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Abstract Background Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. Methods Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan–Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. Results Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54–3.90) for severe liver disease (SLD), and 2.81 (2.60–3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. Conclusions High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.

Abstract Background Infertility produces infertility-related stress in both members of infertile couples, especially for infertile women. Some studies verified the negative relationship between infertility-related stress and outcomes of infertility treatments. Effective mental health care during fertility treatment is urgently needed, but there has been a lack of efficient support services. To reduce the infertility-related stress of infertile women, expressive art therapeutic schemes will be organized and implemented by certified international expressive art therapists. Methods This study is a randomized controlled trial. Participants in the intervention group will receive expressive art therapies after the baseline investigation. Expressive art therapies will be led by the certified international expressive art therapist. The interventions include progressive muscle relaxation training, music meditation and drawing therapy. Participants in the control group will receive routine care. The Hospital Anxiety and Depression Scale (HADS) and Fertility Problem Inventory (FPI) will be used to investigate the anxiety, depression, and infertility-related stress of all participants at admission and at discharge. Discussion This study will verify the effectiveness and efficiency of expressive art therapies for infertile women. The results will provide new knowledge on mental health care strategies for infertile women. Trial registration ChiCTR, ChiCTR2300070618. Registered 14 April 2023.

Abstract Background Carotid artery stenosis (CAS) is a major cause of cerebral ischemic events (CIE). The purpose of the research was to reveal the diagnostic accuracy of long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) in asymptomatic carotid artery stenosis (ACAS) patients and its predictive significance in CIE incidence. Methods 88 patients with ACAS and 80 controls were included. Blood samples were collected and serum HOTAIR levels were detected by qRT-PCR. Logistic regression examined factors associated with the degree of carotid stenosis. The receiver operating characteristic (ROC) curve assessed the diagnostic accuracy of HOTAIR in identifying patients with ACAS. Predictive value of serum HOTAIR levels for the occurrence of CIE was assessed by Kaplan–Meier curves and Cox regression. Results Serum HOTAIR was markedly lower in ACAS patients than in controls (P

Abstract The OVATE gene family plays an important role in regulating the development of plant organs and resisting stress, but its expression characteristics and functions in sorghum have not been revealed. In this study, we identified 26 OVATE genes in the sorghum BTx623 genome, which were divided into four groups and distributed unevenly across 9 chromosomes. Evolutionary analysis showed that after differentiation between sorghum and Arabidopsis, the OVATE gene family may have experienced unique expansion events, and all OVATE family members were negatively selected. Transcriptome sequencing and RT-qPCR results showed that OVATE genes in sorghum showed diverse expression characteristics, such as gene SORBl_3001G468900 and SORBl_3009G173400 were significantly expressed in seeds, while SORBI_3005G042700 and SORBI_3002G417700 were only highly expressed in L1. Meantime, in the promoter region, a large number of hormone-associated cis-acting elements were identified, and these results suggest that members of the OVATE gene family may be involved in regulating specific development of sorghum leaves and seeds. This study improves the understanding of the OVATE gene family of sorghum and provides important clues for further exploration of the function of the OVATE gene family.

Abstract Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people’s health. Current therapies include bone marrow transplantation and several hypomethylating agents. However, many elderly patients cannot benefit from bone marrow transplantation and many patients develop drug resistance to hypomethylating agents, making it urgent to explore novel therapy. RSL3 can effectively induce ferroptosis in various tumors and combination of RSL3 and hypomethylating agents is promising to treat many tumors. However, its effect in MDS was unknown. In this study, we found that RSL3 inhibited MDS cell proliferation through inducing ROS-dependent apoptosis. RSL3 inhibited Bcl-2 expression and increased caspase 3 and PARP cleavage. RNA-seq analysis revealed that MYB may be a potential target of RSL3. Rescue experiments showed that overexpression of MYB can rescue MDS cell proliferation inhibition caused by RSL3. Cellular thermal shift assay showed that RSL3 binds to MYB to exert its function. Furthermore, RSL3 inhibited tumor growth and decreased MYB and Bcl-2 expression in vivo. More importantly, RSL3 decreased the viability of bone marrow mononuclear cells (BMMCs) isolated from MDS patients, and RSL3 had a synergistic effect with DAC in MDS cells. Our studies have uncovered RSL3 as a promising compound and MYB/Bcl-2 signaling pathway as a potential target for MDS treatment.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 μm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Abstract Background Jiaohong pills (JHP) consist of Pericarpium Zanthoxyli (PZ) and Radix Rehmanniae, two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment. However, the precise mechanisms underlying the beneficial effects remain elusive. Here, research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease. Methods BV‐2 cell inflammation was induced by lipopolysaccharide. AD mice were administered amyloid‐β (Aβ). Behavioral experiments were used to evaluate learning and memory ability. The levels of nitric oxide (NO), tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐10 (IL‐10) were detected using enzyme‐linked immunosorbent assay (ELISA). The protein expressions of inducible nitric oxide synthase (iNOS) and the phosphorylation level of mitogen‐activated protein kinase (MAPK) and nuclear factor kappa‐B (NF‐κB) were detected using Western blot. Nissl staining was used to detect neuronal degeneration. Results The results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO, IL‐1β, TNF‐α, and iNOS; increased the expression level of IL‐10; and significantly decreased the phosphorylation levels of MAPK and NF‐κB. These inhibitory effects were further confirmed in the AD mouse model. Meanwhile, JHP improved learning and memory function in AD mice, reduced neuronal damage, and enriched the Nissl bodies in the hippocampus. Moreover, IL‐1β and TNF‐α in the cortex were significantly downregulated after JHP administration, whereas IL‐10 showed increased expression. Conclusions It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF‐κB signaling pathway.

Rigid-flexible composite pavement has gained significant popularity in recent decades. This paper provides a comprehensive review of the research progress concerning rigid-flexible composite pavement, aiming to promote its application and address key issues while identifying future directions. The design theory and methodology of rigid-flexible composite pavement are discussed, followed by a description of its structural and mechanical behavior characteristics. The load stress, temperature stress, and their interactive effects between the asphalt layer and the rigid base were analyzed. It is clarified that the asphalt layer serves a dual role as both a “functional layer” and a “structural layer”. Typical distresses of rigid-flexible composite pavement, which primarily occur in the asphalt layer, were discussed. These distresses include reflective cracking, top-down cracking, rutting, and compressive-shear failure. Generally, the integrity of the rigid base and the interlaminar bonding conditions significantly impact the performance and distress of the asphalt layer. The technology for enhancing the performance of rigid-flexible composite pavement is summarized in three aspects: asphalt layer properties, rigid base integrity, and interlaminar bonding condition. The study concludes that developing high-performance pavement materials based on their structural behaviors is an effective approach to improve the performance and durability of rigid-flexible composite pavement. The integrated design of structure and materials represents the future direction of road design.

