Modeling global oceanic nitrogen deposition from food systems and its mitigation potential by reducing overuse of fertilizers.

Growing population and consumption pose unprecedented demands on food production. However, ammonia emissions mainly from food systems increase oceanic nitrogen deposition contributing to eutrophication. Here, we developed a long-term oceanic nitrogen deposition dataset (1970 to 2018) with updated ammonia emissions from food systems, evaluated the impact of ammonia emissions on oceanic nitrogen deposition patterns, and discussed the potential impact of nitrogen fertilizer overuse. Based on the chemical transport modeling approach, oceanic ammonia-related nitrogen deposition increased by 89% globally between 1970 and 2018, and now, it exceeds oxidized nitrogen deposition by over 20% in coastal regions including China Sea, India Coastal, and Northeastern Atlantic Shelves. Approximately 38% of agricultural nitrogen fertilizer was excessive, which corresponds to 15% of global oceanic ammonia-related nitrogen deposition. Policymakers and water quality managers need to pay increasingly more attention to ammonia associated with food production if the goal of reducing coastal nitrogen pollution is to be achieved for Sustainable Development Goals.

Oxylipin signaling in salt-stressed soybean is modulated by ligand-dependent interaction of Class II acyl-CoA-binding proteins with lipoxygenase.

Plant lipoxygenases (LOXs) oxygenate linoleic and linolenic acids, creating hydroperoxy derivatives, and from these, jasmonates and other oxylipins are derived. Despite the importance of oxylipin signaling, its activation mechanism remains largely unknown. Here, we show that soybean ACYL-COA-BINDING PROTEIN3 (ACBP3) and ACBP4, two Class II acyl-CoA-binding proteins, suppressed activity of the vegetative LOX homolog VLXB by sequestering it at the endoplasmic reticulum. The ACBP4-VLXB interaction was facilitated by linoleoyl-CoA and linolenoyl-CoA, which competed with phosphatidic acid (PA) for ACBP4 binding. In salt-stressed roots, alternative splicing produced ACBP variants incapable of VLXB interaction. Overexpression of the variants enhanced LOX activity and salt tolerance in Arabidopsis and soybean hairy roots, whereas overexpressors of the native forms exhibited reciprocal phenotypes. Consistently, the differential alternative splicing pattern in two soybean genotypes coincided with their difference in salt-induced lipid peroxidation. Salt-treated soybean roots were enriched in C32:0-PA species that showed high affinity to Class II ACBPs. We conclude that PA signaling and alternative splicing suppress ligand-dependent interaction of Class II ACBPs with VLXB, thereby triggering lipid peroxidation during salt stress. Hence, our findings unveil a dual mechanism that initiates the onset of oxylipin signaling in the salinity response.

Exploring global changes in agricultural ammonia emissions and their contribution to nitrogen deposition since 1980.

SignificanceAgricultural systems are already major forces of ammonia pollution and environmental degradation. How agricultural ammonia emissions affect the spatio-temporal patterns of nitrogen deposition and where to target future mitigation efforts, remains poorly understood. We develop a substantially complete and coherent agricultural ammonia emissions dataset in nearly recent four decades, and evaluate the relative role of reduced nitrogen in total nitrogen deposition in a spatially explicit way. Global reduced nitrogen deposition has grown rapidly, and will occupy a greater dominant position in total nitrogen deposition without future ammonia regulations. Recognition of agricultural ammonia emissions on nitrogen deposition is critical to formulate effective policies to address ammonia related environmental challenges and protect ecosystems from excessive nitrogen inputs.

Defective Uterine Spiral Artery Remodeling and Placental Senescence in a Pregnant Rat Model of Polycystic Ovary Syndrome.

Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.

Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

OBJECTIVE: Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). DESIGN, PATIENTS AND MEASUREMENTS: We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. RESULTS: We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. CONCLUSIONS: Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

Overburden of rare ALMS1 deleterious variants in Chinese early-onset type 2 diabetes with severe insulin resistance.

AIMS: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD). MATERIALS AND METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants. RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR. CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.

