A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8+ T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8+ T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8+ T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8+ T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E–restricted CD8+ T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.
Charge noise is critical in the performance of gate-controlled quantum dots (QDs). Such information is not yet available for QDs made out of the new material graphene, where both substrate and edge states are known to have important effects. Here we show the 1/f noise for a microscopic graphene QD is substantially larger than that for a macroscopic graphene field-effect transistor (FET), increasing linearly with temperature. To understand its origin, we suspended the graphene QD above the substrate. In contrast to large area graphene FETs, we find that a suspended graphene QD has an almost-identical noise level as an unsuspended one. Tracking noise levels around the Coulomb blockade peak as a function of gate voltage yields potential fluctuations of order 1 μeV, almost one order larger than in GaAs/GaAlAs QDs. Edge states and surface impurities rather than substrate-induced disorders, appear to dominate the 1/f noise, thus affecting the coherency of graphene nano-devices.
Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its concentration in ISF in relation to CSF, and whether ISF tau is influenced by its aggregation are unknown. To address these issues, we developed a microdialysis technique to analyze monomeric ISF tau levels within the hippocampus of awake, freely moving mice. We detected tau in ISF of wild-type mice, suggesting that tau is released in the absence of neurodegeneration. ISF tau was significantly higher than CSF tau and their concentrations were not significantly correlated. Using P301S human tau transgenic mice (P301S tg mice), we found that ISF tau is fivefold higher than endogenous murine tau, consistent with its elevated levels of expression. However, following the onset of tau aggregation, monomeric ISF tau decreased markedly. Biochemical analysis demonstrated that soluble tau in brain homogenates decreased along with the deposition of insoluble tau. Tau fibrils injected into the hippocampus decreased ISF tau, suggesting that extracellular tau is in equilibrium with extracellular or intracellular tau aggregates. This technique should facilitate further studies of tau secretion, spread of tau pathology, the effects of different disease states on ISF tau, and the efficacy of experimental treatments.
As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.
220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.
rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D’: 0.969). 158 of 220 recruited individuals had the target INR (1.5–2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.
A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.
International normalized ratio (INR) self-testing can improve the management of anticoagulation therapy with warfarin for the patients following mechanical heart valve replacement. Several reviews and studies have demonstrated self-management as an option to improve patient’s outcome considerably after mechanical heart valve replacement. We sought to analyze the security, economy and discuss the prospect of self-testing of anticoagulation therapy in patients following mechanical heart valve replacement in China, and evaluate the accuracy and stability of CoaguChek XS portable INR-testing device.
This was a prospective self-controlled clinical study conducted with 526 patients receiving oral warfarin anticoagulation therapy after mechanical heart valve replacement in the period of Mar.1, 2012 – Nov.1, 2012 in Cardiovascular Surgery Department of West China Hospital of Sichuan University. The same patient performed INR testing with CoaguChek XS portable coagulometer (group1) and central lab (group 2) in parallel. The follow-up time was 6 months. Meanwhile, a questionnaire was handed out to survey the expenses required for the re-examination visits to the hospital, time, and anticoagulation complications.
No severe anticoagulation complications occurred in all the patients. No significant difference of the INR results were observed between group 1 and group 2, they showed significant relevance, r = 0.953(p < 0.05). Compared with the conventional method of INR testing in hospital, the portable coagulometer is convenient, quick and less traumatic. Self-testing of anticoagulation therapy reduced the cost and the time required for re-examination.
Results of CoaguChek XS monitor are precise and have a good consistency and stability as compared with traditional laboratory testing. For the patients receiving anticoagulation therapy after mechanical heart valve replacement, the self-testing of anticoagulation therapy with portable coagulometer is a safe choice, and it has a promising future application in China.
Heart valve replacement; Anticoagulation therapy; Portable coagulometer; Self-testing; Cost
Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research.
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.
Paraquat; Pulmonary fibrosis; Rapamycin; Transforming growth factor-β1; α-Smooth muscle actin; Methylprednisolone
AIM: To retrospectively evaluate the diagnostic efficacy of interventional digital subtraction angiography (DSA) for bleeding small bowel gastrointestinal stromal tumors (GISTs).
