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Abstract Background Obesity is closely associated with upper gastrointestinal disorders. The recommendations for routine preoperative esophagogastroduodenoscopy (EGD) before bariatric surgery remains a topic of debate. This study aimed to describe the pathological endoscopic findings in individuals qualified for bariatric surgery. Methods Retrospective analysis was conducted on preoperative gastroscopy reports of patients who underwent bariatric surgery at our hospital between October 2022 and October 2023. Results A total of 405 patients were included in the study. The two most prevalent endoscopic findings during EGD in this patient cohort were chronic superficial gastritis (326/405, 80.5%) and reflux esophagitis (82/405, 20.2%). Some patients exhibited two or more abnormalities. Patients with reflux esophagitis were older, had a higher proportion of men, higher BMI, higher rates of smoking and drinking compared to those without it (P = 0.033, P

Background: This study aimed to construct an enteral nutrition evaluation system for critically ill patients using the Delphi method to direct the formulation of enteral nutrition support strategies and reduce interruption to enteral feeding. Methods: We used domestic and foreign databases to obtain and analyze the literature and form “The Whole-Proceeding Enteral Nutrition Evaluation System for Critically Ill Patients.” The Delphi method was used to conduct two rounds of expert opinion consultation, combined with the suggestions from the research group to finalize the nutrition evaluation content of the system. Results: After two rounds of expert consultation, a nutrition evaluation system was formed around three dimensions: before the start, during, and after the end of nutritional support. The effective recovery rates of the two rounds of expert consultation were 90.0% (18/20) and 100.0% (18/18), respectively. Authority coefficients were 0.865 and 0.908, while Kendall coordination coefficients were 0.108 (P < 0.05) and 0.115 (P < 0.001), respectively. Finally, the full enteral nutrition evaluation system for critically ill patients was constructed based on the Delphi method, including three primary items and seven secondary and 28 tertiary indicators. Conclusion: The established “Whole-Proceeding Enteral Nutrition Evaluation System for Critically Ill Patients” has high consistency from expert opinions and reliability, which can provide a practical evaluation tool for the process of enteral nutrition for severe patients.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated.Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1.Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (−38.33 kcal·mol−1) was lower than that of compound EVO-6 (−33.25 kcal·mol−1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6.Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

ObjectiveThis study aims to retrieve, evaluate, and summarize domestic and foreign evidence on the prevention and treatment of embolism syndrome following transcatheter arterial chemoembolization (TACE) for primary liver cancer and to provide an evidence-based foundation for clinical practice.MethodsUtilizing the “6S” model, we conducted a systematic search of UpToDate, BMJ Best Practice, domestic and foreign guidelines, and related databases on the prevention and treatment of embolism syndrome following TACE for primary liver cancer. This search included clinical decision-making, guidelines, systematic reviews, evidence summaries, randomized controlled trials, and expert consensus. The search time frame extended from January 1, 2013 to May 1, 2023. Evidence was synthesized after an independent review of the included studies by two investigators.ResultsA total of 11 articles were included in the analysis, comprising one clinical decision-making article, three clinical guidelines, six expert consensus articles, and one randomized controlled trial. We summarized 31 pieces of evidence across three categories: preoperative preparation, intraoperative interventions, and postoperative symptom management.ConclusionThis study presents a comprehensive summary of the best available evidence on the prevention and treatment of embolism syndrome following TACE for primary liver cancer. These findings can serve as a valuable reference for clinical practitioners, enabling nurses to deliver individualized care based on the symptoms and specific needs of liver cancer patients.Systematic review registrationhttp://ebn.nursing.fudan.edu.cn, identifier ES20232398.

Astrocytes are the most abundant cell subtypes in the central nervous system. Previous studies believed that astrocytes are supporting cells in the brain, which only provide nutrients for neurons. However, recent studies have found that astrocytes have more crucial and complex functions in the brain, such as neurogenesis, phagocytosis, and ischemic tolerance. After an ischemic stroke, the activated astrocytes can exert neuroprotective or neurotoxic effects through a variety of pathways. In this review, we will discuss the neuroprotective mechanisms of astrocytes in cerebral ischemia, and mainly focus on reactive astrocytosis or glial scar, neurogenesis, phagocytosis, and cerebral ischemic tolerance, for providing new strategies for the clinical treatment of stroke.

Abstract Background Previous studies have demonstrated that electrical stimulation of the cerebellar fastigial nucleus (FNS) can considerably decrease infarction volume and improve neurofunction restoration following cerebral ischemia. Nevertheless, the molecular mechanism of the neuroprotective effect of FNS is still vague. Methods In this study, we developed a rat model of ischemia/reperfusion that included 1 h FNS followed by reperfusion for 3, 6, 12, 24, and 72 h. The expression profile of molecular alterations in brain tissues was obtained by transcriptome sequencing at five different time points. The function and pathway of miRNA expression pattern and core genes were annotated by Allen Brain Atlas, STRING database and Cytoscape software, so as to explore the mechanism of FNS-mediated neuroprotection. Results The results indicated that FNS is associated with the neurotransmitter cycle pathway. FNS may regulate the release of monoamine neurotransmitters in synaptic vesicles by targeting the corresponding miRNAs through core Dlg4 gene, stimulate the Alternative polyadenylation (APA) incident’s anti -apoptosis effect on the brain, and stimulate the interaction activation of neurons in cerebellum, cortex/thalamus and other brain regions, regulate neurovascular coupling, and reduce cerebral damage. Conclusion FNS may activate neuronal and neurovascular coupling by regulating the release of neurotransmitters in synaptic vesicles through the methylation of core Dlg4 gene and the corresponding transcription factors and protein kinases, inducing the anti-apoptotic mechanism of APA events. The findings from our investigation offer a new perspective on the way brain tissue responds to FNS-driven neuroprotection.