Abstract We describe the case of a 57-year-old male with jaundice, abdominal distension and fatigue. He was diagnosed as chronic active Epstein-Barr virus infection (CAEBV) due to intermittent elevated liver enzymes, hepatosplenomegaly and pancytopenia, with persistent positive of EBV biomarkers in blood and also positive in liver tissue. The patient was reinfected by SARS-CoV-2 within 2 months companied with CAEBV. The patient’s second infection with SARS-CoV-2 led to the aggravated liver dysfunction with pneumonia and re-admission. After receiving symptomatic treatment, the patient showed significantly improvement of symptoms with partially restoration of liver function. After discharge, the patient’s health status continued to deteriorate and eventually died. The instances of SARS-CoV-2 co-infection with the original chronic virus are not uncommon, but the exact mechanism of EBV and SARS-CoV-2 coinfection and the relationship between them are still unclear. Since co-infection of SARS-CoV-2 with original chronic virus might affect each other and lead disease aggravated and complicated, it is necessary to differentiate in the diagnosis of disease and it is important to be aware of the re-infection signs of SARS-CoV-2 in people with chronic virus infection diseases, as well as the risk of co-infection of SARS-CoV-2 with other viruses.

Abstract Background Anthracnose, mainly caused by Colletotrichum fructicola, leads to severe losses in pear production. However, there is limited information available regarding the molecular response to anthracnose in pears. Results In this study, the anthracnose-resistant variety ‘Seli’ and susceptible pear cultivar ‘Cuiguan’ were subjected to transcriptome analysis following C. fructicola inoculation at 6 and 24 h using RNA sequencing. A total of 3186 differentially expressed genes were detected in ‘Seli’ and ‘Cuiguan’ using Illumina sequencing technology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that the transcriptional response of pears to C. fructicola infection included responses to reactive oxygen species, phytohormone signaling, phenylpropanoid biosynthesis, and secondary metabolite biosynthetic processes. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway and phenylpropanoid biosynthesis were involved in the defense of ‘Seli’. Furthermore, the gene coexpression network data showed that genes related to plant–pathogen interactions were associated with C. fructicola resistance in ‘Seli’ at the early stage. Conclusion Our results showed that the activation of specific genes in MAPK, calcium signaling pathways and phenylpropanoid biosynthesis was highly related to C. fructicola resistance in ‘Seli’ and providing several potential candidate genes for breeding anthracnose-resistant pear varieties.

Abstract Background Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. Methods Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). Results Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45–49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35–39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P

Abstract Objective The aim of this study was to investigate the relationship between thyroid autoantibodies (TGAb and TPOAb) and X chromosome monosomy in the chorionic tissue of patients with missed early miscarriage. Methods The baseline data, thyroid function, thyroid antibody and the chromosomes from the chorionic tissue of 228 patients with missed early miscarriage were examined. Results (1) Among the 228 patients, 121 had a normal chromosome number, and 107 had an abnormal chromosome number. The majority of them were autosomal trisomy, of which trisomy 16 (40.19%) was predominant. Sex chromosome monosomy (28.04%) was secondary. (2) Among the 228 patients, 208 patients in this study had normal thyroid function (including 134 cases of negative thyroid antibodies and 74 cases of positive thyroid antibodies alone); 6 patients had abnormal thyroid function (including 2 cases of clinical hyperthyroidism, 3 cases of subclinical hypothyroidism, 1 case of hypothyroxinemia); and 14 patients had normal TSH and elevated T4 alone.(3) After exclusion of patients with thyroid function abnormalities, there were no significant differences in baseline data between the normal chromosome group and the abnormal chromosome group (P > 0.05). However, there was a significant difference in TGAb and TPOAb between the normal chromosome and abnormal chromosome group with 45, X karyotype, with a higher proportion of TGAb and/or TPOAb positivity in the 45, X karyotype group (P

Abstract Objective Endometrial cancer (EC) is an oestrogen-dependent tumour, the occurrence of which is closely related to an imbalance of oestrogen homeostasis. Our previous studies explored the effects of Resveratrol(Res) on oestrogen metabolism. However, systematic research on the exact mechanism of action of Res is still lacking. Based on network pharmacology, molecular docking and animal experiments, the effects and molecular mechanisms of Res on endometrial cancer were investigated. Methods The target of Res was obtained from the high-throughput experiment and reference-guided database of TCM (HERB) and the Encyclopedia of Traditional Chinese Medicine (ETCM) databases, and the target of endometrial cancer was obtained by using the Genecards database. Venny map was used to obtain the intersection target of Res in the treatment of endometrial cancer, and the protein interaction network of the intersection target was constructed by importing the data into the STRING database. Then, the drug–disease–target interaction network was constructed based on Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for intersection targets using the OmicShare cloud platform. Res and core targets were analysed by molecular docking. EC model mice induced by MNNG were randomly divided into the control group, Res group, MNNG group, MNNG + Res group, and MNNG + Res + MAPK/ERKi group. The protein levels of ERK and p-ERK in the mouse uterus were detected by Western blot. The levels of E1, E2, E3, 16-epiE3, 17-epiE3, 2-MeOE1, 4-MeOE1, 2-MeOE2, 4-MeOE2, 3-MeOE1, 2-OHE1, 4-OHE1, 2-OHE2, 4-OHE2, and 16α-OHE1 in the serum and endometrial tissue of mice were measured by LC‒MS/MS. Results A total of 174 intersection targets of Res anti-endometrial cancer were obtained. The signalling pathways analysed by KEGG enrichment included the AGE-RAGE signalling pathway in diabetic complications, the PI3K-Akt signalling pathway and the MAPK signalling pathway. The top 10 core targets were MAPK3, JUN, TP53, CASP3, TNF, IL1B, AKT1, FOS, VEGFA and INS. Molecular docking showed that in addition to TNF, other targets had good affinity for Res, and the binding activity with MAPK3 was stable. Western blot results showed that Res increased the phosphorylation level of ERK and that MAPK/ERKi decreased ERK activation. In the LC-MS/MS analysis, the levels of 2-MeOE1, 2-MeOE2 and 4-MeOE1 in serum and uterine tissue showed a significantly decreasing trend in the MNNG group, while that of 4-OHE2 was increased (P