Differential effect of interventions in patients with prediabetes stratified by a machine learning-based diabetes progression prediction model.

AIM: To investigate whether stratifying participants with prediabetes according to their diabetes progression risks (PR) could affect their responses to interventions. METHODS: We developed a machine learning-based model to predict the 1-year diabetes PR (ML-PR) with the least predictors. The model was developed and internally validated in participants with prediabetes in the Pinggu Study (a prospective population-based survey in suburban Beijing; n = 622). Patients from the Beijing Prediabetes Reversion Program cohort (a multicentre randomized control trial to evaluate the efficacy of lifestyle and/or pioglitazone on prediabetes reversion; n = 1936) were stratified to low-, medium- and high-risk groups using ML-PR. Different effect of four interventions within subgroups on prediabetes reversal and diabetes progression was assessed. RESULTS: Using least predictors including fasting plasma glucose, 2-h postprandial glucose after 75 g glucose administration, glycated haemoglobin, high-density lipoprotein cholesterol and triglycerides, and the ML algorithm XGBoost, ML-PR successfully predicted the 1-year progression of participants with prediabetes in the Pinggu study [internal area under the curve of the receiver operating characteristic curve 0.80 (0.72-0.89)] and Beijing Prediabetes Reversion Program [external area under the curve of the receiver operating characteristic curve 0.80 (0.74-0.86)]. In the high-risk group pioglitazone plus intensive lifestyle therapy significantly reduced diabetes progression by about 50% at year l and the end of the trial in the high-risk group compared with conventional lifestyle therapy with placebo. In the medium- or low-risk group, intensified lifestyle therapy, pioglitazone or their combination did not show any benefit on diabetes progression and prediabetes reversion. CONCLUSIONS: This study suggests personalized treatment for prediabetes according to their PR is necessary. ML-PR model with simple clinical variables may facilitate personal treatment strategies in participants with prediabetes.

Tanshinone IIA Alleviates Traumatic Brain Injury by Reducing Ischemia‒Reperfusion via the miR-124-5p/FoxO1 Axis.

Background: Cerebral ischemia-reperfusion injury is a common complication of ischemic stroke that affects the prognosis of patients with ischemic stroke. The lipid-soluble diterpene Tanshinone IIA, which was isolated from Salvia miltiorrhiza, has been indicated to reduce cerebral ischemic injury. In this study, we investigated the molecular mechanism of Tanshinone IIA in alleviating reperfusion-induced brain injury. Methods: Middle cerebral artery occlusion animal models were established, and neurological scores, tetrazolium chloride staining, brain volume quantification, wet and dry brain water content measurement, Nissl staining, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and reverse transcription-quantitative polymerase chain reaction were performed. The viability of cells was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays, while cell damage was measured by lactate dehydrogenase release in the in vitro oxygen glucose deprivation model. In addition, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to evaluate the therapeutic effect of Tanshinone IIA on ischemia/reperfusion (I/R) induced brain injury, as well as its effects on the inflammatory response and neuronal apoptosis, in vivo and in vitro. Furthermore, this study validated the targeting relationship between miR-124-5p and FoxO1 using a dual luciferase assay. Finally, we examined the role of Tanshinone IIA in brain injury from a molecular perspective by inhibiting miR-124-5p or increasing FoxO1 levels. Results: After treatment with Tanshinone IIA in middle cerebral artery occlusion-reperfusion (MCAO/R) rats, the volume of cerebral infarction was reduced, the water content of the brain was decreased, the nerve function of the rats was significantly improved, and the cell damage was significantly reduced. In addition, Tanshinone IIA effectively inhibited the I/R-induced inflammatory response and neuronal apoptosis, that is, it inhibited the expression of inflammatory cytokines IL-1ß, IL-6, TNF-α, decreased the expression of apoptotic protein Bax and Cleaved-caspase-3, and promoted the expression of antiapoptotic protein Bcl-2. In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cell model, Tanshinone IIA also inhibited the expression of inflammatory factors in neuronal cells and inhibited the occurrence of neuronal apoptosis. In addition, Tanshinone IIA promoted the expression of miR-124-5p. Transfection of miR-124-5p mimic has the same therapeutic effect as Tanshinone IIA and positive therapeutic effect on OGD cells, while transfection of miR-124-5p inhibitor has the opposite effect. The targeting of miR-124-5p negatively regulates FoxO1 expression. Inhibition of miR-124-5p or overexpression of FoxO1 can weaken the inhibitory effect of Tanshinone IIA on brain injury induced by I/R, while inhibition of miR-124-5p and overexpression of FoxO1 can further weaken the effect of Tanshinone IIA. Conclusion: Tanshinone IIA alleviates ischemic-reperfusion brain injury by inhibiting neuroinflammation through the miR-124-5p/FoxO1 axis. This finding provides a theoretical basis for mechanistic research on cerebral ischemia-reperfusion injury.

