Potential mechanisms of cancer prevention and treatment by sulforaphane, a natural small molecule compound of plant-derived.

Despite recent advances in tumor diagnosis and treatment technologies, the number of cancer cases and deaths worldwide continues to increase yearly, creating an urgent need to find new methods to prevent or treat cancer. Sulforaphane (SFN), as a member of the isothiocyanates (ITCs) family, which is the hydrolysis product of glucosinolates (GLs), has been shown to have significant preventive and therapeutic cancer effects in different human cancers. Early studies have shown that SFN scavenges oxygen radicals by increasing cellular defenses against oxidative damage, mainly through the induction of phase II detoxification enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2). More and more studies have shown that the anticancer mechanism of SFN also includes induction of apoptotic pathway in tumor cells, inhibition of cell cycle progression, and suppression of tumor stem cells. Therefore, the application of SFN is expected to be a necessary new approach to treating cancer. In this paper, we review the multiple molecular mechanisms of SFN in cancer prevention and treatment in recent years, which can provide a new vision for cancer treatment.

Long-term intake of sulforaphene alleviates D-galactose-induced skin senescence by activating AMPK-Sirt 1 pathway.

D-Galactose (D-gal) accumulation triggers the generation of oxygen free radicals, resulting in skin aging. Sulforaphene (SFE), an isothiocyanate compound derived from radish seeds, possesses diverse biological activities, including protective effects against inflammation and oxidative damage. This investigation delves into the antioxidant impact of SFE on age-related skin injury. In vivo experiments demonstrate that SFE treatment significantly improves the macro- and micro-morphology of dorsal skin. It effectively diminishes the elevation of oxidative stress biomarkers in mice skin tissue treated with D-gal, concurrently enhancing the activity of antioxidant enzymes. Additionally, SFE mitigates collagen mRNA degradation, lowers pro-inflammatory cytokine levels, and downregulates MAPK-related protein expression in the skin. Moreover, SFE supplementation reduces lipid metabolite levels and elevates amino acid metabolites, such as L-cysteine and L-histidine. These findings suggest that SFE holds promise as a natural remedy to mitigate aging induced by oxidative stress.

Analysis of early clinical signs and risk factors for severe hemorrhagic cystitis after stem cell transplantation in children.

INTRODUCTION: To analyze the characteristics of early clinical symptoms of hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) and the risk factors of severe HC. METHODS: We retrospectively analyzed 77 children with post-HSCT HC treated at our hospital between June 2013 and June 2021. Clinical characteristics were collected and catalogued. RESULTS: Among the children with urinary tract irritation symptoms (UTIS) as the first symptom, symptoms appeared earlier than hematuria symptoms (28 day vs. 31 day, p = 0.027), and the time progressing to severe HC was significantly longer in these children (12 day vs. 7 day, p = 0.038), but there was no significant difference in the number of participants (57.8% vs. 59.4%, p = 0.889). BK polyomavirus (BKV) infection was an independent risk factor (hazard ratio [HR] = 2.782, p = 0.035) for severe HC, which was also positively associated with multi-viral infection (HR = 2.215, p = 0.020). CONCLUSIONS: In HC children, when the first urinary tract symptom was UTIS, it appeared earlier than hematuria, and the time of progression to severe HC was significantly longer, suggesting that we still need more aggressive treatment for these children to prevent the worsening of symptoms. The severity of HC was positively correlated with BKV infection and multiple infections.

Increased long-distance and homo-trans interactions related to H3K27me3 in Arabidopsis hybrids.

