High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.

Human leukocyte antigen (HLA) molecules are essential for presenting Epstein-Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA-bound EBV peptides and NPC risk through in silico HLA-peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA-target sequencing was performed. HLA-peptide binding prediction for EBV, followed by peptidome-wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high-risk mutations were analyzed. We found that NPC-associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA-A alleles (p = 3.10 × 10-4 for immunogenic proteins and p = 8.10 × 10-5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC-risk effect (padj = 3.77 × 10-4 ) and supertype A03 presented an NPC-protective effect (padj = 4.89 × 10-4 ). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC-risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC-risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

Association of Critical Value With 28-Day Mortality After Cardiac Surgery.

OBJECTIVE: The emergence of critical values gives a warning to the medical safety of hospitalized patients, especially Cardiosurgery Intensive Care Unit (CSICU) patients. The aim of this study was to investigate the association between early postoperative critical values and the prognosis of patients after cardiac surgery. METHODS: Clinical data of the patients were obtained from the Cardiac Critical Care Clinical Database of the Cardiovascular Intensive Care Unit of Nanjing First Hospital. A total of 1,598 consecutive patients undergoing cardiac surgery were enrolled in this retrospective cohort study, during the period from July 2019 to December 2020. According to whether critical value occurred within 7 days after cardiac surgery, patients were divided into two groups: the critical value group and control group. COX regression and survival analysis were performed to analyze the clinical data of the two groups. The area under the receiver operating characteristic curve (ROC) was used to assess the critical value's predictive value and determine the optimal cutoff value. RESULTS: With patients in the critical value group, the 28-day mortality after cardiac surgery was 21.98%, significantly higher than that of the control group (P < 0.05). Logistic regression analysis revealed the APACHE II score (Adjusted HR-1.11, 95% CI-1.043-1.185) and critical value group (Adjusted HR-13.57, 95% CI-6.714-27.435 ) were independent predictors of 28-day mortality after cardiac surgery. The ROC curve showed that the critical value case model (AUC = 0.748 ± 0.052, P < 0.05) could effectively predict the 28-day mortality, and the optimum cutoff was 1 case (sensitivity 52.63%, specificity 95.70%). CONCLUSIONS: One or more reported cases of critical values in the early postoperative period could be an independent risk factor for 28-day mortality in patients undergoing cardiac surgery. The predictive model based on critical value might be effective in clinical therapy and risk stratification.

Association between Left Ventricular Longitudinal Strain (GLS) and Prognosis of the Patients Undergoing Heart Valve Surgery with Preserved Left Ventricular Ejection Fraction.

PURPOSE: Global longitudinal strain (GLS) seems accurate for detecting subclinical myocardial dysfunction. This study aimed to determine the association between GLS and postoperative intensity of inotropic support in the patients undergoing heart valve surgery with preserved left ventricular ejection fraction. METHODS: 74 patients with preserved left ventricular ejection fraction who underwent valve surgery during the period between March 2021 and June 2022 were included in this prospective observational study. Transthoracic echocardiography including strain analysis with speckle tracking was performed before surgery. Patients were stratified according to the left ventricle (LV) GLS: LV-GLS ≥-16% (Impaired GLS group) and LV-GLS <-16% (Normal GLS group). The primary endpoint was postoperative vasoactive inotropic score. A high vasoactive inotropic score (VIS) was defined as a maximum VIS of ≥15 within 24 hours postoperatively. Postoperative adverse events, baseline clinical and echocardiographic data were also recorded. We invested the ability of preoperative GLS in predicting adverse postoperative outcomes, such as prolonged mechanical ventilation and the need for pharmacologic hemodynamic support after cardiac surgery. RESULTS: Seventy-four patients were included and analyzed in this study, including thirty-three in impaired GLS group and forty-one in normal GLS group. In-hospital mortality was 1.27% (1/74). Patients in impaired GLS group were more likely to have prolonged mechanical ventilation (p = 0.041). Multivariable logistic regression analysis revealed that the apical four-chamber view of the left ventricle (A4C)-GLS was significantly associated with high VIS (OR 1.373, p = 0.007). A4C-GLS had a sensitivity of 62.5% and a specificity of 89.66% for predicting high VIS (area under the curve, 0.78). The relationships between GLS and other secondary outcome measures were not statistically significant. The optimal cutoff of A4C-GLS for postoperative high vasoactive inotropic score was -10.85%. CONCLUSION: Preoperative LV dysfunction is an independent risk factor for postoperative high VIS. A4C-GLS may be a reliable tool in predicting high VIS after cardiac surgery. Those patients with impaired contractility were at high risk for elevated inotropic support and prolonged mechanical ventilation after cardiac surgery. These findings suggest an important role for echocardiographic GLS in perioperative assessment of cardiac function in the patients undergoing cardiac surgery.