Effects of nutritional interventions on cognitive function in adult cancer survivors: A systematic review.

AIM: To evaluate the effectiveness and safety of nutritional interventions (i.e. nutritional support, dietary patterns and dietary supplements) on cognitive function in cancer survivors. DESIGN: Systematic review. METHODS: A systematic and comprehensive search of PubMed, Web of Science, the Cochrane Library, Embase, and CINAHL was conducted from the inception until March 10, 2023. The last search was conducted on December 10, 2023. REPORTING METHOD: PRISMA. RESULTS: A total of 59 randomized controlled trials were included for analysis. Nutritional support, dietary patterns and dietary supplements improved cognitive function in cancer survivors with no apparent safety concerns. The anti-inflammatory diet, the fasting-mimicking diet and the web-based diet significantly improved cognitive function. Whereas the ketogenic diet or dietary advice to consume more soluble dietary fibres and less insoluble dietary fibres and lactose could not. There was evidence from dietary supplements to support the beneficial effects of polyunsaturated fatty acid supplements, traditional herbal medicines and other supplements. CONCLUSIONS: Nutritional interventions have great promise for improving cognitive function in adult cancer survivors. Further validation of the nutritional interventions supported in this study in other survivors and exploration of more effective nutritional interventions are needed. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This work can support the construction of nutritional support interventions and dietary guidance programs to prevent cancer-related cognitive decline. IMPACT: This work filled a gap in preventive strategies for cancer-related cognitive decline from a nutritional perspective. Nutritional support, dietary patterns, and dietary supplements can prevent cancer-related cognitive decline without serious safety concerns. This work highlighted nutritional interventions that have the potential to improve cognitive function in cancer survivors, benefiting the further construction of evidence-based nutritional intervention programs. PROTOCOL REGISTRATION: PROSPERO. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

The effectiveness of health education based on the 5Ts for teach-back on oral nutritional supplements compliance of post-discharge patients after surgery for gastric cancer: a randomized controlled trial.

OBJECTIVE: This study aims to explore the 5Ts teach-back(5Ts) to improve oral nutritional supplements (ONS) compliance of discharged patients after gastric cancer surgery. SETTING AND METHODS: Patients were recruited from the Bethune First Hospital of Jilin University. The patients were randomly assigned to 5Ts (n = 54) and routine health education (n = 54). Weekly ONS compliance was collected by "weekly ONS diary." ONS knowledge, health literacy, and health education satisfaction were collected at baseline and 5 weeks after discharge. Chi-square test, Mann-Whitney U test, and T test were used for data analysis. RESULTS: At the end of the intervention, there were 41 and 40 patients in intervention and control group. 5Ts significantly improve ONS compliance, ONS knowledge level (P = 0.000), health literacy level (P = 0.011), and health education satisfaction (P = 0.009) of patients. At the end of follow-up, there were 30 and 27 patients in two groups, and no significant difference in ONS compliance (P = 0.728). CONCLUSION: The 5Ts can significantly improve patients' ONS compliance and the effect of health education. TRIAL REGISTRATION NUMBER: This prospective trial was registered in the Chinese Clinical Trial Registry at ChiCTR2000040986 ( http://www.chictr.org.cn ). PATIENT OR PUBLIC CONTRIBUTION: Jia Wang and Haiyan Hu contributed to the performance of the study, analysis and interpretation the data, and drafted the manuscript; Jianan Sun and Qing Zhang contributed to the supervision of the study and interpreted the data; Zhiming Chen contributed to the analysis and interpretation the data; Qiuchen Wang contributed to the performance of the study and revised the manuscript; Mingyue Zhu contributed to interpretation the data; Jiannan Yao contributed to revise the manuscript; Hua Yuan and Xiuying Zhang contributed to the conception of the study, performed the study, interpreted the data, and significantly revised the manuscript. All authors screened the final version of the manuscript.

Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury.

Background: Spinal cord injury (SCI) is a common injury of the central nervous system (CNS), and astrocytes are relatively abundant glial cells in the CNS that impairs the recovery of motor function after SCI. It was confirmed that the oxidative stress of mitochondria leads to the accumulation of reactive oxygen species (ROS) in cells, which plays a key role in the motor function of astrocytes. However, the mechanism by which oxidative stress affects astrocyte motility after SCI is still unexplained. Therefore, this study investigated the influence of SET8-regulated oxidative stress on astrocyte autophagy levels after SCI in rats and the potential mechanisms of action. Methods: We used real-time quantitative PCR, western blotting, and immunohistochemical staining to analyze SET8, Keap1, and Nrf2 expression at the cellular level and in SCI tissues. ChIP to detect H4K20me1 enrichment in the Keap1 promoter region under OE-SET8 (overexpression of SET8) conditions. Western blotting was used to assess the expression of signature proteins of astrocytes, proteins associated with autophagy, proteins associated with glial scar formation, reactive oxygen species (ROS) levels in cells using DHE staining, and astrocyte number, morphological alterations, and induction of glial scar formation processes using immunofluorescence. In addition, the survival rate of neurons after SCI in rats was examined by using NiSSl staining. Results: OE-SET8 upregulates the enrichment of H4K20me1 in Keap1, inhibits Keap1 expression, activates the Nrf2-ARE signaling pathway to suppress ROS accumulation, inhibits oxidative stress-induced autophagy and glial scar formation in astrocytes, and leads to reduced neuronal loss, which promoted the recovery and improvement of motor function after SCI in rats. Conclusion: Overexpression of SET8 alleviated oxidative stress by regulating Keap1/Nrf2/ARE, inhibited astrocyte autophagy levels, and reduced glial scar formation as well as neuronal loss, thereby promoting improved recovery of motor function after SCI. Thus, the SET8/H4K20me1 regulatory function may be a promising cellular therapeutic intervention point after SCI.

Proteomic analysis of ITPR2 as a new therapeutic target for curcumin protection against AFB1-induced pyroptosis.

Aflatoxin B1 (AFB1) is extremely carcinogenic and can cause liver cancer in humans and animals with continued ingestion. As a natural compound, curcumin (Cur) exhibits excellent anti-inflammatory, and anti-cancer properties with few side effects. In this study, a total of 60 male mice (6-week-olds, 15 per group). After one week of acclimatization feeding, the mice were divided into control group (Con), AFB1 group, curcumin group (Cur), and AF+Cur group. The mice were gavaged with curcumin (Cur, 100 mg/kg) and/or AFB1 (0.75 mg/kg). To identify a new therapeutic target for AFB1-induced pyroptosis, we performed proteomic profiling for curcumin alleviating liver injury caused by AFB1 to further validate the targets through volcano plot analysis, Venn analysis, heatmap analysis, correlation, cluster analysis, GO and KEGG enrichment. AFB1 exposure resulted in the loss of hepatocyte membrane, swelling of the endoplasmic reticulum, and a significant increase in transaminase (ALT and AST) contents, while curcumin greatly improved these changes. We found that differentially expressed proteins are enriched in the endoplasmic reticulum membrane and identified ITPR2 as a target of curcumin that alleviates AFB1-induced liver injury by proteomics. Furthermore, ITPR2 expression was detected by immunofluorescence, and qRT-PCR for mRNA expression of genes downstream of ITPR2 (calpain1, calpain2, caspase-12, caspase-3). ITPR2-activated endoplasmic reticulum stress-related proteins (calpain1, calpaini2, bcl-2, BAX, cl-caspase-12, cl-caspase-3), apoptosis (PARP) and pyroptosis (DFNA5) related proteins were examined by western blotting. The analysis showed that it effectively prevents AFB1-induced pyroptosis by lowering endoplasmic reticulum stress via interfering with ITPR2 and its downstream proteins (calpain1, calpain2, bcl-2, Bax) and inhibiting caspase-12/caspase-3 pathway. Conclusively, this study applied proteomic profiling to elucidate ITPR2 as a new target, which might give a new perspective on the mechanism of curcumin alleviating AFB1-induced pyroptosis.