In plants, the genome structure of hybrids changes compared with their parents, but the effects of these changes in hybrids remain elusive. Comparing reciprocal crosses between Col × C24 and C24 × Col in Arabidopsis using high-throughput chromosome conformation capture assay (Hi-C) analysis, we found that hybrid three-dimensional (3D) chromatin organization had more long-distance interactions relative to parents, and this was mainly located in promoter regions and enriched in genes with heterosis-related pathways. The interactions between euchromatin and heterochromatin were increased, and the compartment strength decreased in hybrids. In compartment domain (CD) boundaries, the distal interactions were more in hybrids than their parents. In the hybrids of CURLY LEAF (clf) mutants clfCol × clfC24 and clfC24 × clfCol , the heterosis phenotype was damaged, and the long-distance interactions in hybrids were fewer than in their parents with lower H3K27me3. ChIP-seq data revealed higher levels of H3K27me3 in the region adjacent to the CD boundary and the same interactional homo-trans sites in the wild-type (WT) hybrids, which may have led to more long-distance interactions. In addition, the differentially expressed genes (DEGs) located in the boundaries of CDs and loop regions changed obviously in WT, and the functional enrichment for DEGs was different between WT and clf in the long-distance interactions and loop regions. Our findings may therefore propose a new epigenetic explanation of heterosis in the Arabidopsis hybrids and provide new insights into crop breeding and yield increase.

New Insight into the Potential Protective Function of Sulforaphene against ROS-Mediated Oxidative Stress Damage In Vitro and In Vivo.

Sulforaphene (SFE) is a kind of isothiocyanate isolated from radish seeds that can prevent free-radical-induced diseases. In this study, we investigated the protective effect of SFE on oxidative-stress-induced damage and its molecular mechanism in vitro and in vivo. The results of cell experiments show that SFE can alleviate D-gal-induced cytotoxicity, promote cell cycle transformation by inhibiting the production of reactive oxygen species (ROS) and cell apoptosis, and show a protective effect on cells with H2O2-induced oxidative damage. Furthermore, the results of mice experiments show that SFE can alleviate D-galactose-induced kidney damage by inhibiting ROS, malondialdehyde (MDA), and 4-hydroxyalkenals (4-HNE) production; protect the kidney against oxidative stress-induced damage by increasing antioxidant enzyme activity and upregulating the Nrf2 signaling pathway; and inhibit the activity of pro-inflammatory factors by downregulating the expression of Toll-like receptor 4 (TLR4)-mediated inflammatory response. In conclusion, this research shows that SFE has antioxidant effects, providing a new perspective for studying the anti-aging properties of natural compounds.

Impact of low-level viremia with drug resistance on CD4 cell counts among people living with HIV on antiretroviral treatment in China.

BACKGROUND: Maintaining plasma HIV RNA suppression below the limit of quantification is the goal of antiretroviral therapy (ART). When viral loads (VL) remain in low-level viremia (LLV), or between 201 and 999 copies/mL, the clinical consequences are still not clear. We investigated the occurrence of LLV with drug resistance and its effect on CD4 cell counts in a large Chinese cohort. METHODS: We analysed data of 6,530 ART-experienced patients (42.1 ± 10.9 years; 37.3% female) from the China's national HIV drug resistance (HIVDR) surveillance database. Participants were followed up for 32.9 (IQR 16.7-50.5) months. LLV was defined as the occurrence of at least one viral load (VL) measurement of 50-200 copies/mL during ART. Outcomes were drug resistance associated mutations (DRAM) and CD4 cell counts levels. RESULTS: Among 6530 patients, 58.0% patients achieved VL less than 50 copies/mL, 27.8% with VL between 50 and 999 copies/mL (8.6% experienced LLV), and 14.2% had a VL ≥ 1000 copies/mL. Of 1818 patients with VL 50-999 copies/mL, 182 (10.0%) experienced HIVDR, the most common DRAM were M184I/V 28.6%, K103N 19.2%, and V181C/I/V 10.4% (multidrug resistance: 27.5%), and patients with HIVDR had a higher risk of CD4 cell counts < 200 cells/µL (AOR 3.8, 95% CI 2.6-5.5, p < 0.01) comparing with those without HIVDR. Of 925 patients with VL ≥ 1000 copies/mL, 495 (53.5%) acquired HIVDR, the most common DRAM were K103N 43.8%, M184I/V 43.2%, M41L 19.0%, D67N/G 16.4%, V181C/I/V 14.5%, G190A/S 13.9% and K101E 13.7% (multidrug resistance: 75.8%), and patients with HIVDR had a higher risk of CD4 cell counts < 200 cells/µL (AOR 5.8, 95% CI 4.6-7.4, p < 0.01) comparing with those without HIVDR. CONCLUSION: Persistent with VL 50-999 copies/mL on ART is associated with emerging DRAM for all drug classes, and patients in this setting were at increased risk of CD4 cell counts < 200 cells/µL, which suggest resistance monitoring and ART optimization be earlier considered.

Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP.

Galectin-3(Gal-3) is an effective regulator in the pathological process of pulmonary arterial hypertension (PAH). However, the detailed mechanisms underlying Gal-3 contribution to PAH are not yet entirely clear. The aim of the present study was to explore these issues. Proliferation of rat pulmonary arterial smooth muscle cells (PASMCs) was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Small interfering RNA (siRNA) was applied to silence the expression of yes-associated protein (YAP) and Forkhead box M1 (FOXM1). The protein expression and phosphorylation were measured by immunoblotting. The subcellular location of YAP was determined using immunoblotting and immunofluorescence. Gal-3-stimulated PASMCs proliferation in a time- and dose-dependent manner, this was accompanied with, YAP upregulation, dephosphorylation, and nucleus translocation. Gal-3 further increased FOXM1 and cyclinD1 expression via YAP activation. Interfering YAP/FOXM1 axis suppressed Gal-3-induced PASMCs proliferation. Activation of AMPK also inhibited Gal-3-triggered cells proliferation by targeting YAP/FOXM1/cyclinD1 pathway. Gal-3 induced PASMCs proliferation by regulating YAP/FOXM1/cyclinD1 signaling cascade, and activation of AMPK targeted on this axis and suppressed Gal-3-stimulated PASMCs proliferation. Our study provides novel therapeutic targets for prevention and treatment of PAH.

HIV drug resistance in patients in China's national HIV treatment programme who have been on first-line ART for at least 9 months.

BACKGROUND: The aim of this study was to assess trends in drug resistance and associated clinical and programmatic factors at a national level during the rapid scale up of ART. METHODS: Logistic regression was used to identify the factors associated with HIVDR. Variables associated with drug resistance in multivariable logistic regression were included in the Cochran-Armitage test for trend. RESULTS: A total of 11,976 patients were enrolled in the study. The prevalence of HIVDR among patients who received ART for 9-24 months during 2003-2008, 2009-2012, and 2013-2015 significantly decreased (15.5%, 6.3%, and 2.3%, respectively, P < 0.01). With respect to the class of antiretroviral, there were substantial increases in resistance to both non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) (2003-2008, 2009-2012, and 2013-2015: 49.7%, 58.9%, and 73.0%, respectively, P < 0.01). The prevalence of DR to protease inhibitors (PIs) was low, which supported their continued use as second-line therapy in China. CONCLUSIONS: Our results provide evidence for the effectiveness of China's "Treat All" approach to guide policy makers to improve training for healthcare providers and education on ART adherence among patients.

Spatiotemporal characteristics and the epidemiology of tuberculosis in China from 2004 to 2017 by the nationwide surveillance system.

