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Excessive activation of aldose reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood–brain barrier (BBB) damage was mainly caused by increased apoptosis and autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen–glucose deprivation (OGD). In addition, bicalutamide (an AKT inhibitor) and rapamycin (an mTOR inhibitor) increased the epalrestat-induced reduction in apoptosis and autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating AKT/mTOR signaling pathway to inhibit apoptosis and autophagy in BMVECs.

Lijun Liu,1,2 Anxin Wang,1,2 Dandan Wang,1,2 Jiahuan Guo,1,2 Xiaoli Zhang,2 Xingquan Zhao,1– 3,&ast; Wenjuan Wang1,2,&ast; 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 3Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingquan Zhao; Wenjuan Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 119 West Road, South4th Ring, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86-010-59978330 ; Tel +86-010-59978891, Fax +86-010-67013383, Email zxq@vip.163.com; tong_ttyy@163.comBackground: Since studies on systemic inflammatory response syndrome (SIRS) in patients with acute intracerebral hemorrhage (ICH) are insufficient. This study investigated the associations between SIRS on admission and clinical outcomes after acute ICH.Patients and Methods: The study included 1159 patients with acute spontaneous ICH from January 2014 to September 2016. In accordance with standard criteria, SIRS was defined as two or more of the following: (1) body temperature > 38°C or < 36°C, (2) respiratory rate > 20 per minute, (3) heart rate > 90 per minute, and (4) white blood cell count > 12,000/μL or < 4000/μL. The clinical outcomes of interest were death and major disability (defined as a modified Rankin Scale of 6 and 3– 5), combined and separate at 1 month, 3 months and 1 year follow-up.Results: SIRS was observed in 13.5% (157/1159) of patients and independently increased the risk of death at 1 month, 3 months, or 1 year: hazard ratio (HR) 2.532 (95% confidence interval [CI] 1.487– 4.311), HR 2.436 (95% CI 1.499– 3.958), HR 2.030 (95% CI 1.343– 3.068), respectively (P< 0.05 for all). The relationship between SIRS and ICH mortality was more pronounced in older patients or patients with larger hematoma volumes. Patients with in-hospital infections were at greater risk of major disability. The risk was enhanced when SIRS was incorporated.Conclusion: The presence of SIRS at the time of admission was associated with mortality in patients with acute ICH, particularly in older patients and those with large hematomas. SIRS may exacerbate the disability caused by in-hospital infections in patients with ICH.Keywords: systemic inflammatory response syndrome, intracerebral hemorrhage, in-hospital infections, death, disability

Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide 1 (GLP-1) secretion and, notably, promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism–induced β-cell regeneration. We showed that in db/db mice and type 1 diabetic wild-type or Flox/cre mice, GCGR monoclonal antibody (mAb) improved glucose control, upregulated plasma insulin level, and increased β-cell area. Notably, blockage of systemic or pancreatic GLP-1R signaling by exendin 9-39 (Ex9) or Glp1r knockout diminished the above effects of GCGR mAb. Furthermore, glucagon-neutralizing antibody (nAb), which prevents activation of GLP-1R by glucagon, also attenuated the GCGR mAb–induced insulinotropic effect and β-cell regeneration. In cultured primary mouse islets isolated from normal mice and db/db mice, GCGR mAb action to increase insulin release and to upregulate β-cell–specific marker expression was reduced by a glucagon nAb, by the GLP-1R antagonist Ex9, or by a pancreas-specific Glp1r knockout. These findings suggest that activation of GLP-1R by glucagon participates in β-cell regeneration induced by GCGR antagonism in diabetic mice. Article Highlights Glucagon receptor (GCGR) antagonism promotes β-cell regeneration in type 1 and type 2 diabetic mice and in euglycemic nonhuman primates. Glucagon and glucagon-like peptide 1 (GLP-1) can activate the GLP-1 receptor (GLP-1R), and their levels are upregulated following GCGR antagonism. We investigated whether GLP-1R activated by glucagon and/or GLP-1 contributed to β-cell regeneration induced by GCGR antagonism. We found that blockage of glucagon–GLP-1R signaling attenuated the GCGR monoclonal antibody–induced insulinotropic effect and β-cell regeneration in diabetic mice. Our study reveals a novel mechanism of β-cell regeneration and uncovers the communication between α-cells and β-cells in regulating β-cell mass.

Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172K and IDH2R140Q AML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITD and IDH2 mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2 mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.

To assess the remission rate of eltrombopag in the treatment of severe immune thrombocytopenia (ITP) secondary to connective tissue disease (CTD) and to explore factors related to drug efficacy in the context of literature reports, seventeen CTD patients accompanied with severe ITP treated with eltrombopag between June 2019 and February 2021 were included, with their follow-up information recorded. Combined with literature review, patients were divided into two groups depending on whether the treatment was effective or not to determine efficacy-related factors. Totally, 7 patients with systemic lupus erythematosus, 6 with Sjögren's syndrome, and 4 with undifferentiated connective tissue disease were enrolled. The median duration of eltrombopag treatment was 8 weeks, and the median time to response was 4 weeks. Twelve (70.6%) patients responded to eltrombopag. Patients with higher serum white blood cell counts, lower serum triglyceride levels, or previously received multiple immunosuppressants achieved a better efficacy (p 0.05), while those with megakaryocytopenia in bone marrow tended to have lower remission rate (p = 0.08). By using pooled data including literature reported cases, we demonstrated that evidence of leukopenia, megakaryocytopenia, and being treated with fewer prior immunosuppressants were still associated with poor remission (p 0.05). Meanwhile, there was a trend indicating the primary disease might affect the treatment efficacy (p = 0.06). Eltrombopag is a viable option for treating severe ITP secondary to CTDs, yet it may be less effective for patients with leukopenia, megakaryocytopenia, and being treated with fewer prior immunosuppressants. Key Points • Eltrombopag provides an alternative to the current treatment of CTD-ITP. • White blood cell levels, bone marrow megakaryocyte counts, and prior use of immunosuppressants may affect the efficacy of eltrombopag.

Hemicelluloses, a major component of plant cell walls, are a non-cellulosic heteropolysaccharide composed of several distinct sugars that is second in abundance to cellulose, which are one of the most abundant and cheapest renewable resources on earth. Hemicelluloses structure is complex and its chemical structure varies greatly among the different plant species. In addition to its wide use in production of feed and other chemical materials, hemicelluloses are known for its remarkable biological activities that remain largely underutilised to date. Therefore, comprehensive investigations of hemicelluloses structural and biological properties would be helpful for achieving rational utilisation and high-value conversion of this underutilised substance into agents with enhanced health benefits for incorporation in drugs and health foods. In this review, details of diverse research initiatives that have enhanced our understanding of hemicelluloses properties are summarised, including hemicelluloses sources, extraction and purification methods, structural characteristics and biological activities. Furthermore, hemicelluloses structure-activity relationships and new directions for future hemicelluloses research studies are discussed.

A nanosheet on nanorod WSe2/WO2 heterostructure was as a proof of concept applied to immobilize and catalyze the soluble lithium polyselenides species.

The insertion of bis(diarylcarbene)s onto a glass fiber (GF) membrane surface provided an active coating for the direct capture of protein – exemplified by the enzyme, cellulase – through a mild diazonium coupling process which does not require additional coupling agents.

To explore the relationships between public risk perceptions, emotions and behaviours during a major epidemic.Exploratory cross-sectional design.The 701 subjects were surveyed using self-administered questionnaires, including the General Information Questionnaire, Public Risk Perceptions Questionnaire, Public Emotions Questionnaire and Public Behaviours Questionnaire. The results were analysed using structural equation modelling, and mediated effects were probed at the same time.The median of the total scores of the Public Risk Perceptions Questionnaire was 70, the median of the total scores of the Public Emotions Questionnaire was 65 and the median of the total scores of the Public Behaviours Questionnaire was 83. Spearman's correlation analysis showed that the correlation coefficient ρ between public risk perceptions and emotions was 0.26 (p 0.01); the correlation coefficient ρ between risk perceptions and behaviours was 0.36 (p 0.01); and the correlation coefficient ρ between emotions and behaviours was 0.37 (p 0.01). After many rounds of correction, the final model was established, the fit was good, and the results of the mediating effect analysis showed that the level of public risk perceptions under a major epidemic had a direct positive effect on public emotions (β = 0.41, p 0.01) and public behaviours (β = 0.51, p 0.01). The level of public risk perceptions also had an indirect positive effect on behaviours by affecting public emotions (β = 0.11), while public emotions had a direct positive effect on public behaviours (β = 0.27, p 0.01).Our findings revealed that public perceptions and public emotions directly influenced public behaviours. Additionally, public perceptions can indirectly influence public behaviours through public emotions.