Diabetes mellitus (DM) is an enormous public health issue worldwide. Recent data suggest that chronic arsenic exposure is linked to the risk of developing type 1 and type 2 DM, albeit the underlying mechanisms are unclear. This review discusses the role of the immune system as a link to possibly explain some of the mechanisms of developing T1DM or T2DM associated with arsenic exposure in humans, animal models, and in vitro studies. The rationale for the hypothesis includes: (1) Arsenic is a well-recognized modulator of the immune system; (2) arsenic exposures are associated with increased risk of DM; and (3) dysregulation of the immune system is one of the hallmarks in the pathogenesis of both T1DM and T2DM. A better understanding of DM in association with immune dysregulation and arsenic exposures may help to understand how environmental exposures modulate the immune system and how these effects may impact the manifestation of disease.

Abstract Low-carbon development has been the favorite subject with the aim of making a synergy environment. Extensive research on low-carbon development and socio-economic synergy has been conducted by scholars from different perspectives. This paper explores the synergy between low-carbon development and socio-economic development as a composite system from four levels: resource, energy, economy and society, and improves the theory of low-carbon economic development in a "dual-carbon" perspective. Meanwhile, based on the theoretical research, this paper constructs a synergy model and evaluation index system of low-carbon development and socio-economic development, and conducts an empirical analysis by combining the relevant data of low-carbon governance and socio-economic development in Anhui Province from 2011 to 2020. After obtaining the level of synergistic development and constraints of the composite system, the trend of changes in the level of synergy of the composite system is verified by R/S model. It is found that: (1) the composite system composed of low-carbon development and socio-economic development in Anhui Province has certain synergistic effects, and the level of synergistic development is increasing; (2) the studied time series has significant correlation over a long period of time, while it will continue the past development trend. The contribution of this paper is to take the synergy model as the basis and build the R/S model to extend the time cycle of synergy level, which extends the previous theoretical research system of low-carbon development, helps to deepen the theoretical understanding of the synergy between low-carbon development and socio-economic development, and improves the discussion on building ecological civilization and helping to achieve the goal of "dual-carbon".

Abstract Background Ubiquitous and diverse marine microorganisms utilise the abundant organosulfur molecule dimethylsulfoniopropionate (DMSP), the main precursor of the climate-active gas dimethylsulfide (DMS), as a source of carbon, sulfur and/or signalling molecules. However, it is currently difficult to discern which microbes actively catabolise DMSP in the environment, why they do so and the pathways used. Results Here, a novel DNA-stable isotope probing (SIP) approach, where only the propionate and not the DMS moiety of DMSP was 13C-labelled, was strategically applied to identify key microorganisms actively using DMSP and also likely DMS as a carbon source, and their catabolic enzymes, in North Sea water. Metagenomic analysis of natural seawater suggested that Rhodobacterales (Roseobacter group) and SAR11 bacteria were the major microorganisms degrading DMSP via demethylation and, to a lesser extent, DddP-driven DMSP lysis pathways. However, neither Rhodobacterales and SAR11 bacteria nor their DMSP catabolic genes were prominently labelled in DNA-SIP experiments, suggesting they use DMSP as a sulfur source and/or in signalling pathways, and not primarily for carbon requirements. Instead, DNA-SIP identified gammaproteobacterial Oceanospirillales, e.g. Amphritea, and their DMSP lyase DddD as the dominant microorganisms/enzymes using DMSP as a carbon source. Supporting this, most gammaproteobacterial (with DddD) but few alphaproteobacterial seawater isolates grew on DMSP as sole carbon source and produced DMS. Furthermore, our DNA-SIP strategy also identified Methylophaga and other Piscirickettsiaceae as key bacteria likely using the DMS, generated from DMSP lysis, as a carbon source. Conclusions This is the first study to use DNA-SIP with 13C-labelled DMSP and, in a novel way, it identifies the dominant microbes utilising DMSP and DMS as carbon sources. It highlights that whilst metagenomic analyses of marine environments can predict microorganisms/genes that degrade DMSP and DMS based on their abundance, it cannot disentangle those using these important organosulfur compounds for their carbon requirements. Note, the most abundant DMSP degraders, e.g. Rhodobacterales with DmdA, are not always the key microorganisms using DMSP for carbon and releasing DMS, which in this coastal system were Oceanospirillales containing DddD. Video abstract.

High-entropy alloys (HEAs) with a heterogeneous grain structure have been revealed to possess excellent combination of strength and toughness. However, the atomic-level deformation mechanisms of the heterogeneous HEAs were not reported yet. In this work, physical models were constructed based on the experimental observation and atomic simulations are performed to investigate the tensile behavior of face centered cubic (FCC) heterogeneous CoNiFeAlxCu1-x HEAs at different strain rates (5 × 107–1 × 1010 s−1), Al concentration (x = 0.1, 0.2, 0.3 and 0.4) and degrees of grain heterogeneity. Result analysis reveals the multiple deformation mechanisms including dislocation motion, diffusion from grain interior to grain boundary and stacking faults (SFs) as well as their interaction. The strain rates seriously influence the body centered cubic (BCC) transformation from FCC in the large grains. Besides, with the reduction of Al concentration, the value of stable stacking fault energy (SFE) raises, while the tensile yield stress increases. Finally, increasing the large grain size (DG) of the heterogeneous grain structure improved the plasticity due to the combination of enhanced FCC to BCC phase transformation and high uniform ductility of large grains. This work provides a micromechanical understanding for designing the excellent mechanical property of HEAs by optimizing material structure parameters of heterogeneous grain structure HEAs.