BACKGROUND: China has always been one of the countries with the most serious Tuberculosis epidemic in the world. Our study was to observe the Spatial-temporal characteristics and the epidemiology of Tuberculosis in China from 2004 to 2017 with Joinpoint regression analysis, Seasonal Autoregressive integrated moving average (SARIMA) model, geographic cluster, and multivariate time series model. METHODS: The data of TB from January 2004 to December 2017 were obtained from the notifiable infectious disease reporting system supplied by the Chinese Center for Disease Control and Prevention. The incidence trend of TB was observed by the Joinpoint regression analysis. The Seasonal autoregressive integrated moving average (SARIMA) model was used to predict the monthly incidence. Geographic clusters was employed to analyze the spatial autocorrelation. The relative importance component of TB was detected by the multivariate time series model. RESULTS: We included 13,991,850 TB cases from January 2004 to December 2017, with a yearly average morbidity of 999,417 cases. The final selected model was the 0 Joinpoint model (P = 0.0001) with an annual average percent change (AAPC) of - 3.3 (95% CI: - 4.3 to - 2.2, P < 0.001). A seasonality was observed across the 14 years, and the seasonal peaks were in January and March every year. The best SARIMA model was (0, 1, 1) X (0, 1, 1)12 which can be written as (1-B) (1-B12) Xt = (1-0.42349B) (1-0.43338B12) εt, with a minimum AIC (880.5) and SBC (886.4). The predicted value and the original incidence data of 2017 were well matched. The MSE, RMSE, MAE, and MAPE of the modelling performance were 201.76, 14.2, 8.4 and 0.06, respectively. The provinces with a high incidence were located in the northwest (Xinjiang, Tibet) and south (Guangxi, Guizhou, Hainan) of China. The hotspot of TB transmission was mainly located at southern region of China from 2004 to 2008, including Hainan, Guangxi, Guizhou, and Chongqing, which disappeared in the later years. The autoregressive component had a leading role in the incidence of TB which accounted for 81.5-84.5% of the patients on average. The endemic component was about twice as large in the western provinces as the average while the spatial-temporal component was less important there. Most of the high incidences (> 70 cases per 100,000) were influenced by the autoregressive component for the past 14 years. CONCLUSION: In a word, China still has a high TB incidence. However, the incidence rate of TB was significantly decreasing from 2004 to 2017 in China. Seasonal peaks were in January and March every year. Obvious geographical clusters were observed in Tibet and Xinjiang Province. The relative importance component of TB driving transmission was distinguished from the multivariate time series model. For every provinces over the past 14 years, the autoregressive component played a leading role in the incidence of TB which need us to enhance the early protective implementation.

High BCL11A Expression in Adult Acute Myeloid Leukemia Patients Predicts a Worse Clinical Outcome.

BACKGROUND: Recent reports showed BCL11A may be causatively involved in myeloid leukemia. This study investigated the relationship between BCL11A expression levels and adult acute myeloid leukemia patient characteristics as well as clinical outcomes. METHODS: RT-PCR was employed to detect BCL11A gene expression levels in 80 patients with acute myeloid leukemia. RESULTS: Median BCL11A expression levels of 80 AML bone marrow samples were found to be higher than the control group (0.039 vs. 0.014, p < 0.005). Patients with low BCL11A expression levels had a significantly higher CR (complete remission) rate compared with patients with high BCL11A expression levels (90% vs. 53%, p < 0.005). Moreover, the median OS (overall survival) in patients with low BCL11A expression (268 d) was also longer than that in patients with high BCL11A expression (101.5 d) (p < 0.05). No significant difference was observed between the high and low BCL11A groups with respect to white blood cells, haemoglobin, platelet count, French-American-Britain (FAB) subtypes, percentage of blasts in bone marrow, peripheral blood, cytogenetic risk groups, and CD34 expression. CONCLUSIONS: Adult acute myeloid leukemia had a higher BCL11A expression level. High BCL11A expression level was correlated with lower CR rate and shorter OS, suggesting that BCL11A expression could potentially be used as a prognosis indicator.

Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture.

Obesity is accompanied by an increase in the size and the number of adipocytes. As adipocytes are thought to differentiate from pre-adipocytes, we postulate that non-adipogenic fibroblasts contribute to adipocyte formation under certain conditions such as obesity. We report for the first time that NIH-3T3 fibroblasts, which are generally considered to be non-adipogenic, can be converted into mature adipocytes by treatment with a defined hormone mixture comprising EGF (epidermal growth factor), HGF (hepatocyte growth factor), Dex (dexamethasone) and insulin. Furthermore, NIH-3T3 cells transplanted into obese immunodeficient NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice formed adipocytes in vivo. Interestingly, the mixture elicited conversion of NIH-3T3 cells directly into adipocytes without a preceding pre-adipocyte stage. Functional analysis revealed that each component of the mixture was necessary for the induction of adipogenesis, including Dex which inhibited the cell proliferation stimulated by EGF. Upon profiling the signalling pathways employed by EGF and HGF, we found STAT5 (signal transducer and activator of transcription 5) signalling to be activated, predominantly at the levels of both transcription and post-translational modification. Inhibition of the STAT5 pathway, either by genetic knockdown or a specific pharmacological agent, blocked adipogenesis in NIH-3T3 cells. Taken together, these data not only establish a newly recognized grouping of factors that can induce trans-differentiation of non-adipogenic fibroblasts into adipocytes, but also give us a greater understanding of obesity.