Abstract Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) suppress production of pro-inflammatory cytokines and chemokines in human smooth muscle cells (SMCs) through sequestration of RelA in the NF-κB complex, but additional mechanisms are likely involved. The cGAS-STING pathway is activated by double-stranded DNA in the cytosolic compartment and acts through TANK-binding kinase 1 (TBK1) to spark inflammation. The present study tested if MRTFs suppress inflammation also by targeting cGAS-STING signaling. Interrogation of a transcriptomic dataset where myocardin was overexpressed using a panel of 56 cGAS-STING cytokines showed the panel to be repressed. Moreover, MYOCD, MRTFA, and SRF associated negatively with the panel in human arteries. RT-qPCR in human bronchial SMCs showed that all MRTFs reduced pro-inflammatory cytokines on the panel. MRTFs diminished phosphorylation of TBK1, while STING phosphorylation was marginally affected. The TBK1 inhibitor amlexanox, but not the STING inhibitor H-151, reduced the anti-inflammatory effect of MRTF-A. Co-immunoprecipitation and proximity ligation assays supported binding between MRTF-A and TBK1 in SMCs. MRTFs thus appear to suppress cellular inflammation in part by acting on the kinase TBK1. This may defend SMCs against pro-inflammatory insults in disease.

Abstract The electrical outputs of single-layer antiferromagnetic memory devices relying on the anisotropic magnetoresistance effect are typically rather small at room temperature. Here we report a new type of antiferromagnetic memory based on the spin phase change in a Mn-Ir binary intermetallic thin film at a composition within the phase boundary between its collinear and noncollinear phases. Via a small piezoelectric strain, the spin structure of this composition-boundary metal is reversibly interconverted, leading to a large nonvolatile room-temperature resistance modulation that is two orders of magnitude greater than the anisotropic magnetoresistance effect for a metal, mimicking the well-established phase change memory from a quantum spin degree of freedom. In addition, this antiferromagnetic spin phase change memory exhibits remarkable time and temperature stabilities, and is robust in a magnetic field high up to 60 T.

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

In order to investigate the effects of fermented oyster enzymatic hydrolysates on the quality of oyster juice, this study firstly identified oyster species suitable for the processing of oyster juice and established an exclusive sensory descriptive library for oyster juice. And then, through single-factor experimental analysis based on sensory scores and amino acid nitrogen content, the optimal fermentation conditions were determined. The free amino acids, volatile flavor components, and sensory properties were compared between unfermented oyster hydrolysates, fermented oyster hydrolysates, and seasoning fermented oyster hydrolysates. The results showed that Rushan oysters (Crassostrea gigas) were selected for oyster juice processing and an exclusive sensory descriptive library was developed. Lactiplantibacillus pentosus was vaccinate as the fermenting agent. Optimum fermentation condition was at 37 ℃ with the inoculum of 7% for 3 h. Under the optimized conditions, both the amino nitrogen content and flavor were significantly improved. The optimal flavoring conditions for the fermented oyster hydrolysates involved high temperature and pressure treatment (100 kPa, 121 ℃, 20 min) with 8% glucose addition and 2% salt addition, followed by volume concentration to 50% of the original. These conditions resulted in further enhancement of amino nitrogen content with the content of 1.06±0.03 g/100 g and aroma. Additionally, fermentation led to a significant increase (P

Abstract Aim To explore the views and experiences of formal caregivers caring for older inpatients with physical disabilities. Methods It was a qualitative phenomenological study. Using purposive sampling, twelve formal caregivers were chosen in a tertiary comprehensive hospital in Hangzhou, China. Semi-structured, face-to-face interviews were conducted, guided by open-ended questions that focused on gaining rich insights into participants’ views and experiences. Coding reliability thematic analysis was used to guide data analysis and categorize, based on Lazarus and Folkman’s theory of transactional coping. Results Four themes emerged from the data analysis: (1) Caregiving Threats. (2) motivations. (3) Responsibility Management. (4) Fear. Conclusion Despite facing significant pressure at work, formal caregivers of elderly inpatients with physical disabilities possess the drive and various coping strategies to excel in their role. Identifying caregivers’ experiences of care can be helpful in improving resilience to stress and maintaining stability in formal caregivers.

Abstract Metabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors. As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects. In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status. Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related pathways have been validated in BC cell lines after IMMT inhibition. Consequently, this investigation furnishes compelling evidence supporting the classification of IMMT as prognostic marker in BC, and underscoring its prospective utility as a novel target for metabolic therapy.

Abstract Background HIV prevention remains a global priority, especially in sub-Saharan Africa. Our research team previously developed an evidence-based peer group program for HIV prevention called Mzake ndi Mzake (Friend to Friend). A community-engaged collaboration adapted the program for community ownership and implementation. Here we report whether this HIV prevention program, implemented by community volunteers, increased condom use among sexually active individuals in rural Malawi. Methods Three communities sequentially rolled out the program. Effectiveness was evaluated using a stepped wedge design. Repeated surveys 11–13 months apart were conducted between 2016 and 2019. At Time 1, no community had offered the intervention. At Time 2, the first community had offered the intervention and two had not (control group). At Time 3, two communities had offered the intervention and one had not (control group). We used two condom use indicators; condom use frequency in the last 2 months (N = 771) and condom use at last sex (N = 880). The analytical sample included all sexually active persons answering that question at one or more time points. Mixed-effects cumulative logit and Generalized Estimating Equation (GEE) models were used to model the two condom indicators over time, controlling for demographic factors, UNAIDS HIV knowledge, safer sex self-efficacy and partner communication. Results This peer group intervention implemented by trained community volunteers increased both condom use indicators at Times 2 and 3. In the final adjusted models with non-significant factors removed, condom use in the last two months increased for the intervention group vs. control group [Time 2: Adjusted Odds Ratio (AOR) = 1.59 (1.15, 2.21); Time 3: AOR 2.01 (1.23, 3.30)]. Similarly, condom use at last sex increased for the intervention group vs. control group [Time 2: AOR = 1.48 (1.08, 2.03); Time 3: AOR 1.81 (1.13, 2.90)]. Other significant predictors of greater condom use were also described. Although the intervention increased UNAIDS HIV knowledge, knowledge did not predict condom use. Conclusions In this community-engaged implementation study, an evidence-based peer group program for HIV prevention increased condom use when delivered by trained community volunteers. Community ownership and program delivery by trained volunteers offer an innovative and cost-effective strategy to address ongoing HIV prevention needs without overburdening healthcare systems in sub-Saharan Africa. Trial registration Clinical Trials.gov NCT02765659 Registered May 6, 2016.