Background: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy usually presents as meningoencephalomyelitis. Many patients developed flu-like symptoms preceding the neurologic symptoms. Reversible lesion in the splenium of the corpus callosum (SCC) is a clinical and radiological syndrome secondary to many kinds of etiologies, including infections, which is termed RESLES. Case presentation: we reported a case developing irregularly high fever, both temporal pain, low limbs fatigue with frequent urination admitted to our neurology department. CSF test showed GFAP-IgG positive, elevated WBC counts and protein, with low glucose and chlorine, while MRI showed a reversible lesion on SCC, leading us to diagnose autoimmune GFAP autocytopathy accompanied with RESLES. The boy had significantly improved after anti-virus and steroids therapy. Discussion: Autoimmune GFAP autocytopathy accompanied with RESLES is rarely seen, and pathogenesis for the co-existence has not been clarified. Autoimmune GFAP autocytopathy and RESLES are both related to viral infection. Our case covered infectious symptoms and improved after antiviral treatment, suggesting virus infection may perform a key role in pathogenesis.

Abstract Ischemic stroke (IS) is one of the major causes of death and disability worldwide. However, the specific mechanism of gene interplay and the biological function in IS are not clear. Therefore, more research into IS is necessary. Dataset GSE110993 including 20 ischemic stroke (IS) and 20 control specimens are used to establish both groups and the raw RNA‐seq data were analysed. Weighted gene co‐expression network analysis (WGCNA) was used to screen the key micro‐RNA modules. The centrality of key genes were determined by module membership (mm) and gene significance (GS). The key pathways were identified by enrichment analysis with Kyoto Protocol Gene and Genome Encyclopedia (KEGG), and the key genes were validated by protein‐protein interactions network. Result: Upon investigation, 1185 up‐ and down‐regulated genes were gathered and distributed into three modules in response to their degree of correlation to clinical traits of IS, among which the turquoise module show a trait‐correlation of 0.77. The top 140 genes were further identified by GS and MM. KEGG analysis showed two pathways may evolve in the progress of IS. Discussion: CXCL12 and EIF2a may be important biomarkers for the accurate diagnosis and treatment in IS.

Few studies have systematically assessed the ecological status of mangrove wetlands following the stress of anthropogenic activities in China. This study investigated the spatial and seasonal distribution of benthic macroinvertebrate communities and assessed the ecological quality of mangrove habitats on an island scale in Hainan, China (containing the third largest mangrove area of China and the highest mangrove species richness). For the benthic macrofauna community structure, a total of 102 macrobenthic taxa belonging to 50 families were identified, with Crustaceans, Molluscs, Polychaetes, and Oligochaeta having relative abundances of 52.3%, 36.1%, 10.8%, and 0.8%, respectively. Decapoda and Gastropoda dominated the benthic community abundance. Non-metric multidimensional scaling and an analysis of similarities revealed significantly different macroinvertebrate assemblages among the regions during the two seasons. The South mangroves had the lowest macrofauna species numbers, biodiversity, richness, and abundance. The macrofaunal species richness, Shannon index, Margalef index, abundance, and biomass markedly affected by region and season. As indicated by the biotic indices AMBI (AZTI’s Marine Biotic Index) and M-AMBI, more than half of the mangrove habitats on Hainan Island were slightly to heavily disturbed and had poor to moderate ecological quality. Our results recommend long-term monitoring for evaluating the quality status of mangrove wetlands and avoiding extensive land-use conversion of mangroves. Holistic approaches considering ecological characteristics and combining information on both floral and faunal functionality would contribute to the effective management and conservation of mangroves in disturbed areas.

Extreme weather like typhoon leaves significantly terrible influence on the stability of power grid in the coastal area. A high-voltage transmission line includes hundreds of towers and usually stretches hundreds of kilometers. It is not economical to install typhoon monitoring system throughout the transmission line. This paper proposes a typhoon inversion method (TIM) for transmission line which utilizes engineering wind field model and only requires monitoring data from a few towers. The developed method is called YanMeng wind field (YM) with directional mutation genetic algorithm (DMGA) for transmission lines, or YM-DMGA method. DMGA utilizes real-time monitoring data, and improves simulation accuracy of average wind speed by dynamically optimizing two critical parameters $B$ and $z_{0}$ in wind field model, which is a great improvement over the traditional YM model relying on historical data. The TIM is mainly composed of three parts, the meteorological monitoring system (MMS), the YM-DMGA model, and the software system. The TIM collects real-time measured wind data of particular monitoring stations through the MMS. Meanwhile, wind data of the whole transmission line is simulated using the YM-DMGA and displayed by the software system. Then the method proposed is verified to be effective in three aspects. First of all, the YM-DMGA method has great enhancement in accuracy, for the coefficient of determination $R_{square}$ increases from 0.811 to 0.986. Secondly, DMGA in the method has quicker convergent speed than typical GA, with fitness converged in the 269th epoch, earlier than that for typical GA, 656th epoch. Lastly, DMGA has better optimal fitness value of 0.6239, bigger than that of typical GA, 0.5891. At the end of the paper, an application of the method to an 110kV double-circuit transmission line is presented to reveal the risk under the impact of the super typhoon Rammasun.