Implementation of an Enhanced Crayfish Optimization Algorithm.

This paper presents an enhanced crayfish optimization algorithm (ECOA). The ECOA includes four improvement strategies. Firstly, the Halton sequence was used to improve the population initialization of the crayfish optimization algorithm. Furthermore, the quasi opposition-based learning strategy is introduced to generate the opposite solution of the population, increasing the algorithm's searching ability. Thirdly, the elite factor guides the predation stage to avoid blindness in this stage. Finally, the fish aggregation device effect is introduced to increase the ability of the algorithm to jump out of the local optimal. This paper performed tests on the widely used IEEE CEC2019 test function set to verify the validity of the proposed ECOA method. The experimental results show that the proposed ECOA has a faster convergence speed, greater performance stability, and a stronger ability to jump out of local optimal compared with other popular algorithms. Finally, the ECOA was applied to two real-world engineering optimization problems, verifying its ability to solve practical optimization problems and its superiority compared to other algorithms.

Exploring the relationship between immune heterogeneity characteristic genes of rheumatoid arthritis and acute myeloid leukemia.

BACKGROUND: People with autoimmune diseases are prone to cancer, and there is a close relationship between rheumatoid arthritis (RA) and acute myeloid leukemia (AML). The bone marrow (BM) is affected throughout the course of RA, with a variety of hematologic involvement. Hopes are pinned on rheumatoid arthritis research to obtain BM biomarkers for AML. METHODS: Synovial transcriptome sequencing data for RA and osteoarthritis (OA), and single-cell sequencing data for RA and controls were obtained from the GEO database.Bone marrow sequencing data for AML patients and normal subjects were obtained from the UCSC Xena database. The final immune heterogeneity characteristics of RA were determined through ssGSEA analysis, gene differential expression analysis, fuzzy c-means clustering algorithm, and XGboost algorithm. Random Ferns classifiers (RFs) are used to identify new bone marrow markers for AML. RESULTS: SELL, PTPRC, IL7R, CCR7, and KLRB1 were able to distinguish leukemia cells from normal cells well, with AUC values higher than 0.970. CONCLUSION: Genes characterizing the immune heterogeneity of RA are associated with AML, and KLRBA may be a potential target for AML treatment.

Metal ion stimulation-related gene signatures correlate with clinical and immunologic characteristics of glioma.

Background: Environmental factors serve as one of the important pathogenic factors for gliomas. Yet people focus only on the effect of electromagnetic radiation on its pathogenicity, while metals in the environment are neglected. This study aimed to investigate the relationship between metal ion stimulation and the clinical characteristics and immune status of GM patients. Methods: Firstly, mRNA expression profiles of GM patients and normal subjects were obtained from Chinese GM Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) to identify differentially expressed metal ion stimulation-related genes(DEMISGs). Secondly, two molecular subtypes were identified and validated based on these DEMISGs using consensus clustering. Diagnostic and prognostic models for GM were constructed after screening these features based on machine learning. Finally, supervised classification and unsupervised clustering were combined to classify and predict the grade of GM based on SHAP values. Results: GM patients are divided into two different response states to metal ion stimulation, M1 and M2, which are related to the grade and IDH status of the GM. Six genes with diagnostic value were obtained: SLC30A3, CRHBP, SYT13, DLG2, CDK1, and WNT5A. The AUC in the external validation set was higher than 0.90. The SHAP value improves the performance of classification prediction. Conclusion: The gene features associated with metal ion stimulation are related to the clinical and immune characteristics of transgenic patients. XGboost/LightGBM Kmeans has a higher classification prediction accuracy in predicting glioma grades compared to using purely supervised classification techniques.

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway.