Acute liver injury induced by carbon tetrachloride reversal by Gandankang aqueous extracts through nuclear factor erythroid 2-related factor 2 signaling pathway.

The aims of this study were to evaluated the effect and underlying mechanism of Gandankang (GDK) aqueous extract in alleviating the acute liver injury induced by carbon tetrachloride (CCl4) in vivo and in vitro. Mice were divided into 5 groups (n = 8) for acute (Groups: control, 0.3 % CCl4, BD (Bifendate), 1.17, 2.34 and 4.68 mg/kg GDK) liver injury study. 10 µL/g CCl4 with corn oil were injected interperitoneally (i.p) expect the control group. HepG2 cells were used in vitro study. The results showed GDK can effectively inhibit liver damage and restore the structure and function of the liver. In mechanism, GDK inhibited CCl4-induced liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response; and inhibited CCl4-induced oxidative stress by upregulating the Keap1/Nrf2 pathway-related proteins and promoting the synthesis of several antioxidants. Additionally, it inhibited ferroptosis in the liver by regulating the expression of ACSl4 and GPX4. GDK reduced lipid peroxide generation in vitro by downregulating the production of reactive oxygen species and Fe2+ aggregation, thereby inhibiting ferroptosis and alleviating CCl4-induced hepatocyte injury. In conclusion, we describe the potential complex mechanism underlying the effect of GDK against acute liver injury.

Protective role of curcumin on broiler liver by modulating aflatoxin B1-induced DNA methylation and CYPs expression.

The purpose of this study was to investigate the role of epigenetic DNA methylation and CYPs expression in AFB1-exposed broiler liver and the protective effect of curcumin. Sixty-four one-day-old AA broilers were randomly divided into four groups, including control group, AFB1 group (1 mg/kg AFB1), curcumin + AFB1 group (1 mg/kg curcumin) and curcumin group (300 mg/kg curcumin). Histological observation, CYP450 enzyme activities, the expression levels of DNA methyltransferases and CYP450 enzymes, and the overall DNA methylation level in broiler liver were investigated. Dietary AFB1 was found to induce severe liver injury in broilers, upregulate the mRNA and protein expression of CYP450 enzymes (CYP1A1, CYP1A2 and CYP3A4) and the enzyme activities of CYP1A2 and CYP3A4. According to HPLC, qPCR and western blot analyses, the overall DNA methylation level and the mRNA and protein expression of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) in the liver were significantly increased after AFB1 exposure. Importantly, the Pearson test and correlation analysis data revealed that the overall DNA methylation level of broiler liver was positively correlated with DNMTs, while CYP1A1, CYP1A2 and CYP3A4 were negatively correlated. Surprisingly, curcumin supplementation strongly ameliorated AFB1-induced hepatotoxicity by restoring the histological changes, decreasing the expression and enzymatic activity of liver CYP450 enzymes (CYP1A1, CYP1A2, and CYP3A4), and increasing the overall DNA methylation level and the expression of DNMTs. Taken together, we concluded that curcumin could protect against AFB1-induced liver injury by mediating the effects of DNA methylation and CYPs expression.

Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.

Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.

Betaxolol as a Potent Inhibitor of NDM-1-Positive E. coli That Synergistically Enhances the Anti-Inflammatory Effect in Combination with Meropenem.