No definitive blood markers of DWI-FLAIR mismatch, a pivotal indicator of salvageable ischemic penumbra brain tissue, are known. We previously reported that CDC42 and RHOA are associated with the ischemic penumbra. Here, we investigated whether plasma CDC42 and RHOA are surrogate markers of DWI-FLAIR mismatch. Sixteen cynomolgus macaques (3 as controls and 13 for the stroke model) were included. Guided by digital subtraction angiography (DSA), a middle cerebral artery occlusion (MCAO) model was established by occluding the middle cerebral artery (MCA) with a balloon. MRI and neurological deficit scoring were performed to evaluate postinfarction changes. Plasma CDC42 and RHOA levels were measured by enzyme-linked immunosorbent assay (ELISA). The stroke model was successfully established in eight monkeys. Based on postinfarction MRI images, experimental animals were divided into a FLAIR (−) group (N = 4) and a FLAIR (+) group (N = 4). Plasma CDC42 in the FLAIR (−) group showed a significant decrease compared with that in the FLAIR (+) group (p < 0.05). No statistically significant difference was observed for plasma RHOA. The FLAIR (−) group showed a milder neurological function deficit and a smaller infarct volume than the FLAIR (+) group (p < 0.05). Therefore, plasma CDC42 might be a new surrogate marker for DWI-FLAIR mismatch.

Ischemic stroke is a major type of stroke worldwide currently without effective treatment, although antiplatelet therapy is an existing option for it. In previous studies, heat shock protein 47 (Hsp47) was found to be expressed on the surface of human and mice platelets and to strengthen the interaction between platelets and collagen. In recent years, Col003 was discovered to inhibit the interaction of Hsp47 with collagen. We evaluated whether the Hsp47 inhibitor Col003 is a promising therapeutic agent for ischemic stroke. Here, we first verified that Hsp47 is also expressed on the surface of rat platelets, and its inhibitor Col003 significantly inhibited thrombus formation in the FeCl3-induced rat carotid arterial thrombus model. Both Col003 and clopidogrel did not alter the bleeding time or coagulation parameters, while aspirin increased the tail-bleeding time (p < 0.05). The low cytotoxicity level of Col003 to rat platelets and human liver cells was similar to those of aspirin and clopidogrel. Col003 inhibited collagen-induced platelet aggregation, adhesion, [Ca2+]i mobilization, P-selectin expression, reactive oxygen species production and the downstream signal pathway of collagen receptors. The results of the middle cerebral artery occlusion model indicated that Col003 has a protective effect against cerebral ischemic–reperfusion injury in rats. The Hsp47 inhibitor Col003 exerted antiplatelet effect and protective effect against brain damage induced by ischemic stroke through the inhibition of glycoprotein VI (GPVI)and mitogen-activated protein kinase (MAPK) signaling events, which might yield a new antiplatelet agent and strategy to treat ischemic stroke.

Abstract Background The X-linked form of Charcot-Marie-Tooth disease type 1 (CMTX1) is an inherited peripheral neuropathy that arises in patients with mutations in the gap-junction beta-1 gene (GJB1). Case presentation Three young male patients from Southern China with pes cavus experienced multiple episodes of transient central nervous system (CNS) dysfunction. Three patients all had reversible posterior leukoencephalopathy as detected by brain diffusion-weighted magnetic resonance imaging (MRI-DWI). Nerve conduction velocity (NCV) showed sensorimotor polyneuropathy with mixed demyelinating and axonal features. Genetic testing indicated a c.425G > A (p.Arg142Glu) or c.563 C > T (p.Thr188Ile) or c.103G > C (p.Val35Leu) mutation in GJB1. The unique feature of this report is the identification of two novel mutations: c.563 C > T and sc.103G > C of the GJB1 gene detected in two families respectively. Another unique feature is that peripheral neuropathy symptoms in the three patients were insidious and found at the onset of CNS symptoms. Conclusions Posterior leukoencephalopathy is involved in CMTX1 patients. The white matter changes in MRI of CMTX1 patients are reversible and recover later than CNS symptoms.

Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs.

Hepatitis B e antigen (HBeAg) has been considered to cause immunotolerance to hepatitis B virus (HBV) in newborn infants after fetal HBeAg exposure. This study compared anti-HBs responses to hepatitis B vaccination in infants who were born to HBeAg-positive and -negative mothers respectively, to investigate whether fetal HBeAg exposure may induce immunotolerance to HBV. Totally 265 infants who received recommended neonatal immunoprophylaxis against hepatitis B and had no HBV infection were included. Anti-HBs levels were compared between 124 infants with cord blood positive HBeAg and 141 infants with cord blood negative HBeAg at 7–12 months of age. The infants in two groups had similar age at the follow-up (10.0 ± 2.3 vs 10.1 ± 2.3 months, P = 0.590). Overall, 259 (97.7%) of 265 infants achieved anti-HBs levels (mIU/ml) ≥10 and 6 (2.3%) others had anti-HBs 0.05). Additionally, the distribution of anti-HBs response levels were also comparable in infants with high and low HBeAg levels (P = 0.818). In conclusions, the fetal HBeAg exposure does not inhibit the antibody response to neonatal hepatitis B vaccination. The data suggest that HBeAg appears not inducing immunotolerance to HBV.