METHODS: Between January 2006 and December 2013, small bowel tumors in 25 consecutive patients undergoing emergency interventional DSA were histopathologically confirmed as GIST after surgical resection. The medical records of these patients and the effects of interventional DSA and the presentation and management of the condition were retrospectively reviewed.
RESULTS: Of the 25 patients with an age range from 34- to 70-year-old (mean: 54 ± 12 years), 8 were male and 17 were female. Obscure gastrointestinal bleeding, including tarry or bloody stool and intermittent melena, was observed in all cases, and one case also involved hematemesis. Nineteen patients required acute blood transfusion. There were a total of 28 small bowel tumors detected by DSA. Among these, 20 were located in the jejunum and 8 were located in the ileum. The DSA characteristics of the GISTs included a hypervascular mass of well-defined, homogeneous enhancement and early developed draining veins. One case involved a complication of intussusception of the small intestine that was discovered during surgery. No pseudoaneurysms, arteriovenous malformations or fistulae, or arterial rupture were observed. The completely excised size was approximately 1.20 to 5.50 cm (mean: 3.05 ± 1.25 cm) in maximum diameter based on measurements after the resection. There were ulcerations (n = 8), erosions (n = 10), hyperemia and edema (n = 10) on the intra-luminal side of the tumors. Eight tumors in patients with a large amount of blood loss were treated with transcatheter arterial embolization with gelfoam particles during interventional DSA.
CONCLUSION: Emergency interventional DSA is a useful imaging option for locating and diagnosing small bowel GISTs in patients with bleeding, and is an effective treatment modality.
Gastrointestinal stromal tumors; Small bowel; Digital subtraction angiography; Interventional; Embolization; Bleeding
The mechanisms underlying autophagy during myocardial ischemia and reperfusion remain unclear. The present study investigated the relationship between high-mobility group box 1 protein (HMGB1) and autophagy in hypoxia/reoxygenation (H/R)-induced neonatal rat cardiomyocytes. Neonatal rat cardiomyocytes were treated with recombinant HMGB1 (200 ng/L) or ammonium glycyrrhizinate (100 μM) at appropriate concentrations. Cell viabilities and lactate dehydrogenase (LDH) and creatine kinase (CK) activity levels were measured. HMGB1, LC3 and Beclin-1 expression were assessed by Western blot. The results demonstrated that HMGB1-induced myocardial cells have increased levels of Beclin-1 protein and even higher levels of LC3 protein, while HMGB1-inhibited myocardial cells have decreased levels of Beclin-1 and LC3 proteins. In addition, HMGB1 induction significantly increased LDH and CK levels in the cell culture medium; the inhibition of HMGB1 significantly reduced LDH and CK expression in cardiomyocyte culture medium. In conclusion, the results of the present study suggest that HMGB1 is able to regulate Beclin-1 and LC3 levels following hypoxia and reoxygenation injury in rat cardiomyocytes.
High-mobility group box 1 protein; autophagy; myocardial hypoxia and reoxygenation
AIM: To analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with microwave ablation (MWA) for hepatocellular carcinoma (HCC).
METHODS: Clinical data of 86 patients who underwent TACE combined with MWA between January 2006 and December 2013 were retrospectively analyzed in this study. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 13 prognostic factors affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.
RESULTS: Median follow-up time was 47.6 mo, and median survival time of enrolled patients was 21.5 mo. The 1-, 2-, 3- and 5-year overall survival rates were 72.1%, 44.1%, 31.4% and 13.9%, respectively. Tumor size(χ2 = 14.999, P = 0.000), Barcelona Clinic Liver Cancer (BCLC) stage (χ2 = 29.765, P = 0.000), Child-Pugh class (χ2 = 51.820, P = 0.000), portal vein tumor thrombus (PVTT) (χ2 = 43.086, P = 0.000), arterio-venous fistula (χ2 = 29.791, P = 0.000), MWA therapy times (χ2 = 12.920, P = 0.002), Eastern Cooperative Oncology Group (ECOG) score (χ2 = 28.660, P = 0.000) and targeted drug usage (χ2 = 10.901, P = 0.001) were found to be significantly associated with overall survival by univariate analysis. Multivariate analysis identified that tumor size (95%CI: 1.608-4.962, P = 0.000), BCLC stage (95%CI: 1.016-2.208, P = 0.020), PVTT (95%CI: 2.062-9.068, P = 0.000), MWA therapy times (95%CI: 0.402-0.745, P = 0.000), ECOG score (95%CI: 1.012-3.053, P = 0.045) and targeted drug usage (95%CI: 1.335-3.143, P = 0.001) were independent prognostic factors associated with overall survival.