Corrosion failure of sacrificial anodes in extreme deep-sea environment is a key problem in metal protection technology. This study investigated the failure mechanism of the Al-Zn-In sacrificial anode under the synergic action of water pressure and fluid flow, by microstructure characterization and finite element analysis. The results exhibit that water pressure promotes the dissolution of Al-Zn-In alloy near the precipitates that are enriched at the grain boundaries. The flow amplifies the promoting effect of the pressure on anodic dissolution by inhibiting the formation of corrosion layers, and it accelerates the mass loss by mechanically aggressing the aluminum matrix. The synergic effect of water pressure and fluid flow results in a rapid degradation in the extreme deep-sea environment.

Objective To summarize the clinical characteristics of peripheral nerve hyperexcitability syndrome (PNHS). Methods and Results Ten patients with PNHS were admitted to He'nan Provincial People's Hospital from October 2018 to April 2022, with the clinical phenotypes of Morvan syndrome in 5 cases, Issacs syndrome in 4 cases, and cramp-fasciculation syndrome (CFS) in one case. There were 10 cases with clinical manifestations of muscle twitching, 8 of dysautonomia, 7 of central nervous system symptoms, 7 of limb weakness, 6 of sensory deficits, and 2 of cramping and muscle stiffness. Five cases were positive for autoimmune antibodies. Two cases had MRI abnormalities located in the brainstem, left occipital lobe and right thalamus. Ten cases had EMG abnormalities, including afterdischarges of F - wave in 10 cases, unit potential of spontaneous motion abnormalities in 10 cases, fasciculation potentials in 10 cases, myokymic discharges in 8 cases, and neuromyotonic and myokymic discharges in 3 cases. Three cases underwent only symptomatic therapy, and 7 cases underwent symptomatic therapy and immunomodulatory treatments. Except for one case who lost of follow-up, 5 cases had a good prognosis, 2 cases with poor prognosis, and 2 cases died. Conclusions PNHS is a heterogeneous group of clinical manifestations. Electrophysiological appearance of afterdischarges may be a sensitive indicator for the diagnosis of PNHS.

Abstract Objective Research on factors contributing to depressive symptoms in cancer patients at a national level, encompassing a comprehensive set of variables was limited. This study aimed to address this gap by identifying the factors associated with depressive symptoms among cancer patients through a nationwide cross-sectional analysis. Methods Various factors, including demographic, socioeconomic, behavioral patterns, general and self-rated health status, chronic conditions, dietary habits, and cancer-related factors, were examined. Data was from the National Health and Nutrition Examination Survey. Univariate and multivariate logistic regression analyses were performed to identify associated factors. The receiver-operating characteristic (ROC) curve was used to evaluate the performance of the logistic model. Results The findings showed that five sociodemographic factors, two behavioral styles, self-rated health status, comorbid arthritis, two dietary factors and two cancer-related factors were strongly associated with depressive symptoms. Compared with those aged 20–39 years, cancer individuals aged 40–59 years (OR = 0.48, P 0.05). Shorter cancer diagnosis duration was associated with reduced odds of depression (P

Abstract Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age 7 cm (HR = 1.66, 95%CI 1.20–2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making.

Abstract Objective This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. Methods The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. Results GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10− 09), rs509476 at RGS16 (P = 1.58 × 10− 09) and rs1006751 at RFX4 (P = 1.54 × 10− 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10− 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10− 08) and rs139156969 at ROBO2 (P = 3.58 × 10− 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. Conclusion Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.

Abstract Background Few studies have assessed the burden of mental disorders among children and adolescents considering the impact of co-morbidities and suicide on disability adjusted life years (DALYs). Methods This was a multicenter cross-sectional study. Our survey data in Liaoning Province (LN) were used to estimate the burden of six mental disorders, supplemented with data from other investigative studies conducted in China to assess four other disorders. DALYs were derived from the sum of years lived with a disability (YLDs) adjusted for co-morbidities, and the years of life lost (YLLs) adjusted for suicide. The changes in DALYs, YLDs, and YLLs were compared with and without adjustment for co-morbidities and suicide. Results The DALYs rate of mental disorders among children and adolescents in LN decreased from 1579.6/105 to 1391.4/105, after adjusting for both co-morbidities and suicide (-11.9%). The DALYs rate for major depression, anxiety disorder, and conduct disorder (-80.8/105, -75.0/105 and -30.2/105, respectively) were the top three contributors to the DALYs reduction (-188.2/105). The YLDs decreased from 72724.8 to 62478.5 after co-morbidity adjustment (-17.8%), mainly due to the reduction by major depression (-35.3%) and attention deficit/hyperactivity disorder [ADHD] (-34.2%). The YLLs increased from 130 to 1697.8 after adjusting for suicides (+ 56.9% of all suicide YLLs), mainly due to the contribution of major depression (+ 32.4%) and anxiety disorder (+ 10.4%). Compared to GBD 2010, the estimated DALY rate for mental disorders in LN was to be about 80%, with the proportion of DALYs and DALY rates explained by major depressive disorder accounted for only approximately one-third (14.6% vs. 41.9% and 202.6 vs. 759.9, respectively). But the proportion and absolute level of DALY rates explained by anxiety disorders were approximately 2-fold higher (39.7% vs. 19.6% and 552.2 vs. 323.3, respectively). Conclusions The DALYs of mental disorders among Chinese children and adolescents were approximately 80% of the global level, with anxiety disorders imposing about 2 times the global level. Co-morbidity and suicide must be adjusted when calculating DALYs.