STING-mediated inflammation contributes to Gao binge ethanol feeding model.

Alcohol metabolism causes hepatocytes to release damage-associated molecular patterns (DAMPs). This includes mitochondrial DNA (mtDNA), which is generated and released from damaged hepatocytes and contributes to liver injury by producing proinflammatory cytokines. STING is a pattern recognition receptor of DAMPs known to control the induction of innate immunity in various pathological processes. However, the expression profile and functions of STING in the Gao binge ethanol model remain poorly understood. We demonstrated that STING is upregulated in the Gao binge ethanol model. STING functions as an mtDNA sensor in the Kupffer cells of the liver and induces STING-signaling pathway-dependent inflammation and further aggravates hepatocyte apoptosis in the Gao binge ethanol model. This study provides novel insights into predicting disease progression and developing targeted therapies for alcoholic liver injury.

Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI2) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H2 (PGH2) to PGI2. PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.

The chemical diversity, the attractant, anti-acetylcholinesterase, and antifungal activities of metabolites from biocontrol Trichoderma harzianum uncovered by OSMAC strategy.

Eight new compounds (1-8) were discovered from Trichoderma harzianum associated with edible mushroom by the one strain many compounds (OSMAC) strategy. Triharzianin A (1) is the first naturally scaffold characterized by a C13-prostaglandin skeleton. The configurations of 1-3, and 5 were determined by the Mosher's method, experimental and calculated ECD spectra, and plausible biosynthesis of stereospecific epoxidation. Most compounds indicated obvious feeding attractant activities to silkworm with attraction rates at 30-90%. Compound 7 showed anti-acetylcholinesterase (anti-AChE) activity with a ratio of 29% at a concentration of 50 µM for insecticidal potential. So 2,​3-​dialkylchromone (7) had potential of chemical entrapment and killing of insects. Compounds 2, 3 and 7-11 showed antifungal activities against Aspergillus fumigates, and Trichoderma sp. from mushroom with MICs ≤ 300 µM. The four fermentation extracts also indicated obvious feeding attractant activities to silkworm for the activities brought by active metabolites from T. harzianum. The material base of biocontrol induced by the interaction of host-fungal symbiont can be investigated by the antifungal metabolites against pathogen fungi.

The Cocultured Nigrospora oryzae and Collectotrichum gloeosporioides, Irpex lacteus, and the Plant Host Dendrobium officinale Bidirectionally Regulate the Production of Phytotoxins by Anti-phytopathogenic Metabolites.

The distinctive nature of the endophyte Irpex lacteus, host plant, and the phytopathogen Collectotrichum gloeosporioides resulted in both negative and positive regulation of the production of phytotoxins from Nigrospora oryzae. The coculture of nonhomologous I. lacteus and N. oryzae resulted in a greater number of anti-phytopathogenic metabolites from the dominant endophyte than the coculture of homologous I. lacteus and N. oryzae. The coculture of the phytopathogen N. oryzae and either the nonhomologous (isolation of I. lacteus and N. oryzae from the different plants) or homologous (isolation of I. lacteus and N. oryzae from the same plant) endophyte I. lacteus from different sources indicated that the nonhomologous I. lacteus grew faster than the homologous I. lacteus, and the production of phytotoxic azaphilone from the phytopathogenic N. oryzae decreased due to the inhibition resulting from being cocultured with nonhomologous I. lacteus. On the other hand, the production of phytotoxic azaphilone was promoted by the coculture of two phytopathogens, N. oryzae and C. gloeosporioides. The extract of the host plant, Dendrobium officinale, also increased anti-phytopathogenic metabolite production. Six new phytotoxic azaphilones from N. oryzae, four new tremulane sesquiterpenes from I. lacteus, and a new polyketone were isolated. The endophyte-phytopathogen, phytopathogen-phytopathogen, and endophyte-phytopathogen-host interactions can induce the chemical diversity of novel anti-phytopathogenic metabolites.

Inducing Intermediates in Biotransformation of Natural Polyacetylene and A Novel Spiro-γ-Lactone from Red Ginseng by Solid Co-Culture of Two Gut Chaetomium globosum and The Potential Bioactivity Modification by Oxidative Metabolism.

