, anemia, pneumonia, shock, sepsis, heart failure, neoplastic diseases, combined use of proton pump inhibitors (PPI) were independent risk factors for AKI related to diuretics. The logic regression models for diuretics related AKI were developed based on the included data. The model for diuretics-AKI achieved the area under the receiver operating characteristic curves (AUC) with 0.79 on 10-fold cross validation. It is urgent to improve the understanding and attention of AKI in patients received diuretics for medical workers, and the assessment of risk factors before the use of diuretics should be contributed to the early prevention, diagnosis and treatment of AKI, and ultimately reducing morbidity and improving prognosis.

Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM2.5 on Sertoli cells using the TM4 cell line and a real time whole-body PM2.5 exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM2.5 reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM2.5 exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM2.5 exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM2.5-exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM2.5. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM2.5 induced DNA damage response and cell cycle arrest. Additionally, PM2.5 induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM2.5 via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis.

Abstract Both Alzheimer's disease (AD) and osteoporosis (OP) are common age‐associated degenerative diseases and are strongly correlated with clinical epidemiology. However, there is a lack of clear pathological relationship between the brain and bone in the current understanding. Here, it is found that young osteocyte, the most abundant cells in bone, secretes extracellular vesicles (OCYYoung‐EVs) to ameliorate cognitive impairment and the pathogenesis of AD in APP/PS1 mice and model cells. These benefits of OCYYoung‐EVs are diminished in aged osteocyte‐derived EVs (OCYAged‐EVs). Based on the self‐constructed OCY‐EVs tracer transgenic mouse models and the in vivo fluorescent imaging system, OCY‐EVs have been observed to be transported to the brain under physiological and pathological conditions. In the hippocampal administration of Aβ40 induced young AD model mice, the intramedullary injection of Rab27a‐shRNA adenovirus inhibits OCYYoung‐EVs secretion from bone and aggravates cognitive impairment. Proteomic quantitative analysis reveals that OCYYoung‐EVs, compared to OCYAged‐EVs, enrich multiple protective factors of AD pathway. The study uncovers the role of OCY‐EV as a regulator of brain health, suggesting a novel mechanism in bone‐brain communication.

Abstract Background The incidence of thyroid cancer is increasing worldwide. This study investigated the association of B-type RAF kinase (BRAF)V600E mutation status, the expression of BRAF-activated long non-coding RNA (BANCR) and microRNA miR-9, and the clinicopathological features of papillary thyroid carcinoma (PTC). Methods Clinicopathological data for PTC patients (n = 51) diagnosed and treated between 2018 and 2019 were collected. Carcinoma and adjacent normal tissue samples were analyzed for the presence of the BRAFV600E mutation and/or expression of BANCR and miR-9. Results Larger tumor, higher rate of bilateral tumors and multifocality, extracapsular invasion, and lateral lymph node metastasis (LNM) were observed in PTC patients with BRAF V600E mutation. Patients with higher BANCR expression had a higher rate of extracapsular invasion and lateral LNM in carcinoma tissue and a lower frequency of bilateral tumors and multifocality in normal adjacent tissue. Patients with higher miR-9 expression had a lower rate of central and lateral LNM in carcinoma tissue and higher rates of bilateral tumor location and multifocality in normal adjacent tissue. Patients with BRAFV600E mutation have a higher rate of BANCR overexpression and tended to have a lower rate of miR-9 overexpression (P = 0.057), and a negative association was observed between BANCR and miR-9 expression in carcinoma tissue. Conclusions BRAFV600E mutation and the BANCR and miR-9 expression were closely associated with the tumor size, bilateral tumor location, multifocality, extracapsular invasion, and lateral LNM. PTC patients with these clinicopathological characteristics, BRAFV600E mutation, and high BANCR expression and low miR-9 expression needed earlier surgical treatment and are recommended for total thyroidectomy in primary surgery for reducing the risk of recurrence. These findings provide new insight into the molecular basis for PTC and can inform strategies for the management of PTC.