In the face of unprecedented emission reduction pressure, enterprises urgently need to find effective ways to reduce emissions, and the forestry carbon sink through the use of market mechanisms to control carbon emissions pilot model has been highly concerned by enterprises and academia.This paper takes a number of external factors that drive enterprises to choose forestry carbon sinks as the research object, deeply analyzes the interaction logic and mechanism of interaction between them, reveals the "black box" of enterprises to choose the driving mechanism of forestry carbon sink emission reduction, and puts forward relevant management suggestions for promoting enterprises to choose forestry carbon sink emission reduction and realize the value of forestry carbon sinks.

The objective of this study was to construct lactoferrin (LFA-LFC) chimeric peptide gelatin drug-loaded fiber film by tissue engineering strategy, and study its bacteriostatic effect on oral pathogens (especially Candida albicans) and its effect on biofilm. First of all, LFA-LFC chitosan nanoparticles were prepared firstly, and then fluconazole gelatin (LF/GH/F) film loaded with LFA-LFC was prepared by electrospinning. Scanning electron microscope (SEM), mechanical strength, drug release, cytotoxicity, and real-time PCR were used to test the properties of the synthesized materials. SEM showed that there was the reticular structure for fiber film before and after cross-linking. LF/GH/F film had no obvious cytotoxicity, with good biocompatibility and drug release; real-time PCR and antibacterial test showed that the LF/GH/F film had good antibacterial activity. LF/GH/F film has a good inhibitory effect on oral pathogens, and its mechanism is related to biofilm. The antibacterial experiments of nanofiber membrane in vitro and the effect of bacterial biofilm were carried out. The effect of LF/GH/F on oral microbial flora structure was studied by fluorescence quantitative pest techniques.

The TMEM196 protein, which comprises four membrane-spanning domains, belongs to the TMEM protein family. TMEM196 was identified as a candidate tumor suppressor gene in lung cancer. However, its role and mechanism in lung cancer metastasis remain unclear. Here, we study the role of TMEM196 in tumor metastasis to further verify the function in lung cancer.In this study, we used qRT-PCR, western blot analysis and immunohistochemistry to examine the expression levels of TMEM196 and related proteins in lung cancer tissues and tumor cells. We utilized Transwell assays, xenograft nude mouse models, and TMEM196We found that TMEM196 mRNA and protein expression levels were significantly decreased in lung cancer tissues and cells. Low expression of TMEM196 in clinical patients was associated with poor prognosis. TMEM196 strongly inhibited tumor metastasis and progression in vitro and in vivo. The primary lung tumors induced by tail vein-inoculated B16 cells in TMEM196Our results revealed that TMEM196 acts as a novel lung cancer metastasis suppressor via the Wnt/β-catenin signaling pathway.

Based on station precipitation observations, radar quantitative precipitation estimates (QPE), and radar fusion data during Typhoon Fitow (2013), the influence of multisource precipitation data on multiscale urban typhoon pluvial flood modeling is studied. Using Shanghai, China, as the study area, a simplified 2D hydrodynamic model is applied to simulations. Combined with actual flood incidents reported by the public and soil moisture data, we perform multiscale verifications and determine the applicability of three precipitation datasets in the modeling. The results are as follows: (1) At the city scale, although QPE have higher spatial resolution, these estimates are lower than station observations. Radar fusion data have both high accuracy and high spatial resolution. For flood depths above 5 cm, the radar fusion precipitation scenario can improve the matching probability by 6%. (2) At the neighborhood scale, the radar fusion precipitation scenario can effectively mitigate the problems of an uneven spatial distribution of stations and a weak QPE to accurately capture pluvial details. (3) One fixed-point assessment shows that different precipitation data have little influence on the temporal characteristics of the modeling result—all three types of data can accurately reflect flood occurrence times. This work can provide a scientific basis for constructing effective urban pluvial flood monitoring systems.