CONCLUSION: Superior performance status, MWA treatment and targeted drug were favorable factors, and large HCC, PVTT and advanced BCLC stage were risk factors for survival after TACE-MWA for HCC.
Hepatocellular carcinoma; Transarterial chemoembolization; Microwave ablation; Survival; Prognosis
Two bacterial strains, paraffin removal strain and biosurfactant-producing strain, named BHJ-1 and QFL-1, were isolated from oil production wells in Daqing oilfield of China. They were subsequently identified as Bacillus cereus QAU68 and Bacillus subtilis XCCX, respectively. As an indicator of the degradation paraffin, the inoculum concentration of BHJ-1 and QFL-1 were added in different proportions, the optimum proportion was 5:2. In this proportion the degradation rate of paraffin could reach 64 %, the prevention rate of paraffin could reach 55 %.
Paraffin; Bacillus cereus; Bacillus subtilis; Degradation
Wind-blown sand movement often occurs in a very complicated desert environment where sand dunes and ripples are the basic forms. However, most current studies on the theoretic and numerical models of wind-blown sand movement only consider ideal conditions such as steady wind velocity, flat sand surface, etc. In fact, the windward slope gradient plays a great role in the lift-off and sand particle saltation. In this paper, we propose a numerical model for the coupling effect between wind flow and saltating sand particles to simulate wind-blown sand movement over the slope surface and use the SIMPLE algorithm to calculate wind flow and simulate sands transport by tracking sand particle trajectories. We furthermore compare the result of numerical simulation with wind tunnel experiments. These results prove that sand particles have obvious effect on wind flow, especially that over the leeward slope. This study is a preliminary study on windblown sand movement in a complex terrain, and is of significance in the control of dust storms and land desertification.
Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology.
Alzheimer's; amyloid; antibody; apolipoprotein E
The aim of this study was to evaluate the outcomes of multiple advanced surgical treatments (i.e. microsurgery, laparoscopic surgery and endoscopic surgery) for acquired obstructive azoospermia. We analyzed the surgical outcomes of 51 patients with suspected acquired obstructive azoospermia consecutively who enrolled at our center between January 2009 and May 2013. Modified vasoepididymostomy, laparoscopically assisted vasovasostomy and transurethral incision of the ejaculatory duct with holmium laser were chosen and performed based on the different obstruction sites. The mean postoperative follow-up time was 22 months (range: 9 months to 52 months). Semen analyses were initiated at four postoperative weeks, followed by trimonthly (months 3, 6, 9 and 12) semen analyses, until no sperm was found at 12 months or until pregnancy was achieved. Patency was defined as >10,000 sperm ml−1 of semen. The obstruction sites, postoperative patency and natural pregnancy rate were recorded. Of 51 patients, 47 underwent bilateral or unilateral surgical reconstruction; the other four patients were unable to be treated with surgical reconstruction because of pelvic vas or intratesticular tubules obstruction. The reconstruction rate was 92.2% (47/51), and the patency rate and natural pregnancy rate were 89.4% (42/47) and 38.1% (16/42), respectively. No severe complications were observed. Using multiple advanced surgical techniques, more extensive range of seminal duct obstruction was accessible and correctable; thus, a favorable patency and pregnancy rate can be achieved.