With significant human and economic losses, increasing bacterial resistance is a serious global threat to human life. Due to their high efficacy, broad spectrum, and cost-effectiveness, beta-lactams are widely used in the clinical management of bacterial infection. The emergence and wide spread of New Delhi metallo-ß-lactamase (NDM-1), which can effectively inactivate ß-lactams, has posed a challenge in the design of effective new antimicrobial treatments. Medicine repurposing is now an important tool in the development of new alternative medicines. We present a known glaucoma therapeutic, betaxolol (BET), which with a 50% inhibitory concentration (IC50) of 19.3 ± 0.9 µM significantly inhibits the hydrolytic activity of the NDM-1 enzyme and may represent a potential NDM-1 enzyme inhibitor. BET combined with meropenem (MEM) showed bactericidal synergism in vitro. The efficacy of BET was further evaluated against systemic bacterial infections in BALB/c mice. The results showed that BET+MEM decreased the numbers of leukocytes and inflammatory factors in peripheral blood, as well as the organ bacterial load and pathological damage. Molecular docking and kinetic simulations showed that BET can form hydrogen bonds and hydrophobic interactions directly with key amino acid residues in the NDM-1 active site. Thus, we demonstrated that BET inhibited NDM-1 by competitively binding to it and that it can be developed in combination with MEM as a new therapy for the management of infections caused by medicine-resistant bacteria.

The Mediating Effect of General Self-Efficacy Between Occupational Stress and Negative Emotion Among Psychiatric Nurses.

The current study investigated occupational stress, anxiety, and depression among psychiatric nurses and explored the intermediary role of general self-efficacy between occupational stress, anxiety, and depression. In November 2020, 171 psychiatric nurses completed a self-report questionnaire. Spearman's correlation analysis was used to determine the relationship between the four variables and the bootstrap method was used to test the intermediary hypothesis. Results showed that 35.1% of psychiatric nurses had health risk stress. Among participants, detection rates of anxiety and depression were 24% and 46.8%, respectively. There was a positive correlation between occupational stress and anxiety (r = 0.577, p < 0.05) and depression (r = 0.653, p < 0.05). There was a negative correlation between general self-efficacy and anxiety (r = -0.358, p < 0.05) and depression (r = -0.500, p < 0.05), and general self-efficacy had a significant mediating effect between occupational stress and depression. However, the mediating effect of general self-efficacy on anxiety was not significant. Nurse managers should be aware of the importance of nurses' general self-efficacy and self-confidence. [Journal of Psychosocial Nursing and Mental Health Services, 61(3), 33-39.].

Factors Influencing Self-Management of Schizophrenia: A Cross-Sectional Study.

The purpose of the current study was to (a) understand the influencing factors of self-management in schizophrenia, (b) explore the relationship between social support and self-management, and (c) explore the intermediary role of coping modes between social support and self-management. From May to December 2020, a total of 320 community-dwelling persons with schizophrenia were recruited and completed self-report questionnaires. Spearman's correlation analysis was used to determine the relationship between the three variables and the bootstrap method was used to test the intermediary hypothesis. Results showed that 21.9% of persons with schizophrenia had low social support, 78.1% had medium social support, and convalescent persons with schizophrenia had high social support. Self-management was positively correlated with social support (r = 0.372, p < 0.05), confrontation coping mode (r = 0.576, p < 0.05), and avoidance coping mode (r = 0.204, p < 0.05), and negatively correlated with resignation coping mode (r = -0.057, p < 0.05). Confrontation and avoidance coping modes have a mediating effect between social support and self-management. Mental health nurses should understand the influence of social support and coping modes on self-management, and help persons with schizophrenia find social resources, build confidence, and confront the disorder positively. [Journal of Psychosocial Nursing and Mental Health Services, 61(2), 19-26.].

Metagenomic analysis reveals crosstalk between gut microbiota and glucose-lowering drugs targeting the gastrointestinal tract in Chinese patients with type 2 diabetes: a 6 month, two-arm randomised trial.