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show in mice that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

The human brain contains billions of neurons working together to process the vast array of information we receive from our environment. These neurons communicate at junctions known as synapses, where chemical packages called vesicles released from one neuron stimulate a response in another. This synaptic communication is crucial for our ability to think, learn and remember. However, this activity depends on a complex interplay of proteins, whose balance and location within the neuron are tightly controlled. Any disruption to this delicate equilibrium can cause significant problems, including neurodevelopmental and neuropsychiatric disorders, such as schizophrenia and intellectual disability. One key regulator of activity at the synapse is a protein called Bcl11b, which has been linked to conditions affected by synaptic dysfunction. It plays a critical role in maintaining specific junctions known as mossy fibre synapses, which are important for learning and memory. One of the genes regulated by Bcl11b is C1ql2, which encodes for a synaptic protein. However, it is unclear what molecular mechanisms Bcl11b uses to carry out this role. To address this, Koumoundourou et al. explored the role of C1ql2 in mossy fibre synapses of adult mice. Experiments to manipulate the production of C1ql2 independently of Bcl11b revealed that C1ql2 is vital for recruiting vesicles to the synapse and strengthening synaptic connections between neurons. Further investigation showed that C1ql2's role in this process relies on interacting with another synaptic protein called neurexin-3. Disrupting this interaction reduced the amount of C1ql2 at the synapse and, consequently, impaired vesicle recruitment. These findings will help our understanding of how neurodevelopmental and neuropsychiatric disorders develop. Bcl11b, C1ql2 and neurexin-3 have been independently associated with these conditions, and the now-revealed interactions between these proteins offer new insights into the molecular basis of synaptic faults. This research opens the door to further study of how these proteins interact and their roles in brain health and disease.

Study on Surface Integrity and Fatigue Properties of TC4 Titanium Alloy by Surface Ultrasonic Rolling.

In this paper, the influence of a surface ultrasonic rolling process on the surface integrity of TC4 titanium alloy and its influence on the fatigue properties were studied. By comparing and analyzing the surface roughness, microhardness, residual stress, microstructure, and fatigue fracture, the surface strengthening and modification mechanism of TC4 titanium alloy is discussed. The results show that the surface roughness of titanium alloy is observably decreased after the suitable surface ultrasonic rolling process, and the maximum Ra value can be reduced to 0.052 µm. The axial residual stress on the specimen surface can be increased to -685 MPa. The hardening rate of the surface hardness of the sample was 35%. The residual compressive stress and hardness of the sample surface increased with the increase of static pressure. However, the increase of feed rate and rational speed was less. After surface ultrasonic rolling, the sample surface exhibited obvious grain refinement, the number of high-angle boundaries increased to include the formation of nano-equiaxed grains. The fatigue strength increased by 52% from 280 MPa to 425 MPa. Under 450 MPa, the fatigue life of samples with SUR 2 was the highest, at about 7.7 times that of the original samples. The surface integrity of titanium alloy samples after surface ultrasonic rolling treatment is greatly improved, which is the reason for the significant increase in fatigue life of the samples.

NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3.

Ischemic stroke is the main type of cerebrovascular disease. Emergency thrombectomy combined with medication therapy is currently the primary treatment for stroke. Inflammation and oxidative stress induced by ischemia-reperfusion cause secondary damage to blood vessels, especially endothelial mesenchymal transformation (EndoMT). However, much is still unclear about the role of EndoMT in ischemia-reperfusion. In this study, an in vivo ischemia-reperfusion model was established by transient middle cerebral artery occlusion (tMCAO) in wild-type (WT) C57BL/6 mice and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) knockout (KO) C57BL/6 mice. An in vitro ischemia-reperfusion model was established by oxygen glucose deprivation and reoxygenation (OGD/R) of human brain microvascular endothelial cells (HBMECs). α-SMA (alpha smooth muscle actin), CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1/CD31), NDUFC2 (NADH: ubiquinone oxidoreductase subunit C2), and NLRP3 were used to evaluate EndoMT and inflammation. Real-time PCR measured superoxide dismutase 1 (SOD1) and catalase (CAT) mRNA expression to evaluate oxidative stress levels. NLRP3 was activated by ischemia-reperfusion injury and NLRP3 inactivation inhibited the EndoMT in tMCAO mice. Further experiments demonstrated that OGD/R treatment induced NLRP3 activation and EndoMT in HBMECs, which resulted in NDUFC2 deficiency. NDUFC2 overexpression suppressed NLRP3 activation and EndoMT in HBMECs induced by OGD/R. Moreover, NDUFC2 overexpression rescued SOD1 and CAT mRNA expression. These results demonstrated that NDUFC2 deficiency decreased the antioxidant levels, leading to NLRP3 activation and EndoMT during ischemia-reperfusion injury and suggesting that NDUFC2 is a potential drug target for the treatment of ischemic stroke.