Abstract Objective We sought to investigate the impact of individualized exercise guidance during pregnancy on the incidence of macrosomia and the mediating effect of gestational weight gain (GWG). Design A prospective randomized clinical trial. Setting A Hospital in Xingtai District, Hebei Province. Population Older than 20 years of age, mid-pregnancy, and singleton pregnant women without contraindications to exercise during pregnancy. Methods A randomized clinical trial was conducted from December 2021 to September 2022 to compare the effects of standard prenatal care with individualized exercise guidance on the incidence of macrosomia. Main outcome measure Incidence of macrosomia. Results In all, 312 singleton women were randomized into an intervention group (N = 162) or a control group (N = 150). Participants who received individualized exercise guidance had a significantly lower incidence of macrosomia (3.73% vs. 13.61%, P = 0.002) and infants large for gestational age (9.94% vs. 19.73%, P = 0.015). However, no differences were observed in the rate of preterm birth (1.86% vs. 3.40%, P = 0.397) or the average gestational age at birth (39.14 ± 1.51 vs. 38.69 ± 1.85, P = 0.258). Mediation analysis revealed that GWG mediated the effect of exercise on reducing the incidence of macrosomia. Conclusion Individualized exercise guidance may be a preventive tool for macrosomia, and GWG mediates the effect of exercise on reducing the incidence of macrosomia. However, evidence does not show that exercise increases the rate of preterm birth or affects the average gestational age at birth. Trial registration The trial is registered at www.clinicaltrails.gov [registration number: NCT05760768; registration date: 08/03/2023 (retrospectively registered)].

Abstract Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

Abstract Background Pudendal neuralgia is a chronic and debilitating condition. Its prevalence ranges from 5 to 26%. Currently, therapeutic approaches to treat pudendal neuralgia include patient education, medication management, psychological and physical therapy, and procedural interventions, such as nerve block, trigger point injections, and surgery. Drug therapy has a limited effect on pain relief. A pudendal nerve block may cause a significant decrease in pain scores for a short time; however, its efficacy significantly decreases over time. In contrast, pudendal nerve pulsed radiofrequency can provide pain relief for 3 months, and ganglion impar block has been widely used for treating chronic perineal pain and chronic coccygodynia. This study aimed to determine the efficacy and safety of monotherapy (pudendal nerve pulsed radiofrequency) and combination therapy (pudendal nerve pulsed radiofrequency plus ganglion impar block) in patients with pudendal neuralgia. Methods This randomized, controlled clinical trial will include 84 patients with pudendal neuralgia who failed to respond to drug or physical therapy. Patients will be randomly assigned into one of the two groups: mono or combined treatment groups. The primary outcome will be a change in pain intensity measured using the visual analog scale. The secondary outcomes will include a Self-Rating Anxiety Scale score, Self-Rating Depression Scale score, the use of oral analgesics, the Medical Outcomes Study Health Survey Short Form-36 Item score, and the occurrence of adverse effects. The study results will be analyzed using intention-to-treat and per-protocol analyses. Primary and secondary outcomes will be evaluated between the mono and combined treatment groups. Subgroup analyses will be conducted based on the initial ailment, age, and baseline pain intensity. The safety of the treatment will be assessed by monitoring adverse events, which will be compared between the two groups. Discussion This study protocol describes a randomized, controlled clinical trial to determine the efficacy and safety of mono and combination therapies in patients with pudendal neuralgia. The study results will provide valuable information on the potential benefits of this combination therapy and contribute to the development of more effective and safer treatments for patients with pudendal neuralgia. Trial registration Chinese Clinical Trial Registry (ChiCTR2200061800).

Abstract Background Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations. Methods We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants. Results We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes. Conclusions Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.

Abstract Purpose The study was designed to investigate the occurrence and risk factors of malnutrition in diabetic foot ulcers (DFU) patients and examine the association between malnutrition and length of stay (LOS). Methods This observational study included DFU hospitalized patients in two campuses of a hospital from January 2021 to June 2023. The diagnosis standard of malnutrition was established by using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Patients were followed up to ascertain the length of hospitalization, and hospital stays longer than 17 days were considered as prolonged LOS. To explore the risk factors of malnutrition and the association between malnutrition and LOS, univariate and multivariate logistic regression analyses were performed. Results Overall 219 DFU patients were enrolled, malnutrition was identified in 38.36% of patients according to GLIM criteria, and 92 patients (42%) were recognized as prolonged LOS. Logistic regression analyses showed that BMI (P

IntroductionThe goal of this study was to examine potential disparities in positive mental health (PMH) among adults in Canada by sexual orientation and gender modality. MethodsUsing 2019 Canadian Community Health Survey (CCHS) Annual Component data (N = 57 034), we compared mean life satisfaction and the prevalence of high selfrated mental health (SRMH), happiness and community belonging between heterosexual and sexual minority adults, and between cisgender and gender minority adults. We used 2019 CCHS Rapid Response on PMH data (N = 11 486) to compare the prevalence of high psychological well-being between heterosexual and sexual minority adults. Linear and logistic regression analyses examined the between-group differences in mean life satisfaction and the other PMH outcomes, respectively. ResultsSexual minority (vs. heterosexual) adults reported lower mean life satisfaction (B = −0.7, 95% CI: −0.8, −0.5) and were less likely to report high SRMH (OR = 0.4, 95% CI: 0.3, 0.5), happiness (OR = 0.4, 95% CI: 0.3, 0.5), community belonging (OR = 0.6, 95% CI: 0.5, 0.7) and psychological well-being (OR = 0.4, 95% CI: 0.3, 0.6). Differences were not always significant for specific sexual minority groups in sexstratified analyses. Gender minority adults reported lower mean life satisfaction and were less likely to report high SRMH and happiness than cisgender adults. ConclusionFuture research could investigate how these PMH disparities arise, risk and protective factors in these populations, how other sociodemographic factors interact with sexual orientation and gender identity to influence PMH and changes in disparities over time.