The ω-hydroxyl-panaxytriol (1) and ω-hydroxyl-dihydropanaxytriol (2)-are rare examples of polyacetylene metabolism by microbial transformation, and these new metabolites (1, 2) from fermented red ginseng (FRG) by solid co-culture induction of two Chaetomium globosum should be the intermediates of biotransformation of panaxylactone (metabolite A). The metabolic pathway of panaxylactone was also exhibited. The ingredients of red ginseng (RG) also induced the production of rare 6/5/5 tricyclic ring spiro-γ-lactone skeleton (3). The ω-hydroxylation of new intermediates (1, 2) decreases cytotoxicity and antifungal activity against C. globosum compared with that of its bioprecursor panaxytriol. Additionally, compounds 1 and 2 indicated obvious inhibition against nitric oxide (NO) production, with ratios of 44.80 ± 1.37 and 23.10 ± 1.00% at 50 µM. 1 has an equivalent inhibition of NO production compared with the positive drug. So, the microbial biotransformation that occurred in FRG fermented by gut C. globosum can change the original bioactivity of polyacetylene, which gave a basis about the metabolic modification of red ginseng by intestinal fungus fermentation.

Longterm Analysis of Biliary Complications After Duct-to-Duct Biliary Reconstruction in Living Donor Liver Transplantations.

Biliary complication (BC) is still regarded as the Achilles' heel of a living donor liver transplantation (LDLT). This study aims to evaluate the longterm outcomes of the duct-to-duct (DD) biliary reconstruction using 7-0 suture and to identify the risk factors of BCs after LDLTs. Data of 140 LDLTs between 2006 and 2015 were analyzed. All biliary reconstructions were performed as DD anastomoses using 7-0 suture: 102 for the right lobe, 20 for the left lobe, and 18 for right posterior sector grafts. BC was defined as a bile leakage (BL) or a biliary stricture (BS), and the median follow-up time after LDLT was 65 months. A total of 19 recipients (13.5%) developed BCs (8 BLs and 16 BSs) after LDLT. The survival rates between recipients with and without BCs were 83% and 86.7%, respectively (P = 0.88). In univariate analyses, the risk factors for BC were small diameter of the graft's bile duct, long warm ischemic time, small graft-to-recipient weight ratio, and no use of external biliary stent (EBS). The graft's bile duct diameter ≤ 3 mm and no use of EBS were determined as independent risk factors (hazard ratios of 9.74 and 7.68, respectively) in multivariate analyses. The 116 recipients with EBS had no BL, 11 had BSs (9%), while 24 without EBS had 8 BLs (33%) and 5 BSs (21%). After a propensity score match between the recipients with and without EBS, the EBS group (24) developed only 1 BS (4%). In conclusion, DD anastomosis using 7-0 suture combined with EBS could provide favorable longterm outcomes after LDLT, which should thus be considered the surgical technique of choice for LDLTs.

Pterostilbene (3',5'-dimethoxy-resveratrol) exerts potent antitumor effects in HeLa human cervical cancer cells via disruption of mitochondrial membrane potential, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway.

PURPOSE: To examine the molecular mechanism of action behind the anticancer effects of pterostilbene in HeLa human cervical cancer cells. METHODS: MTS assay was used to study the pterostilbene cytotoxic effects, while inverted phase contrast and fluorescence microscopy was used to study the effects of the drug on the cell apoptosis and changes in cell morphology. Flow cytometry was used to study changes in mitochondrial membrane potential (MMP), while immunoblotting assay was used to demonstrate its effects on m-TOR/PI3K/Akt protein signalling pathway. RESULTS: Pterostilbene induced potent, dose-dependent and time-dependent cytotoxic effects in HeLa cancer cells exhibiting IC50 of 101.2 µM and 65.9 µM at 24 and 48 hrs time intervals, respectively. As compared to the untreated control cells which revealed normal cell morphology, pterostilbene-treated cells exhibited significant cellular shrinkage which increased with increasing doses of the drug. Untreated control cells showed complete green fluorescence corresponding to absence of apoptosis. However, pterostilbene-treated cells with 25, 100 and 200 µM showed increasing emission of red/orange fluorescence corresponding to apoptotic induction. Pterostilbene-treated cells showed evident signs of DNA ladder formation and the effect increased with increasing concentrations of the drug. The percentage of cells with depolarized mitochondria (loss of MMP) increased from 2.3% in the control group to 24.5, 43.2 and 65.8% in cells treated with 0, 25, 100 and 200 µM concentration of pterostilbene, respectively. CONCLUSION: Pterostilbene exerts potent anticancer effects in HeLa human cervical cancer cells via disruption of MMP, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway.