azoospermia; endoscopy; laparoscopy; male infertility; microsurgery
Characteristics of heart failure with preserved ejection fraction (HFPEF) have not yet been fully understood. The objectives of this pilot study are to detect protein expression profile in the sera of HFPEF patients, and to identify potential biomarkers for the disease. Five hundred and seven proteins were detected in the sera of healthy volunteers and patients with either HFPEF or hypertension using antibody microarrays (three in each group). The results showed that the serum concentrations of 17 proteins (e.g. angiogenin, activin A and artemin) differed considerably between HFPEF and non-HFPEF patients (hypertensive patients and healthy controls), while a protein expression pattern distinct from that in non-HFPEF patients was associated with HFPEF patients. The up-regulation of angiogenin in both HFPEF patients with LVEF ≥50% (P = 0.004) and a subset of HFPEF patients with LVEF = 41–49% (P < 0.001) was further validated in 16 HFPEF patients and 16 healthy controls. Meanwhile, angiogenin distinguished HFPEF patients from controls with a mean area under the receiver operating characteristic curve of 0.88 (P < 0.001) and a diagnostic cut-off point of 426 ng/ml. Moreover, the angiogenin levels in HFPEF patients were positively correlated with Lg(N-terminal pro-B-type natriuretic peptide, NT-proBNP) (P < 0.001). In addition, high angiogenin level (≥426 ng/ml) was a predictor of all-cause death within a short-term follow-up duration, but not in the longer term of 36 months. This pilot study indicates that the aforementioned 17 potential biomarkers, such as angiogenin, may hold great promise for both diagnosis and prognosis assessment of HFPEF.
heart failure with preserved ejection fraction; angiogenin; biomarker; proteomics
In the title compound, the planes of the two indole ring systems are approximately perpendicular to each other, with a dihedral angle of 89.3 (5)°.
In the title compound, C27H21N3O6·C2H5OH, the indole ring systems are approximately perpendicular to each other, with a dihedral angle of 89.3 (5)°; the plane of the benzene ring is oriented with respect to the indole ring systems at 49.9 (5) and 73.4 (3)°. In the crystal, molecules are linked by N—H⋯O and O—H⋯O hydrogen bonds and weak C—H⋯π interactions into a three-dimensional supramolecular architecture. A void of 33.0 (7) Å3 is observed in the crystal structure. The solvent ethanol molecule acts as a donor, forming an O—H⋯O hydrogen bond, reinforcing the framework structure.
indole; crystal structure; MRI contrast agent
Ampelopsin (AMP), a plant flavonoid, has been reported to inhibit cell growth and/or induce apoptosis in various types of tumor. The aim of the present study was to assess the apoptosis-inducing activity of AMP in A549 human lung adenocarcinoma epithelial cells and the associated underlying mechanism. A549 cells were incubated with different concentrations of AMP in culture medium. Cell growth and apoptosis were evaluated by MTT assay and Annexin V/propidium iodide double staining and flow cytometry, respectively. In addition, western blotting and reverse transcription quantitative polymerase chain reaction analysis were used to examine the time-dependent changes in protein expression. Certain changes in apoptotic protein expression were detected following exposure to AMP, including X-linked inhibitor of apoptosis protein release, reduced B-cell lymphoma 2, myeloid cell leukemia 1 and survivin expression levels, increased Bcl-2-associated X protein expression levels and cleaved-poly ADP ribose polymerase expression. The results revealed that AMP was a potent inhibitor of A549 cell proliferation. The c-Myc/S-phase kinase-associated protein 2 (Skp2) and histone deacetylase (HDAC)1/2 pathways were found to exert an important role in AMP-induced A549 cell apoptosis, as increased levels of c-Myc mRNA and reduced levels of c-Myc/Skp2 and HDAC1 and 2 proteins following AMP treatment were observed. The levels of F-box and WD repeat-containing protein 7α (Fbw7α), Fbw7β, Fbw7γ, phosphorylated-(p−)c-Myc (Thr58) and glycogen synthase kinase 3β (GSK3β) proteins involved in c-Myc ubiquitin-dependent degradation were also analyzed. Following exposure to AMP, the expression levels of Fbw7α, Fbw7γ and GSK3β were reduced and p-c-Myc (Thr58) expression levels were increased. The results suggest that AMP exerts an anticancer effect, which is associated with the degradation of c-Myc, Skp2 and HDAC1 and 2. The ability of AMP to induce apoptosis independently of Fbwα and Fbw7γ suggests a possible use in drug-resistant cancer associated with Fbw7 deficiency. Understanding the exact underlying mechanism requires further investigation of the association between c-Myc and Fbw7α/γ reversal, and analysis of whether Thr58 phosphorylation of c-Myc is dependent on GSK3β.
lung cancer; ampelopsin; c-Myc; S-phase kinase-associated protein 2; F-box/WD repeat-containing protein 7
Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.