Covalent organic frameworks (COFs) show great potential in biomedicine, but the synthesis of fluorescent ones with a highly conjugated structure in mild conditions remains a challenge. Herein, we reported a facile method to synthesize a nanosized, highly conjugated, and N-enriched COF material with bright fluorescence and further integrated it as a novel nanoplatform for efficient cancer starvation/gas therapy. High surface area and a porous structure endowed COFs with large loading capacity for both glucose oxidase and l-arginine, while conjugated monomer and N-doping guaranteed bright fluorescence and relatively strong interactions between loaded cargos. Well-designed size allowed easy cell uptake of drug-loaded COFs, which finally resulted in a highly efficient starvation therapy by consuming large amounts of glucose in cancer cells. H

Dandan Wang, Changchun Zhan School of Management, Jiangsu University, Zhenjiang, People’s Republic of ChinaCorrespondence: Changchun Zhan, Tel +86-15952808385, Email Zcc1973@126.comPurpose: To identify the factors that influence whistleblowing behavior as it relates to health care insurance fraud in Jiangsu Province, China.Methods: To construct a factor model and formulate research hypotheses using the Motivation–Opportunity–Ability framework. We designed a questionnaire containing 24 items and distributed it on-site to 2081 respondents in Jiangsu Province, China. Afterward, we applied structural equation modeling to validate the research hypotheses.Results: Policy awareness negatively contributes to whistleblowing behavior, risk perception does not reduce the incentive to blow the whistle, and an inability to recognize fraud is another critical barrier to converting whistleblowing intentions into behavior.Conclusion: Practices that are likely to promote citizen whistleblowing on insurance fraud may focus on the constraints identified by the comprehensive Motivation–Opportunity–Ability framework.Keywords: health care insurance fraud, whistleblowing behavior, Motivation–Opportunity–Ability framework, structural equation modeling

Long12 block of Longhupao oilfield is located in the western slope area of Qijia-Gulong Sag, which lay in the central depression of Songliao basin. Recent exploration and development shows that Putaohua oil layer has great potential storage. However, the block is located in the ring concave fault zone, with complex geological background and extensive low resistivity oil layers and water layers of high resistivity, resulting in an unclear condition of reservoir forming and oil-water distribution rules of Putaohua oil layer, which deeply restricts the pace of increasing storage and production of the oilfield. In this study, the data of logging, logging, drilling, analysis, and testing are adopted to study carries out a reservoir forming conditions such as source rocks, reservoirs, caprocks, traps, and migration conditions. Meanwhile this study discuss the main controlling factors of Putaohua reservoir formation in combination with the law of oil-water distribution, so as to provide a geological basis for clarifying the reservoir forming law of long 12 block and the prediction of favorable target areas.

In response to the carbon peak and carbon neutral plan proposed by the General Secretary Xi Jinping, Anhui Province actively promotes the comprehensive green transformation of economic and social development, and helps to achieve accurate, scientific energy conservation and carbon reduction by making use of the characteristics and advantages of blockchain technology, such as chained data structure, decentralized distribution, smart contracts and open source programmability. On the basis of blockchain technology, "carbon index", energy trading and other theories, this paper combines blockchain technology with the work of energy conservation and carbon reduction in Anhui Province, and realizes the systematic construction of blockchain technology in energy conservation and carbon reduction by establishing a conceptual model of energy blockchain trading.

Switching of G-quadruplex (G4) structures between variant types of folding has been proved to be a versatile tool for regulation of genomic expression and development of nucleic acid-based constructs. Various specific ligands have been developed to target G4s in K+ solution with therapeutic prospects. Although G4 structures have been reported to be converted by sequence modification or a unimolecular ligand binding event in K+-deficient conditions, switching G4s towards non-G4 folding continues to be a great challenge due to the stability of G4 in physiological K+ conditions. Herein, we first observed the G4 switching towards parallel-stranded duplex (psDNA) by multimolecular ligand binding (namely ligand clustering) to overcome the switching barrier in K+. Purine-rich sequences (e.g. those from the KRAS promoter region) can be converted from G4 structures to dimeric psDNAs using molecular rotors (e.g. thioflavin T and thiazole orange) as initiators. The formed psDNAs provided multiple binding sites for molecular rotor clustering to favor subsequent structures with stability higher than the corresponding G4 folding. Our finding provides a clue to designing ligands with the competency of molecular rotor clustering to implement an efficient G4 switching.