IntroductionL’objectif de cette étude était d’examiner les disparités potentielles en matière de santé mentale positive chez les adultes au Canada selon leur orientation sexuelle et leur modalité de genre. MéthodologieÀ l’aide des données de la composante annuelle de l’Enquête sur la santé dans les collectivités canadiennes (ESCC) de 2019 (N = 57 034), nous avons comparé la satisfaction moyenne à l’égard de la vie et la prévalence d’un niveau élevé de santé mentale auto-évaluée (SMAE), de bonheur et de sentiment d’appartenance à la communauté entre les adultes hétérosexuels et les adultes faisant partie d’une minorité sexuelle, ainsi qu’entre les adultes cisgenres et les adultes faisant partie d’une minorité de genre. Nous avons utilisé les données de la composante de réponse rapide sur la santé mentale positive de l’ESCC de 2019 (N = 11 486) pour comparer la prévalence d’un niveau élevé de bien-être psychologique chez les adultes hétérosexuels et les adultes faisant partie d’une minorité sexuelle. Des analyses de régression linéaire nous ont permis de relever les différences entre ces groupes en ce qui concerne la satisfaction moyenne à l’égard de la vie et des analyses de régression logistique en ce qui concerne les autres paramètres de la santé mentale positive. RésultatsPar rapport aux adultes hétérosexuels, les adultes faisant partie d’une minorité sexuelle ont fait état d’une moins grande satisfaction moyenne à l’égard de la vie (B = −0,7, IC à 95 % : −0,8 à −0,5) et étaient moins susceptibles de déclarer un niveau élevé de SMAE (RC = 0,4, IC à 95 % : 0,3 à 0,5), de bonheur (RC = 0,4, C à 95 % : 0,3 à 0,5), de sentiment d’appartenance à la communauté (RC = 0,6, IC à 95 % : 0,5 à 0,7) et de bien-être psychologique (RC = 0,4, IC à 95 % : 0,3 à 0,6). Les différences n’étaient pas toujours statistiquement significatives pour certains groupes de minorités sexuelles dans les analyses stratifiées selon le sexe. Les adultes faisant partie d’une minorité de genre ont fait état d’une moins grande satisfaction moyenne à l’égard de la vie et étaient moins susceptibles de déclarer un niveau élevé de SMAE et de bonheur que les adultes cisgenres. ConclusionLes travaux de recherche ultérieurs pourraient porter sur l’origine de ces disparités en matière de santé mentale positive, sur les facteurs de risque et les facteurs de protection au sein de ces populations, sur la façon dont d’autres facteurs sociodémographiques interagissent avec l’orientation sexuelle et l’identité de genre et influent sur la santé mentale positive, et sur l’évolution de ces disparités au fil du temps.

Abstract DBF4 zinc finger (DBF4) is a critical component involved in DNA replication and cell proliferation. It acts as a positive regulator of the cell division cycle 7 kinase. In this study, our investigation encompassed the impact of DBF4 on hepatocellular carcinoma (HCC) progression and delved into the potential mechanisms. We utilized open-access databases like TCGA and GEO to analyze the association between DBF4 and 33 different tumor types. We also conducted immunohistochemistry experiments to validate the expression of DBF4 in HCC, STAD, COAD, READ, PAAD, and LGG. Furthermore, we employed lentiviral transduction to knockdown DBF4 in HLF and SMMC cells, as well as to overexpress DBF4 in Huh7 cells. Subsequently, we evaluated the impact of DBF4 on proliferation, migration, and invasion of hepatocellular carcinoma cells. RNA sequencing and KEGG pathway enrichment analysis were also conducted to identify potential pathways, which were further validated through WB experiments. Finally, pathway inhibitor was utilized in rescue experiments to confirm whether DBF4 exerts its effects on tumor cells via the implicated pathway. Our findings revealed that DBF4 exhibited significant expression levels in nearly all examined tumors, which were further substantiated by the results of immunohistochemistry analysis. High DBF4 expression was correlated with poor overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), disease-free interval (DFI), relapse-free interval (RFI) in majority of tumor types, particularly in patients with HCC. In vitro experiments demonstrated that inhibition of DBF4 impaired the proliferative, migratory, and invasive abilities of HCC cells, whereas overexpression of DBF4 promoted these phenotypes. Sequencing results indicated that DBF4 may induce these changes through the ERBB signaling pathway. Further experimental validation revealed that DBF4 activates the ERBB signaling pathway, leading to alterations in the JNK/STAT, MAPK, and PI3K/AKT signaling pathways, thereby impacting the proliferative, migratory, and invasive abilities of tumor cells. Lastly, treatment of Huh7 cells overexpressing DBF4 with the ERBB2 inhibitor dacomitinib demonstrated the ability of ERBB2 inhibition to reverse the promoting effect of DBF4 overexpression on the proliferative, migratory, and invasive abilities of HCC cells. DBF4 plays a pivotal oncogenic role in HCC by promoting the ERBB signaling pathway and activating its downstream PI3K/AKT, JNK/STAT3, and MAPK signaling pathways. DBF4 may serve as a prognostic biomarker for patients with HCC.

Abstract Background Glycometabolism and lipid metabolism are critical in cancer metabolic reprogramming. The primary aim of this study was to develop a prognostic model incorporating glycometabolism and lipid metabolism-related genes (GLRGs) for accurate prognosis assessment in patients with endometrial carcinoma (EC). Methods Data on gene expression and clinical details were obtained from publicly accessible databases. GLRGs were obtained from the Genecards database. Through nonnegative matrix factorization (NMF) clustering, molecular groupings with various GLRG expression patterns were identified. LASSO Cox regression analysis was employed to create a prognostic model. Use rich algorithms such as GSEA, GSVA, xCELL ssGSEA, EPIC,CIBERSORT, MCPcounter, ESTIMATE, TIMER, TIDE, and Oncoppredict to analyze functional pathway characteristics of the forecast signal, immune status, anti-tumor therapy, etc. The expression was assessed using Western blot and quantitative real-time PCR techniques. A total of 113 algorithm combinations were combined to screen out the most significant GLRGs in the signature for in vitro experimental verification, such as colony formation, EdU cell proliferation, wound healing, apoptosis, and Transwell assays. Results A total of 714 GLRGs were found, and 227 of them were identified as prognostic-related genes. And ten GLRGs (AUP1, ESR1, ERLIN2, ASS1, OGDH, BCKDHB, SLC16A1, HK2, LPCAT1 and PGR-AS1) were identified to construct the prognostic model of patients with EC. Based on GLRGs, the risk model’s prognosis and independent prognostic value were established. The signature of GLRGs exhibited a robust correlation with the infiltration of immune cells and the sensitivity to drugs. In cytological experiments, we selected HK2 as candidate gene to verify its value in the occurrence and development of EC. Western blot and qRT-PCR revealed that HK2 was substantially expressed in EC cells. According to in vitro experiments, HK2 knockdown can increase EC cell apoptosis while suppressing EC cell migration, invasion, and proliferation. Conclusion The GLRGs signature constructed in this study demonstrated significant prognostic value for patients with endometrial carcinoma, thereby providing valuable guidance for treatment decisions.