Abstract Background Signal transducer and activator of transcription 3 (STAT3) is an oncogene constitutively activated in hepatocellular carcinoma (HCC) cells and HCC cancer stem cells (CSCs). Constitutively activated STAT3 plays a pivotal role in holding cancer stemness of HCC CSCs, which are essential for hepatoma initiation, relapse, metastasis and drug resistance. Therefore, STAT3 has been validated as a novel anti-cancer drug target and the strategies targeting HCC CSCs may bring new hopes to HCC therapy. This study aimed to isolate and identify small-molecule STAT3 signaling inhibitors targeting CSCs from the ethyl acetate (EtOAc) extract of the roots of Polygonum cuspidatum and to evaluate their in vitro anti-cancer activities. Methods The chemical components of the EtOAc extract and the subfractions of P. cuspidatum were isolated by using various column chromatographies on silical gel, Sephadex LH-20, and preparative HPLC. Their chemical structures were then determined on the basis of spectroscopic data including NMR, MS and IR analysis and their physicochemical properties. The inhibitory effects of the isolated compounds against STAT3 signaling were screened by a STAT3-dependent luciferase reporter gene assay. The tyrosine phosphorylation of STAT3 was examined by Western Blot analysis. In vitro anti-cancer effects of the STAT3 pathway inhibitor were further evaluated on cell growth of human HCC cells by a MTT assay, on self-renewal capacity of HCC CSCs by the tumorsphere formation assay, and on cell cycle and apoptosis by flow cytometry analysis, respectively. Results The EtOAc extract of the roots of P. cuspidatum was investigated and a novel juglone analogue 2-ethoxystypandrone (1) along with seven known compounds (2–8) was isolated. Among the eight isolated compounds 1–8, 2-ethoxystypandrone was a novel and potent STAT3 signaling inhibitor (IC50 = 7.75 ± 0.18 μM), and inhibited the IL-6-induced and constitutive activation of phosphorylation of STAT3 in HCC cells. Moreover, 2-ethoxystypandrone inhibited cell survival of HCC cells (IC50 = 3.69 ± 0.51 μM ~ 20.36 ± 2.90 μM), blocked the tumorspheres formation (IC50 = 2.70 ± 0.28 μM), and induced apoptosis of HCC CSCs in a dose-dependent manner. Conclusion A novel juglone analogue 2-ethoxystypandrone was identified from the EtOAc extract of the roots of P. cuspidatum and was demonstrated to be a potent small-molecule STAT3 signaling inhibitor, which strongly blocked STAT3 activation, inhibited proliferation, and induced cell apoptosis of HCC cells and HCC CSCs. 2-Ethoxystypandrone as a STAT3 signaling inhibitor might be a promising lead compound for further development into an anti-CSCs drug.

Cadmium (Cd) is one of the most prevalent environmental heavy metal contaminants and is considered an endocrine disruptor and carcinogen. In women with uterine fibroids, there is a correlation between blood Cd levels and fibroid tumor size. In this study, fibroid cells were exposed to 10 µM CdCl2 for 6 months and a fast-growing Cd-Resistant Leiomyoma culture, termed CR-LM6, was recovered. To characterize the morphological and mechanodynamic features of uterine fibroid cells associated with prolonged Cd exposure, we conducted time lapse imaging using a Zeiss confocal microscope and analyzed data by Imaris and RStudio. Our experiments recorded more than 64,000 trackable nuclear surface objects, with each having multiple parameters such as nuclear size and shape, speed, location, orientation, track length, and track straightness. Quantitative analysis revealed that prolonged Cd exposure significantly altered cell migration behavior, such as increased track length and reduced track straightness. Cd exposure also significantly increased the heterogeneity in nuclear size. Additionally, Cd significantly increased the median and variance of instantaneous speed, indicating that Cd exposure results in higher speed and greater variation in motility. Profiling of mRNA by NanoString analysis and Ingenuity Pathway Analysis (IPA) strongly suggested that the direction of gene expression changes due to Cd exposure enhanced cell movement and invasion. The altered expression of extracellular matrix (ECM) genes such as collagens, matrix metallopeptidases (MMPs), secreted phosphoprotein 1 (SPP1), which are important for migration contact guidance, may be responsible for the greater heterogeneity. The significantly increased heterogeneity of nuclear size, speed, and altered migration patterns may be a prerequisite for fibroid cells to attain characteristics favorable for cancer progression, invasion, and metastasis.

Despite the presence of hepatitis B virus (HBV) in the human breastmilk of mothers infected with HBV, it has been shown that breastfeeding does not increase the risk of mother-to-child transmission (MTCT) of HBV. We tested the hypothesis that human breastmilk may contain active components that bind to HBV and inhibit the infectivity of HBV. The results show that human whey significantly inhibited the binding of the hepatitis B surface antigen (HBsAg) to its antibodies in competitive inhibition immunoassays. The far-western blotting showed that HBsAg bound to a protein of 80 kD in human whey, which was identified as lactoferrin by mass spectrometry. Competitive inhibition immunoassays further demonstrated that both human lactoferrin and bovine lactoferrin bound to HBsAg. Human whey, human lactoferrin, and bovine lactoferrin each significantly inhibited the infectivity of HBV in vitro. Our results indicate that human breastmilk can bind to HBsAg and inhibit the infectivity of HBV, and the active component is lactoferrin. The findings may explain the reason that breastfeeding has no additional risk for MTCT of HBV, although human breastmilk contains HBV. Our study provides experimental evidence that HBV-infected mothers should be encouraged to breastfeed their infants

Background: Long noncoding RNAs (lncRNAs) have been confirmed to be associated with ischemic stroke (IS); however, their involvement still needs to be extensively explored. Therefore, we aimed to study the expression profile of lncRNAs and the potential roles and mechanisms of lncRNAs in the pathogenesis of acute ischemic stroke (AIS) in the Southern Chinese Han population.Methods: In this study, lncRNA and mRNA expression profiles in AIS were analyzed using high-throughput RNA sequencing (RNA-Seq) and validated using quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and network analyses were performed to predict the functions and interactions of the aberrantly expressed genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of lncRNAs in AIS.Results: RNA-Seq analysis showed that 428 lncRNAs and 957 mRNAs were significantly upregulated, while 791 lncRNAs and 4,263 mRNAs were downregulated in patients with AIS when compared with healthy controls. GO enrichment and KEGG pathway analyses of differentially expressed genes showed that the apoptosis, inflammatory, oxidative and calcium signaling pathways were potentially implicated in AIS pathology. The PCR results showed that the selected lncRNA-C14orf64 and lncRNA-AC136007.2 were significantly downregulated in AIS. ROC curve analysis showed that the area under the ROC curve (AUC) values of lncRNA-C14orf64 and lncRNA-AC136007.2 between AIS and healthy controls were 0.74 and 0.94, respectively.Conclusion: This study provides evidence of altered expression of lncRNAs and their potential functions in AIS. Our findings may facilitate pathological mechanistic studies of lncRNAs in AIS and provide potential diagnostic biomarkers and therapeutic targets for AIS.