Dual stimuli-responsive Fe3O4 graft poly(acrylic acid)-block-poly(2-methacryloyloxyethyl ferrocenecarboxylate) copolymer micromicelles: surface RAFT synthesis, self-assembly and drug release applications.

BACKGROUND: Stimuli-responsive polymer materials are a new kind of intelligent materials based on the concept of bionics, which exhibits more significant changes in physicochemical properties upon triggered by tiny environment stimuli, hence providing a good carrier platform for antitumor drug delivery. RESULTS: Dual stimuli-responsive Fe3O4 graft poly(acrylic acid)-block-poly(2-methacryloyloxyethyl ferrocenecarboxylate) block copolymers (Fe3O4-g-PAA-b-PMAEFC) were engineered and synthesized through a two-step sequential reversible addition-fragmentation chain transfer polymerization route. The characterization was performed by FTIR, 1H NMR, SEC, XRD and TGA techniques. The self-assembly behavior in aqueous solution upon triggered by pH, magnetic and redox stimuli was investigated via zeta potentials, vibration sample magnetometer, cyclic voltammetry, fluorescent spectrometry, dynamic light scattering, XPS, TEM and SEM measurements. The experimental results indicated that the Fe3O4-g-PAA-b-PMAEFC copolymer materials could spontaneously assemble into hybrid magnetic copolymer micromicelles with core-shell structure, and exhibited superparamagnetism, redox and pH stimuli-responsive features. The hybrid copolymer micromicelles were stable and nontoxic, and could entrap hydrophobic anticancer drug, which was in turn swiftly and effectively delivered from the drug-loaded micromicelles at special microenvironments such as acidic pH and high reactive oxygen species. CONCLUSION: This class of stimuli-responsive copolymer materials is expected to find wide applications in medical science and biology, etc., especially in drug delivery system.

Enhancement in Tonically Active Glutamatergic Inputs to the Rostral Ventrolateral Medulla Contributes to Neuropathic Pain-Induced High Blood Pressure.

Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI). A significant increase in BP and renal sympathetic nerve activity (RSNA) was found in rats with ION-CCI (BP, n = 5, RSNA, n = 7, p < 0.05). The concentration of glutamate in the RVLM was significantly increased in the ION-CCI group (n = 4, p < 0.05). Blockade of glutamate receptors by injection of kynurenic acid into the RVLM significantly decreased BP and RSNA in the ION-CCI group (n = 5, p < 0.05). In two major sources (the paraventricular nucleus and periaqueductal gray) for glutamatergic inputs to the RVLM, the ION-CCI group (n = 5, p < 0.05) showed an increase in glutamate content and expression of glutaminase 2, vesicular glutamate transporter 2 proteins, and c-fos. Our results suggest that enhancement in tonically active glutamatergic inputs to the RVLM contributes to neuropathic pain-induced high blood pressure.

CDH13 Genetic Polymorphisms, Adiponectin and Ischemic Stroke: a Chinese Family-based Sib-pair Study.

OBJECTIVE: To understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors. METHODS: We recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model. RESULTS: In individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = -0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = -0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = -0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001). CONCLUSION: CDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.

Inhibition of complement C3 might rescue vascular hyporeactivity in a conscious hemorrhagic shock rat model.

BACKGROUND: Vascular hyporeactivity in severe hemorrhagic shock could induce refractory hypotension and is an important cause of death. The global acute inflammatory response induced in shock triggers the over-expression of reactive oxygen species, NO, ET1 and TNF-α, which play essential roles in the pathology of vascular hyporeactivity. This leads to a hypothesis that inhibition of the complement system, the mediator of the inflammatory cascade, might be a promising therapeutic exploration for vascular hyporeactivity. METHODS: We use cobra venom factor (CVF) and the soluble form of CR1 (sCR1) which deplete or inhibit complement C3 respectively to examine its role in vascular hyporeactivity in a conscious hemorrhagic shock rat model. RESULTS: We first confirmed the over-activation of C3 during shock and the down-regulation effects of CVF and sCR1 on C3. Then, both CVF and sCR1 could significantly mitigate the over-expression of serum NO, ET-1, TNF-α and reactive oxygen species. Finally, the vascular reactivity of superior mesenteric arteries (SMA) was examined in vitro, which confirmed the massive reduction of vascular reactivity in shock, which was significantly rescued by both CVF and sCR1. CONCLUSIONS: Inhibition of C3 might improve the reactivity of SMA to norepinephrine during hemorrhagic shock possibly through the downregulation of NO, ET1, TNF-α and reactive oxygen radicals.

[Transurethral seminal vesiculoscopy for the treatment of vesiculitis with hemospermia:A report of 64 cases].