Abstract Background Chronic lung and heart diseases are more likely to lead an intensive end point after stroke onset. We aimed to investigate characteristics and outcomes of endovascular thrombectomy (EVT) in patients with acute large vessel occlusion stroke (ALVOS) and identify the role of comorbid chronic cardiopulmonary diseases in ALVOS pathogenesis. Methods In this single-center retrospective study, 191 consecutive patients who underwent EVT due to large vessel occlusion stroke in neurological intensive care unit were included. The chronic cardiopulmonary comorbidities and several conventional stroke risk factors were assessed. The primary efficacy outcome was functional independence (defined as a mRS of 0 to 2) at day 90. The primary safety outcomes were death within 90 days and the occurrence of symptomatic intracranial hemorrhage(sICH). Univariate analysis was applied to evaluate the relationship between factors and clinical outcomes, and logistic regression model were developed to predict the prognosis of ALVOS. Results Endovascular therapy in ALVOS patients with chronic cardiopulmonary diseases, as compared with those without comorbidity, was associated with an unfavorable shift in the NHISS 24 h after EVT [8(4,15.25) versus 12(7.5,18.5), P = 0.005] and the lower percentage of patients who were functionally independent at 90 days, defined as a score on the modified Rankin scale of 0 to 2 (51.6% versus 25.4%, P = 0.000). There was no significant between-group difference in the frequency of mortality (12.1% versus 14.9%, P = 0.580) and symptomatic intracranial hemorrhage (13.7% versus 19.4%, P = 0.302) or of serious adverse events. Moreover, a prediction model showed that existence of cardiopulmonary comorbidities (OR = 0.456, 95%CI 0.209 to 0.992, P = 0.048) was independently associated with functional independence at day 90. Conclusions EVT was safe in ALVOS patients with chronic cardiopulmonary diseases, whereas the unfavorable outcomes were achieved in such patients. Moreover, cardiopulmonary comorbidity had certain clinical predictive value for worse stroke prognosis.

Abstract Background Understanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear. Methods Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. Results Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. Conclusions Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

To develop a new type of food packaging film and improve the level of resource utilization of enoki mushroom, polyvinyl alcohol (PVA) was used as the film-forming substrate, and the composite film of PVA-enoki mushroom aqueous extract was prepared by blending with enoki mushroom aqueous extract. The physical properties of the composite film, such as tensile strength, elongation at break, water resistance, thickness, opacity and water vapor transmission rate were taken as parameters to study the effects of PVA addition, 2-acetyltriethyl citrate (ATEC) addition, enoki mushroom aqueous extract addition, drying time and drying temperature on the physical properties of the composite film. Principal component analysis was used to comprehensive evaluation of composite film performance. The multiple regression equation model was established for the preparation of PVA-enoki mushroom aqueous extract composite film by response surface analysis, and the conditions for the preparation of the composite film were optimized. The effects of composite film on freshness indexes such as browning degree, weight loss, vitamin C and malondialdehyde of strawberries during storage (6 d) at 20 ℃ were also investigated. The results showed that 4.0 g of PVA, 4.0 g of ATEC, 3.9 g of aqueous extract of enoki mushroom, 62 ℃ drying temperature and 3.5 h drying time were the optimal conditions for composite film preparation. The tensile strength of the composite film was 31.76±0.50 N/cm2, elongation at break was 97.99%±0.25%, water vapor transmission rate was 1.44×10−9±1.53×10−11 g·mm/m2·h·kPa, water resistance was 549.14±0.94 s/mm, film thickness was 0.062±0.002 mm, opacity was 20.97±0.39, and a combined physical property score of 102.25±0.16, with a relative error of 0.57% from the model prediction. Infrared spectroscopy, scanning electron microscopy and X-ray diffraction analyses showed that the composite film was structurally intact, and the aqueous extract of enoki mushroom was compatible with the matrix and bound by hydrogen bonding. According to the indicators including the browning degree, weight loss, vitamin C, and malondialdehyde, the prepared composite film showed a better preservation effect during strawberry storage.

Aiming at the specific operation path cruising problem of greenhouse tomato picking robots, this paper designs a laser SLAM (Simultaneous Localization And Mapping)-based autonomous navigation system for greenhouse tomato picking robots.The autonomous navigation system utilizes LiDAR to detect the greenhouse environment, creates an environment map with the Gmapping algorithm employing particle filtering, locates the robot with the AMCL (Adaptive Monte Carlo Localization) algorithm, devises the robot's path for picking tasks with the A* algorithm, and dynamically navigates around obstacles during operations with the DWA (Dynamic Window Approach) algorithm. The greenhouse experiment revealed that the robot's average deviance for both directions (X and Y) is 2.87 and 0.80 centimeters, respectively, when traveling a 320 centimeter path. On the other hand, its average variation across the directions of X and Y is 1.48 versus 1.08 centimeters when it passes through a 40 centimeter zone. The robot exhibits averaged variations of 1.73 and 2.24 millimeters in the X and Y axes, each, when navigating a 40-centimeter-radius turn. Furthermore, the robot exhibits average variations of 1.12 centimeters in the X and 0.78 centimeters in the Y directions when it follows a certain ''S''-shaped course. Based on the fulfillment of prescribed path cruising, the system has a high level of navigation and positioning accuracy, better meeting the requirements for greenhouse tomato harvesting robot direction and placement.