Abstract Background Pregnancy is a unique physiological condition with the cellular immune functions compromised at some extents to allow the mature of growing fetus. Whether pregnancy may influence the replication of hepatitis B virus (HBV) is less studied. The present study aimed to investigate the influence of pregnancy on the replication of HBV and expression of viral antigens by comparing the levels of HBV DNA and viral antigens in pregnant and non-pregnant women. Methods A total of 727 HBsAg-positive serum samples, collected from 214 pregnant women and 513 non-pregnant women of childbearing age, were included. Based on the pregnancy status, subjects were divided into four groups: nulliparous (n = 158), pregnant (n = 214), 7–12 months postpartum (n = 170), and 2–5 years postpartum (n = 185). The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were quantitatively measured with microparticle enzyme immunoassay. HBV DNA levels were detected by fluorescent real-time PCR. Results The median ages of four groups were 25.0, 25.3, 26.2 and 29.3 years, respectively (p

Abstract Background Goose parvovirus (GPV) causes acute enteritis, hepatitis, myocarditis and high morbidity and mortality in geese and ducks. GPV H strain was isolated from a Heilongjiang goose farm where the geese were showing signs of hemorrhage in the brain, liver, and intestinal tract. In this study, we explored the genetic diversity among waterfowl parvovirus isolates and the pathological characteristics of GPV H in Shaoxing ducklings. Methods The complete capsid protein (VP) and non-structural (NS) sequences of the isolated H strain were sequenced, and phylogenetic trees of VP and NS were constructed in MEGA version 5.05 using the neighbor-joining method. Three-day-old Shaoxing ducklings were inoculated with GPV and were euthanized at 1, 2, 4, 6, and 8 days post-inoculation (PI), and their organs were removed and collected. The organs of 6-day PI ducklings were fixed in formalin, embedded in paraffin, sectioned for histology, stained with HE and analyzed for pathological lesions. The distribution of the GPV H strain in the tissues of the inoculated ducklings was detected using the polymerase chain reaction (PCR) method. Results Genetic analysis of the NS and VP genes indicated that the H strain was closely related to strains circulating in China during 1999–2014, and the nucleic acid identity of those strains was 98%–99%. Classical symptoms were observed in the inoculated ducklings. GPV remained in many tissues and replicated in a majority of the tissues, leading to histopathological lesions in four tissues. Conclusions We first reported the distribution and histopathological lesions of a Chinese strain of GPV in infected shaoxing ducklings. This H strain was moderate pathogenic for Shaoxing ducklings.

Recently, we showed that infants with or without fetal hepatitis B e antigen (HBeAg) exposure had comparable antibody response to hepatitis B vaccination and proposed that fetal HBeAg exposure appears to not induce immunotolerance to HBV. Here, we summarized the different results on the topic of fetal HBeAg exposure in inducing immunotolerance to HBV nucleocapsid protein, and the evidence to back up that the tendency of high infection rate in infants of HBeAg-positive mothers is more likely associated with higher maternal viral loads and is less likely associated with the fetal HBeAg exposure. We consider that whether fetal HBeAg exposure plays an important role in the pathogenesis of chronic HBV infection remains to be an open question.

Advanced research in recent years has revealed the important role of nutrients in the protection of women’s health and in the prevention of women’s diseases. Genistein is a phytoestrogen that belongs to a class of compounds known as isoflavones, which structurally resemble endogenous estrogen. Genistein is most often consumed by humans via soybeans or soya products and is, as an auxiliary medicinal, used to treat women’s diseases. In this review, we focused on analyzing the geographic distribution of soybean and soya product consumption, global serum concentrations of genistein, and its metabolism and bioactivity. We also explored genistein’s dual effects in women’s health through gathering, evaluating, and summarizing evidence from current in vivo and in vitro studies, clinical observations, and epidemiological surveys. The dose-dependent effects of genistein, especially when considering its metabolites and factors that vary by individuals, indicate that consumption of genistein may contribute to beneficial effects in women’s health and disease prevention and treatment. However, consumption and exposure levels are nuanced because adverse effects have been observed at lower concentrations in in vitro models. Therefore, this points to the duplicity of genistein as a possible therapeutic agent in some instances and as an endocrine disruptor in others.