Abstract Background Total hip arthroplasty (THA) is one of the most successful orthopedic surgeries. There are many common surgical approaches for THA. The direct anterior approach (DAA) and posterolateral approach (PLA) were compared, leading to controversial results. Methods We report on a prospective randomized study which compared the changes of perioperative hemoglobin (Hb), the Harris hip score (HHS) and a visual analog scale (VAS) pain score following THA using DAA or PLA. A total of 130 participants were randomly divided into two groups (65 DAA versus 65 PLA). Perioperative ΔHb and other clinical outcomes were recorded. Results A total of 130 participants completed follow-up, while 14 patients were not recorded in blood outcomes due to blood transfusions and complications. The average Hb decrease immediately after surgery in the DAA group was greater than that in the PLA group (21.1 versus 15.8 g/L, P < .001). However, post-operative Hb descent velocity was slower in the DAA group, and the lowest point was reached earlier. No significant differences in ΔHb levels could be observed after 1 month in the two groups. When compared with the PLA group, the DAA group had a shorter incision (9.1 versus 13.5 cm, P < .001) and shorter hospital stay (4.2 versus 4.7 days, P = .004). However, the operation time of the DAA group was longer (88.0 versus 66.8 min, P < .001). The DAA group had a better HHS and VAS pain score at 6 weeks post-surgery. However, no significant differences were observed at later time points. Conclusion We concluded that DAA performed better on enhanced recovery after surgery (ERAS) than PLA in THA, while both DAA and PLA could result in a positive, similar result after 3 months. Trial registration The study was registered by the Chinese Clinical Trial Registry ( ChiCTR1900020770 , 19 January 2019).

Fine particulate matter (PM2.5)-induced male reproductive toxicity arouses global public health concerns. However, the mechanisms of toxicity remain unclear. This study aimed to further investigate toxicity pathways by exposure to PM2.5in vitro and in vivo through the application of metabolomics and transcriptomics. In vitro, spermatocyte-derived GC-2spd cells were treated with 0, 25, 50, 100 μg/mL PM2.5 for 48 h. In vivo, the real-world exposure of PM2.5 for mouse was established. Forty-five male C57BL/6 mice were exposed to filtered air, unfiltered air, and concentrated ambient PM2.5 in Tangshan of China for 8 weeks, respectively. The results in vitro and in vivo showed that PM2.5 exposure inhibited GC-2spd cell proliferation and reduced sperm motility. Mitochondrial damage was observed after PM2.5 treatment. Increased Humanin and MOTS-c levels and decreased mitochondrial respiratory indicated that mitochondrial function was disturbed. Furthermore, nontargeted metabolomics analysis revealed that PM2.5 exposure could disturb the citrate cycle (TCA cycle) and reduce amino acids and nucleotide synthesis. Mechanically, the aryl hydrocarbon receptor (AhR) pathway was activated after exposure to PM2.5, with a significant increase in CYP1A1 expression. Further studies showed that PM2.5 exposure significantly increased both intracellular and mitochondrial reactive oxygen species (ROS) and activated NRF2 antioxidative pathway. With the RNA-sequencing technique, the differentially expressed genes induced by PM2.5 exposure were mainly enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, of which Cyp1a1 was the most significantly changed gene. Our findings demonstrated that PM2.5 exposure could induce spermatocyte damage and energy metabolism disorder. The activation of the aryl hydrocarbon receptor might be involved in the mechanism of male reproductive toxicity.

Entity and relation extraction (ERE) is a core task in information extraction. This task has always faced the overlap problem. It was found that heterogeneous graph attention networks could enhance semantic analysis and fusion between entities and relations to improve the ERE performance in our previous work. In this paper, an entity and relation heterogeneous graph attention network (ERHGA) is proposed for joint ERE. A heterogeneous graph attention network with a gate mechanism was constructed containing word nodes, subject nodes, and relation nodes to learn and enhance the embedding of parts for relational triple extraction. The ERHGA was evaluated on the public relation extraction dataset named WebNLG. The experimental results demonstrate that the ERHGA, by taking subjects and relations as a priori information, can effectively handle the relational triple extraction problem and outperform all baselines to 93.3%, especially overlapping relational triples.