The autonomic imbalance during acute ischemia is involved in the occurrence of life-threatening arrhythmias.
To investigate the effect of autonomic nervous system (ANS) modulation by low-level carotid baroreceptor stimulation (LL-CBS) on ventricular ischemia arrhythmias.
Anesthetized dogs were received either sham treatment (SHAM group, n = 10) or LL-CBS treatment (LL-CBS group, n = 10). The voltage lowering the blood pressure was used as the threshold for setting LL-CBS at 80% below the threshold. Treatment started 1 hour before left anterior descending coronary (LAD) occlusion, and continued until the end of experience. Ventricular effective refractory periods (ERP), monophasic action potential duration at 90% (APD90), ventricular arrhythmias, indices of heart rate variability, left stellate ganglion nerve activity (LSGNA) and infarct sizes were measured and analyzed.
Ventricular ischemia resulted in an acute reduction of blood pressure, which was not significantly affected by LL-CBS. After 1 hour of LL-CBS, there was a progressive and significant increase in ERP, increase in APD90, and decrease in LSGNA vs the SHAM group (all P<0.05). LL-CBS apparently reduced premature ventricular contractions (PVC, 264±165 in the SHAM group vs 60±37 in the LL-CBS group; P<0.01) during LAD occlusion. Number of episodes of ventricular fibrillation (VF) was 8 in the Control group versus 3 in the LL-CBS group (80% versus 30%, P<0.05). LL-CBS obviously increased high frequency (HF) component (P<0.05) and decreased low frequency/high frequency ratio (P<0.05) compared with the SHAM group. Ischemic size was not affected by LL-CBS between the two groups.
LL-CBS reduced the occurrences of ventricular arrhythmias during acute ischemia without affecting blood pressure. The procedure was associated with changes of electrophysiological characteristics, nerve activity and heart rate variability. Therefore, LL-CBS may protect from ventricular arrhythmias during acute ischemic events by modulating ANS.
Despite high prevalence of anxiety accompanying with chronic pain, the mechanisms underlying pain-related anxiety are largely unknown. With its well-documented role in pain and emotion processing, the amygdala may act as a key player in pathogenesis of neuropathic pain-related anxiety. Pain-related plasticity and sensitization of CeA (central nucleus of the amygdala) neurons have been shown in several models of chronic pain. In addition, firing pattern of neurons with spike output can powerfully affect functional output of the brain nucleus, and GABAergic neurons are crucial in the modulation of neuronal excitability. In this study, we first investigated whether pain-related plasticity (e.g. alteration of neuronal firing patterns) and sensitization of CeA neurons contribute to nerve injury-evoked anxiety in neuropathic rats. Furthermore, we explored whether GABAergic disinhibition is responsible for regulating firing patterns and intrinsic excitabilities of CeA neurons as well as for pain-related anxiety in neuropathic rats.
We discovered that spinal nerve ligation (SNL) produced neuropathic pain-related anxiety-like behaviors in rats, which could be specifically inhibited by intra-CeA administration of anti-anxiety drug diazepam. Moreover, we found potentiated plasticity and sensitization of CeA neurons in SNL-induced anxiety rats, of which including: 1) increased burst firing pattern and early-adapting firing pattern; 2) increased spike frequency and intrinsic excitability; 3) increased amplitude of both after-depolarized-potential (ADP) and sub-threshold membrane potential oscillation. In addition, we observed a remarkable reduction of GABAergic inhibition in CeA neurons in SNL-induced anxiety rats, which was proved to be important for altered firing patterns and hyperexcitability of CeA neurons, thereby greatly contributing to the development of neuropathic pain-related anxiety. Accordantly, activation of GABAergic inhibition by intra-CeA administration of muscimol, a selective GABAA receptors agonist, could inhibit SNL-induced anxiety-like behaviors in neuropathic rats. By contrast, suppression of GABAergic inhibition by intra-CeA administration of bicuculline, a selective GABAA receptors antagonist, produced anxiety-like behavior in normal rats.
This study suggests that reduction of GABAergic inhibition may be responsible for potentiated plasticity and sensitization of CeA neurons, which likely underlie the enhanced output of amygdala and neuropathic pain-related anxiety in SNL rats.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-014-0072-z) contains supplementary material, which is available to authorized users.