Listeria is ubiquitous in a variety of environments and can be isolated from a wide range of animal hosts. Rodents are capable of carrying pathogenic bacteria in their intestines, such as Listeria, and can disseminate those pathogens into the natural environment and to where human activity occurs. In this study, we investigated the occurrence and antimicrobial susceptibility of Listeria spp. isolated from wild rodents found in natural environments in China. We collected 341 intestinal fecal samples of rodents from five different regions of China, all representing different rodent habitats. The antimicrobial susceptibility of the Listeria spp. isolates obtained were firstly assessed using the Kirby–Bauer disk diffusion method. Thirty-one samples were positive for Listeria spp., of which 11 were positive for Listeria monocytogenes and seven were positive for Listeria ivanovii. Other species identified include Listeria innocua, Listeria fleischmannii and Listeria floridensis. All Listeria spp. isolates were sensitive to the majority of the antimicrobials tested, but largely resistant to oxacillin (94.1%) and cefuroxime (70.6%). All L. monocytogenes isolates were further characterized by serotyping, multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). L. monocytogenes strains were grouped into three serotypes, five sequence types and five pulsotypes (PTs) by serotyping, MLST and PFGE, respectively. Almost half of the isolates (five of 11) belonged to serotype 1/2b, ST87 and PT1. This study determined that Listeria is carried in the intestinal tracts of wild rodents from multiple regions at a low rate, filling an epidemiological data gap on Listeria in natural environments in China.Emerging Microbes & Infections (2017) 6, e44; doi:http://10.1038/emi.2017.28; published online 7 June 2017

The association between airborne fine particulate matter (PM2.5) concentration and the risk of respiratory diseases has been well documented by epidemiological studies. However, the mechanism underlying the harmful effect of PM2.5 has not been fully understood. In this study, we exposed the C57BL/6J mice to airborne PM2.5 for 3 months (mean daily concentration ~50 or ~110 μg/m3, defined as PM2.5–3L or PM2.5–3H) or 6 months (mean daily concentration ~50 μg/m3, defined as PM2.5–6L) through a whole-body exposure system. Histological and biochemical analysis revealed that PM2.5–3H exposure caused more severe lung injury than did PM2.5–3L, and the difference was greater than that of PM2.5–6L vs PM2.5–3L exposure. With RNA-sequencing technique, we found that the lungs exposed with different concentration of PM2.5 have distinct transcriptional profiles. PM2.5–3H exposure caused more differentially expressed genes (DEGs) in lungs than did PM2.5–3L or PM2.5–6L. The DEGs induced by PM2.5–3L or PM2.5–6L exposure were mainly enriched in immune pathways, including Hematopoietic cell lineage and Cytokine-cytokine receptor interaction, while the DEGs induced by PM2.5–3H exposure were mainly enriched in cardiovascular disease pathways, including Hypertrophic cardiomyopathy and Dilated cardiomyopathy. In addition, we found that upregulation of Cd5l and reduction of Hspa1 and peroxiredoxin-4 was associated with PM2.5-induced pulmonary inflammation and oxidative stress. These results may provide new insight into the cytotoxicity mechanism of PM2.5 and help to development of new strategies to attenuate air pollution associated respiratory disease. Keywords: PM2.5, Lung injury, RNA-Sequencing, Inflammation, Oxidative stress

The compatible solute dimethylsulfoniopropionate (DMSP), made by many marine organisms, is one of Earth's most abundant organosulfur molecules. Many marine bacteria import DMSP and can degrade it as a source of carbon and/or sulfur via DMSP cleavage or DMSP demethylation pathways, which can generate the climate active gases dimethyl sulfide (DMS) or methanthiol (MeSH), respectively. Here we used culture-dependent and -independent methods to study bacteria catabolizing DMSP in the East China Sea (ECS). Of bacterial isolates, 42.11% showed DMSP-dependent DMS (Ddd+) activity, and 12.28% produced detectable levels of MeSH. Interestingly, although most Ddd+ isolates were Alphaproteobacteria (mainly Roseobacters), many gram-positive Actinobacteria were also shown to cleave DMSP producing DMS. The mechanism by which these Actinobacteria cleave DMSP is unknown, since no known functional ddd genes have been identified in genome sequences of Ddd+Microbacterium and Agrococcus isolates or in any other sequenced Actinobacteria genomes. Gene probes to the DMSP demethylation gene dmdA and the DMSP lyase gene dddP demonstrated that these DMSP-degrading genes are abundant and widely distributed in ECS seawaters. dmdA was present in relatively high proportions in both surface (19.53% ± 6.70%) and bottom seawater bacteria (16.00% ± 8.73%). In contrast, dddP abundance positively correlated with chlorophyll a, and gradually decreased with the distance from land, which implies that the bacterial DMSP lyase gene dddP might be from bacterial groups that closely associate with phytoplankton. Bacterial community analysis showed positive correlations between Rhodobacteraceae abundance and concentrations of DMS and DMSP, further confirming the link between this abundant bacterial class and the environmental DMSP cycling.

Dimethylsulfoniopropionate (DMSP) is one of Earth’s most abundant organosulfur molecules. Recently, many marine heterotrophic bacteria were shown to produce DMSP, but few studies have combined culture-dependent and independent techniques to study their abundance, distribution, diversity and activity in seawater or sediment environments. Here we investigate bacterial DMSP production potential in East China Sea (ECS) samples. Total DMSP (DMSPt) concentration in ECS seawater was highest in surface waters (SW) where phytoplankton were most abundant, and it decreased with depth to near bottom waters. However, the percentage of DMSPt mainly apportioned to bacteria increased from the surface to the near bottom water. The highest DMSP concentration was detected in ECS oxic surface sediment (OSS) where phytoplankton were not abundant. Bacteria with the genetic potential to produce DMSP and relevant biosynthesis gene transcripts were prominent in all ECS seawater and sediment samples. Their abundance also increased with depth and was highest in the OSS samples. Microbial enrichments for DMSP-producing bacteria from sediment and seawater identified many novel taxonomic groups of DMSP-producing bacteria. Different profiles of DMSP-producing bacteria existed between seawater and sediment samples and there are still novel DMSP-producing bacterial groups to be discovered in these environments. This study shows that heterotrophic bacteria significantly contribute to the marine DMSP pool and that their contribution increases with water depth and is highest in seabed surface sediment where DMSP catabolic potential is lowest. Furthermore, distinct bacterial groups likely produce DMSP in seawater and sediment samples, and many novel producing taxa exist, especially in the sediment.