Abstract Background Two-tiered plant immune responses involve cross-talk among defense-responsive (DR) genes involved in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), effector-triggered immunity (ETI) and effector-triggered susceptibility (ETS). Bacterial leaf streak (BLS), caused by Xanthomonas oryzae pv. oryzicola (Xoc) is an important bacterial disease that causes serious threats to rice yield and quality. Transcriptomic profiling provides an effective approach for the comprehensive and large-scale detection of DR genes that participate in the interactions between rice and Xoc. Results In this study, we used RNA-seq to analyze the differentially expressed genes (DEGs) in susceptible rice after inoculation with two naturally pathogenic Xoc strains, a hypervirulent strain, HGA4, and a relatively hypovirulent strain, RS105. First, bacterial growth curve and biomass quantification revealed that differential growth occurred beginning at 1 day post inoculation (dpi) and became more significant at 3 dpi. Additionally, we analyzed the DEGs at 12 h and 3 days post inoculation with two strains, representing the DR genes involved in the PTI and ETI/ETS responses, respectively. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the common DEGs, which included 4380 upregulated and 4019 downregulated genes and 930 upregulated and 1383 downregulated genes identified for the two strains at 12 h post inoculation (hpi) and 3 dpi, respectively. Compared to those at 12 hpi, at 3 dpi the number of common DEGs decreased, while the degree of differential expression was intensified. In addition, more disease-related GO pathways were enriched, and more transcription activator-like effector (TALE) putative target genes were upregulated in plants inoculated with HGA4 than in those inoculated with RS105 at 3 dpi. Then, four DRs were randomly selected for the BLS resistance assay. We found that CDP3.10, LOC_Os11g03820, and OsDSR2 positively regulated rice resistance to Xoc, while OsSPX3 negatively regulated rice resistance. Conclusions By using an enrichment method for RNA-seq, we identified a group of DEGs related to the two stages of response to the Xoc strain, which included four functionally identified DR genes.

Abstract Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.

Abstract Background Ovarian cancer (OC) is a gynecological malignancy tumor with high recurrence and mortality rates. Programmed cell death (PCD) is an essential regulator in cancer metabolism, whose functions are still unknown in OC. Therefore, it is vital to determine the prognostic value and therapy response of PCD-related genes in OC. Methods By mining The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Genecards databases, we constructed a prognostic PCD-related genes model and performed Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic (ROC) curve for its predictive ability. A nomogram was created via Cox regression. We validated our model in train and test sets. Quantitative real-time PCR (qRT-PCR) was applied to identify the expression of our model genes. Finally, we analyzed functional analysis, immune infiltration, genomic mutation, tumor mutational burden (TMB) and drug sensitivity of patients in low- and high-risk group based on median scores. Results A ten-PCD-related gene signature including protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), 8-oxoguanine-DNA glycosylase (OGG1), HECT and RLD domain containing E3 ubiquitin protein ligase family member 1 (HERC1), Caspase-2.(CASP2), Caspase activity and apoptosis inhibitor 1(CAAP1), RB transcriptional corepressor 1(RB1), Z-DNA binding protein 1 (ZBP1), CD3-epsilon (CD3E), Clathrin heavy chain like 1(CLTCL1), and CCAAT/enhancer-binding protein beta (CEBPB) was constructed. Risk score performed well with good area under curve (AUC) (AUC3 − year =0.728, AUC5 − year = 0.730). The nomogram based on risk score has good performance in predicting the prognosis of OC patients (AUC1 − year =0.781, AUC3 − year =0.759, AUC5 − year = 0.670). Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the erythroblastic leukemia viral oncogene homolog (ERBB) signaling pathway and focal adhesion were enriched in the high-risk group. Meanwhile, patients with high-risk scores had worse OS. In addition, patients with low-risk scores had higher immune-infiltrating cells and enhanced expression of checkpoints, programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1) and lymphocyte activation gene-3 (LAG3), and were more sensitive to A.443,654, GDC.0449, paclitaxel, gefitinib and cisplatin. Finally, qRT-PCR confirmed RB1, CAAP1, ZBP1, CEBPB and CLTCL1 over-expressed, while PPP1R15A, OGG1, CASP2, CD3E and HERC1 under-expressed in OC cell lines. Conclusion Our model could precisely predict the prognosis, immune status and drug sensitivity of OC patients.

Abstract The IVa subfamily of glycine-rich proteins (GRPs) comprises a group of glycine-rich RNA binding proteins referred to as GR-RBPa here. Previous studies have demonstrated functions of GR-RBPa proteins in regulating stress response in plants. However, the mechanisms responsible for the differential regulatory functions of GR-RBPa proteins in different plant species have not been fully elucidated. In this study, we identified and comprehensively studied a total of 34 GR-RBPa proteins from five plant species. Our analysis revealed that GR-RBPa proteins were further classified into two branches, with proteins in branch I being relatively more conserved than those in branch II. When subjected to identical stresses, these genes exhibited intensive and differential expression regulation in different plant species, corresponding to the enrichment of cis-acting regulatory elements involving in environmental and internal signaling in these genes. Unexpectedly, all GR-RBPa genes in branch I underwent intensive alternative splicing (AS) regulation, while almost all genes in branch II were only constitutively spliced, despite having more introns. This study highlights the complex and divergent regulations of a group of conserved RNA binding proteins in different plants when exposed to identical stress conditions. These species-specific regulations may have implications for stress responses and adaptations in different plant species.

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. Methods We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. Results Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. Conclusion The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.

Abstract Background The global use of plastic materials has undergone rapid expansion, resulting in the substantial generation of degraded and synthetic microplastics and nanoplastics (MNPs), which have the potential to impose significant environmental burdens and cause harmful effects on living organisms. Despite this, the detrimental impacts of MNPs exposure towards host cells and tissues have not been thoroughly characterized. Results In the present study, we have elucidated a previously unidentified hepatotoxic effect of 20 nm synthetic polystyrene nanoparticles (PSNPs), rather than larger PS beads, by selectively inducing necroptosis in macrophages. Mechanistically, 20 nm PSNPs were rapidly internalized by macrophages and accumulated in the mitochondria, where they disrupted mitochondrial integrity, leading to heightened production of mitochondrial reactive oxygen species (mtROS). This elevated mtROS generation essentially triggered necroptosis in macrophages, resulting in enhanced crosstalk with hepatocytes, ultimately leading to hepatocyte damage. Additionally, it was demonstrated that PSNPs induced necroptosis and promoted acute liver injury in mice. This harmful effect was significantly mitigated by the administration of a necroptosis inhibitor or systemic depletion of macrophages prior to PSNPs injection. Conclusion Collectively, our study suggests a profound toxicity of environmental PSNP exposure by triggering macrophage necroptosis, which in turn induces hepatotoxicity via intercellular crosstalk between macrophages and hepatocytes in the hepatic microenvironment.