Anxiety; Neuropathic pain; Firing pattern; CeA; GABA
In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming inversion dimers, which are linked by a further N—H⋯O hydrogen bond, forming chains along . There are intra- and intermolecular C—H⋯π interactions present, the latter linking the chains to form a three-dimensional supramolecular structure.
In the title compound, C27H21ClN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.021 and 0.024 Å) are approximately perpendicular to one another, with a dihedral angle of 79.54 (12)°. The benzene ring is twisted with respect to the mean planes of the two indole ring systems at angles of 80.14 (15) and 86.30 (15)°. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming inversion dimers with an R
2(18) ring motif. The dimers are linked by a further N—H⋯O hydrogen bond, forming chains along . There are intra- and intermolecular C—H⋯π interactions present, the latter linking the chains to form a three-dimensional supramolecular structure.
crystal structure; indole; bis-indolymethane; MRI contrast agent; N—H⋯O hydrogen bonds; C—H⋯π interactions
Angiotensin II (AngII) participates in endothelial damage and inflammation, and accelerates atherosclerosis. Endothelial lipase (EL) is involved in the metabolism and clearance of high density lipoproteins (HDL), the serum levels of which correlate negatively with the onset of cardiovascular diseases including atherosclerosis. However, the relationship between AngII and EL is not yet fully understood. In this study, we investigated the effects of AngII on the expression of EL and the signaling pathways that mediate its effects in human umbilical vein endothelial cells (HUVECs).
Methods and Findings
HUVECs were cultured in vitro with different treatments as follows: 1) The control group without any treatment; 2) AngII treatment for 0 h, 4 h, 8 h, 12 h and 24 h; 3) NF-κB activation inhibitor pyrrolidine dithiocarbamate (PDTC) pretreatment for 1 h before AngII treatment; and 4) mitogen-activated protein kinase (MAPK) p38 inhibitor (SB203580) pretreatment for 1 h before AngII treatment. EL levels in each group were detected by immunocytochemical staining and western blotting. HUVECs proliferation was detected by MTT and proliferating cell nuclear antigen (PCNA) immunofluorescence staining. NF-kappa B (NF-κB) p65, MAPK p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were assayed by western blotting. The results showed that the protein levels of EL, NF-κB p65, MAPK p38, JNK, and p-ERK protein levels, in addition to the proliferation of HUVECs, were increased by AngII. Both the NF-kB inhibitor (PDTC) and the MAPK p38 inhibitor (SB203580) partially inhibited the effects of AngII on EL expression.
AngII may upregulate EL protein expression via the NF-κB and MAPK signaling pathways.
Objective: To investigate the association of Kruppel-like factor 4 (KLF4) expressions with the prognosis of esophageal squamous cell carcinoma (SCC) patients. Methods: Ninety-eight cases of esophageal carcinoma patients were enrolled. The expression of KLF4 in the esophageal SCC and normal esophageal mucosa tissues were examined by immunohistochemistry. The correlations between the expression of KLF4 protein and patients’ clinical characteristics and prognosis were analyzed. Results: We observed higher expressed KLF4 in normal esophageal mucosa tissues than esophageal SCC tissues, with positive rate of 82.7% (81/98) and 43.8% (43/98) respectively. In patients with lymphatic metastasis, the positive rate of KLF4 was 24.4% (10/41), whereas it was 57.9% (33/57) in patients without lymphatic metastasis, and the difference was significant (x2 = 10.871, P = 0.001). The positive rates of KLF4 were 62.5% (5/8), 53.1% (26/49) and 29.3% (12/41) in stage I, II and III patients, respectively. There were no correlations between the expression of KLF4 and gender, age, tumor size, location, differentiation grade and infiltration depth. The 5-year survival rates and median survival times were 48.8% and 25.5%, and 55 and 26 months for the patients with KLF4 positive and negative expression, respectively. There were significant differences between the patients with KLF4 positive expression and negative expression in the 5-year survival rates and median survival times (x2 = 5.747 and 4.493, P = 0.017 and 0.034). Conclusion: KLF4 might act as a tumor suppressor in esophageal SCC and the expression status of KLF4 could be considered as a prognosis predictor for esophageal SCC patients.
Esophageal squamous cell carcinoma; Kruppel-like factor 4; prognosis