Effect of grazing and climatic factors on biodiversity-ecosystem functioning relationships in grassland ecosystems - a case study of typical steppe in Inner Mongolia, China.

Biodiversity underpins grassland ecological functions and productive capacities. By studying the mechanisms for the maintenance of species diversity in animal communities, we can provide important theoretical guidance for the optimization of grazing management and biodiversity protection. The typical grassland of Xilingol in Inner Mongolia, China, was used as the experimental area, and a grazing intensity experiment was set up. This consisted of four gradient levels that were grazed by sheep, which were available for continuous monitoring, namely control standard sheep unit·day·hectare-1·year-1 (CK, 0 SSU·d·hm-2y-1), light grazing (LG, 170 SSU·d·hm-2·y-1), moderate grazing (MG, 340 SSU·d·hm-2·y-1), and high grazing (HG, 510 SSU·d·hm-2·y-1). Nine consecutive years of multi-indicator monitoring of vegetation was carried out from 2014-2022, using monitoring data coupled with time series and inter-annual climatic (relative moisture index, RMI) fluctuations. This was done to analyze the impacts of disturbances, such as grazing use and climatic fluctuations, on the diversity of species and above-ground productivity of the community, thereby exploring the relationship between diversity and productivity, and provide possible explanations for the emergence of a range of ecological responses. The statistical analysis methods used were One-way Analysis of Variance (ANOVA), general linear regression and mixed-effects models. The main conclusions of this study are as follows: (1) The grassland in the experimental area under CK had the highest diversity and productivity and the ecosystem was better able to buffer the negative impacts of climatic drought. Furthermore, the effect of climate on productivity and diversity weakened as the intensity of grazing increased. (2) LG to MG had a constant diversity. (3) Grazing utilization changed the relationship between community species diversity and aboveground productivity by releasing spatial community resources, altering the structure of plant communities, weakening competitive exclusion, and strengthening complementary effects. However, under all of the conditions there is a brief stage in the time series when diversity is stimulated to increase, and the higher the grazing intensity, the earlier this occurs.

Derivation of trophoblast stem cells from human expanded potential stem cells.

Human trophoblast development study has long been limited by the lack of suitable materials. Here we present a detailed protocol for the differentiation of human expanded potential stem cells (hEPSCs) into human trophoblast stem cells (TSCs) and for the subsequent establishment of TSC lines. The hEPSC-derived TSC lines can be continuously passaged and are functional in further differentiation into syncytiotrophoblasts and extravillous trophoblasts. The hEPSC-TSC system offers a valuable cell source for studying human trophoblast development in pregnancy. For complete details on the use and execution of this protocol, please refer to Gao et al. (2019)1 and Ruan et al. (2022).2.

Expanded Potential Stem Cells from Human Embryos Have an Open Chromatin Configuration with Enhanced Trophoblast Differentiation Ability.

Human expanded potential stem cells (hEPSC) have been derived from human embryonic stem cells and induced pluripotent stem cells. Here direct derivation of hEPSC from human pre-implantation embryos is reported. Like the reported hEPSC, the embryo-derived hEPSC (hEPSC-em) exhibit a transcriptome similar to morula, comparable differentiation potency, and high genome editing efficiency. Interestingly, the hEPSC-em show a unique H3 lysine-4 trimethylation (H3K4me3) open chromatin conformation; they possess a higher proportion of H3K4me3 bound broad domain (>5 kb) than the reported hEPSC, naive, and primed embryonic stem cells. The open conformation is associated with enhanced trophoblast differentiation potency with increased trophoblast gene expression upon induction of differentiation and success in derivation of trophoblast stem cells with bona fide characteristics. Hippo signaling is specifically enriched in the H3K4me3 broad domains of the hEPSC-. Knockout of the Hippo signaling gene, YAP1 abolishes the ability of the embryo-derived EPSC to form trophoblast stem cells.