Abstract Background After the earthquake on 14, April 2010 at Yushu in China, a plague epidemic hosted by Himalayan marmot (Marmota himalayana) became a major public health concern during the reconstruction period. A rapid assessment of the distribution of Himalayan marmot in the area was urgent. The aims of this study were to analyze the relationship between environmental factors and the distribution of burrow systems of the marmot and to predict the distribution of marmots. Methods Two types of marmot burrows (hibernation and temporary) in Yushu County were investigated from June to September in 2011. The location of every burrow was recorded with a global positioning system receiver. An ecological niche model was used to determine the relationship between the burrow occurrence data and environmental variables, such as land surface temperature (LST) in winter and summer, normalized difference vegetation index (NDVI) in winter and summer, elevation, and soil type. The predictive accuracies of the models were assessed by the area under the curve of the receiving operator curve. Results The models for hibernation and temporary burrows both performed well. The contribution orders of the variables were LST in winter and soil type, NDVI in winter and elevation for the hibernation burrow model, and LST in summer, NDVI in summer, soil type and elevation in the temporary burrow model. There were non-linear relationships between the probability of burrow presence and LST, NDVI and elevation. LST of 14 and 23 °C, NDVI of 0.22 and 0.60, and 4100 m were inflection points. A substantially higher probability of burrow presence was observed in swamp soil and dark felty soil than in other soil types. The potential area for hibernation burrows was 5696 km2 (37.7 % of Yushu County), and the area for temporary burrows was 7711 km2 (51.0 % of Yushu County). Conclusions The results suggested that marmots preferred warm areas with relatively low altitudes and good vegetation conditions in Yushu County. Based on these results, the present research is useful in understanding the niche selection and distribution pattern of marmots in this region.

Small molecule organic solar cells (SMOSCs) have attracted extensive attention in recent years. Squaraine (SQ) is a kind of small molecule material for potential use in high-efficiency devices, because of its high extinction coefficient and low-cost synthesis. However, the charge carrier mobility of SQ-based film is much lower than other effective materials, which leads to the pretty low fill factor (FF). In this study, we improve the performance of SQ derivative-based solar cells by incorporating PCDTBT into LQ-51/PC71BM host binary blend film. The incorporation of PCDTBT can not only increase the photon harvesting, but also provide an additional hole transport pathway. Through the charge carrier mobility and transient photovoltage measurement, we find that the hole mobility and charge carrier lifetime increase in the ternary system. Also, we carefully demonstrate that the charge carrier transport follows a parallel-like behavior.

Methamphetamine (Meth) abusing represents a major public health problem worldwide. Meth has long been known to induce neurotoxicity. However, the mechanism is still remained poorly understood. Growing evidences indicated that the voltage-gated potassium channels (Kv) were participated in neuronal damage and microglia function. With the whole cell patch clamp, we found that Meth significantly increased the outward K⁺ currents, therefore, we explored whether Kv1.3, one of the major K⁺ channels expressed in microglia, was involved in Meth-induced microglia damage. Our study showed that Meth significantly increased the cell viability in a dose dependent manner, while the Kv blocker, tetraethylamine (TEA), 4-Aminopyridine (4-AP) and Kv1.3 specific antagonist margatoxin (MgTx), prevented against the damage mediated by Meth. Interestingly, treatment of cells with Meth resulted in increasing expression of Kv1.3 rather than Kv1.5, at both mRNA and protein level, which is partially blocked by MgTx. Furthermore, Meth also stimulated a significant increased expression of IL-6 and TNF-α at protein level, which was significantly inhibited by MgTx. Taken together, these results demonstrated that Kv1.3 was involved in Meth-mediated microglial damage, providing the potential target for the development of therapeutic strategies for Meth abuse.

Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day) at different time of perinatal stage: 1) on days 1-6 of pregnancy (P1-P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6-PND0, fetal exposure); 3) from lactation until weaning (PND0-PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6-PND21, fetal and neonatal exposure). At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.

BACKGROUND: Studying the dispersal range of Anopheles sinensis is of major importance for understanding the transition from malaria control to elimination. However, no data are available regarding the dispersal range of An. sinensis in China. The aim of the present study was to study the dispersal range of An. sinensis and provide the scientific basis for the development of effective control measures for malaria elimination in China. METHODOLOGY/PRINCIPAL FINDINGS: Mark-Release-Recapture (MRR) experiments were conducted with 3000 adult wild An. sinensis in 2010 and 3000 newly emerged wild An. sinensis in 2011 in two villages of Yongcheng City in Henan Province. Marked An. sinensis were recaptured daily for ten successive days using light traps. The overall recapture rates were 0.83% (95% CI, 0.50%~1.16%) in 2010 and 1.33% (95% CI, 0.92%~1.74%) in 2011. There was no significant difference in the recapture rates of wild An. sinensis and newly emerged An. sinensis. The majority of An. sinensis were captured due east at study site I compared with most in the west at study site II. Eighty percent and 90% of the marked An. sinensis were recaptured within a radius of 100 m from the release point in study site I and II, respectively, with a maximum dispersal range of 400 m within the period of this study. CONCLUSIONS/SIGNIFICANCE: Our results indicate that local An. sinensis may have limited dispersal ranges. Therefore, control efforts should target breeding and resting sites in proximity of the villages.