Objective: To explore the treatment of vesiculitis with hemospermia by transurethral seminal vesiculoscopy. Methods: We treated 64 cases of vesiculitis with hemospermia by transurethral seminal vesiculoscopy. During the operation,we removed the stones and inflammatory substances and collected seminal vesicle fluid to be cultured for bacteria,ureaplasma urealyticum(UU),chlamydia trachomatis(CT),and mycoplasma hominis(MH),followed by infusion of levofloxacin at 0. 3 g/100 ml into the seminal vesicle. Regular follow-up was conducted post-operatively. Results: All the operations were successfully accomplished, the operation time averaging(40 ± 15) min(25- 50 min). The ejaculatory duct opening was observed on the verumontanum surface in the posterior urethra in 2 cases, abnormal passages found in the prostatic utricle in 8 cases, and seminal vesicle fenestration from the prostatic utricle conducted in the other 54 cases(32 by seminal vesiculoscopy and 22 with holmium laser). Stones were seen in the prostatic utricle in 5 cases, in the seminal vesicle in 6 cases, and in both the prostatic utricle and seminal vesicle in 2 cases. Culture of the seminal vesicle fluid showed the acinetobacter to be positive in 1 case and UU, CT, and MH to be negative. At 3 months after surgery, hemospermia was cured in 52 cases, relieved in 8,and unimproved in 4. Conclusion: Seminal vesicle fenestration drainage by transurethral seminal vesiculoscopy for the treatment of vesiculitis with hemospermia has the advantages of short operation time, high effectiveness and no obvious complications and can also be employed for the examination of the seminal vesicle as well as removal of stones and inflammatory substances.

Protective effect of ginsenosides Rg1 and Re on lipopolysaccharide-induced sepsis by competitive binding to Toll-like receptor 4.

We previously demonstrated that ginsenosides Rg1 and Re enhanced the immune response in C3H/HeB mice but not in C3H/HeJ mice carrying a mutation in the Tlr4 gene. The results of the present study showed that both Rg1 and Re inhibited mRNA expression and production of proinflammatory mediators that included tumor necrosis factor α, interleukin-1ß, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase from lipopolysaccharide (LPS)-stimulated macrophages. Rg1 was found to be distributed both extracellularly and intracellularly but Re was located only extracellularly to compete with LPS for binding to Toll-like receptor 4. Preinjection of Rg1 and Re into rats suppressed LPS-induced increases in body temperature, white blood cell counts, and levels of serum proinflammatory mediators. Preinjection of Rg1 and Re into mice prevented the LPS-induced decreases in total white blood cell counts and neutrophil counts, inhibited excessive expression of multiple proinflammatory mediators, and successfully rescued 100% of the mice from sepsis-associated death. More significantly, when administered after lethal LPS inoculation, Rg1, but not Re, still showed a potent antisepsis effect and protected 90% of the mice from death. The better protection efficacy of Rg1 could result from its intracellular distribution, suggesting that Rg1 may be an ideal antisepsis agent.

SrGa(0.7)Co(0.3)O(3-δ) perovskite-cobalt oxide-metal nanocomposite films: magnetic and optical properties.

Two-phase nanocomposite films consisting of metallic Co nanoparticles below 50 nm diameter in a perovskite matrix were grown by pulsed laser deposition onto (LaAlO3)0.3(Sr2AlTaO6)0.7 (LSAT) and silicon substrates from a target of SrGa0.73Co0.27O3. The particles made up about 6% by volume of the film and were present within the film and at the substrate interface. The saturation magnetization of the film was up to 85 emu cm(-3) at 80 nm thickness and the Faraday rotation (FR) tracked the out-of-plane hysteresis loop, reaching 3000 deg cm(-1) at 10 kOe for 1550 nm wavelength. The magneto-optical figure of merit defined as FR divided by optical absorption was 0.04-0.06 deg dB(-1) due to the high optical absorption of the Co particles.

Enhanced electrochemical performance and thermal stability of LiNi(0.5)Mn(1.5)O4 using an electrolyte with sulfolane.

A sulfide-based SEI layer was formed on the surface of a LiNi0.5Mn1.5O4 cathode by using a sulfolane-carbonate mixed solvent electrolyte, which led to an improvement in the electrochemical performance. Moreover, the thermal stability of the LiNi0.5Mn1.5O4 cathode was also significantly improved in the presence of the SEI layer. ARC (Accelerating Rate Calorimetry) tests showed that the self-heating rate of the delithiated LiNi0.5Mn1.5O4 material in the sulfolane-carbonate electrolyte was suppressed.