AIMS/HYPOTHESIS: The use of oral glucose-lowering drugs, particularly those designed to target the gut ecosystem, is often observed in association with altered gut microbial composition or functional capacity in individuals with type 2 diabetes. The gut microbiota, in turn, plays crucial roles in the modulation of drug efficacy. We aimed to assess the impacts of acarbose and vildagliptin on human gut microbiota and the relationships between pre-treatment gut microbiota and therapeutic responses. METHODS: This was a randomised, open-labelled, two-arm trial in treatment-naive type 2 diabetes patients conducted in Beijing between December 2016 and December 2017. One hundred participants with overweight/obesity and newly diagnosed type 2 diabetes were recruited from the Pinggu Hospital and randomly assigned to the acarbose (n=50) or vildagliptin (n=50) group using sealed envelopes. The treatment period was 6 months. Blood, faecal samples and visceral fat data from computed tomography images were collected before and after treatments to measure therapeutic outcomes and gut microbiota. Metagenomic datasets from a previous type 2 diabetes cohort receiving acarbose or glipizide for 3 months were downloaded and processed. Statistical analyses were applied to identify the treatment-related changes in clinical variables, gut microbiota and associations. RESULTS: Ninety-two participants were analysed. After 6 months of acarbose (n=44) or vildagliptin (n=48) monotherapy, both groups achieved significant reductions in HbA1c (from 60 to 46 mmol/mol [from 7.65% to 6.40%] in the acarbose group and from 59 to 44 mmol/mol [from 7.55% to 6.20%] in the vildagliptin group) and visceral fat areas (all adjusted p values for pre-post comparisons <0.05). Both arms showed drug-specific and shared changes in relative abundances of multiple gut microbial species and pathways, especially the common reductions in Bacteroidetes species. Three months and 6 months of acarbose-induced changes in microbial composition were highly similar in type 2 diabetes patients from the two independent studies. Vildagliptin treatment significantly enhanced fasting active glucagon-like peptide-1 (GLP-1) levels. Baseline gut microbiota, rather than baseline GLP-1 levels, were strongly associated with GLP-1 response to vildagliptin, and to a lesser extent with GLP-1 response to acarbose. CONCLUSIONS/INTERPRETATION: This study reveals common microbial responses in type 2 diabetes patients treated with two glucose-lowering drugs targeting the gut differently and acceptable performance of baseline gut microbiota in classifying individuals with different GLP-1 responses to vildagliptin. Our findings highlight bidirectional interactions between gut microbiota and glucose-lowering drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02999841 FUNDING: National Key Research and Development Project: 2016YFC1304901.

A new set of 20 Multi-InDel markers for forensic application.

Insertion/deletion markers (InDels) become an important marker for forensic medicine because of their compatible typing techniques with STRs and lower mutation rates. Recent years, a new kind of DNA marker named Multi-InDel was reported as characterized by two or more tightly linked InDel loci within a short length of physical position, usually 200-300 nucleotides. Many pieces of research showed that Multi-InDels had excellent application values in ancestry inference and forensic medicine. Since the identical number of insertion/deletion nucleotides of the InDel markers that composing the Multi-InDel marker, the genotypes of most reported Multi-InDels could not be directly typed by capillary electrophoresis (CE) due to the lack of length discrepancy among the composing InDel sequence. In this study, we applied a typing system of 20 Multi-InDels including 41 InDels, whose genotypes could be deduced by CE and assessed their potential applications in forensic medicine. A total of 200 unrelated Chinese Han individuals and five mother-child-father trios with proven paternity with one STR locus transmission incompatibilities from Shanxi province were genotyped by the multiplex system. The results showed that a total of 70 specific alleles were observed, more than three alleles were observed in 19 loci and seven alleles were observed in one locus. The combined probability of exclusion and the combined power of discrimination were 0.992 and 0.99999999993, respectively. This study demonstrates their potential usefulness for individual identification and paternity tests. The development of Multi-InDels provided another genetic tool inherent in higher polymorphic and lower mutation rates.