Identification of distant co-evolving residues in antigen 85C from Mycobacterium tuberculosis using statistical coupling analysis of the esterase family proteins

A fundamental goal in cellular signaling is to understand allosteric communication, the process by which sig-nals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Statistical coupling analysis (SCA) is a statistical technique that uses evolutionary data of a protein family to measure correlation between distant functional sites and suggests allosteric communication. In proteins, ...     

Targeting the GD3 acetylation pathway selectively induces apoptosis in glioblastoma

The expression of ganglioside GD3, which plays crucial roles in normal brain development, decreases in adults but is upregulated in neoplastic cells, where it regulates tumor invasion and survival. Normally a buildup of GD3 induces apoptosis, but this does not occur in gliomas due to formation of 9-O-acetyl GD3 by the addition of an acetyl group to the terminal sialic acid of GD3; this renders GD3 unable to induce apoptosis. Using human biopsy-derived glioblastoma cell cultures, we have carried out a series of molecular manipulations targeting GD3 acetylation pathways. Using immunocytochemistry, flow cytometry, western blotting, and transwell assays, we have shown the existence of a critical ratio between GD3 and 9-O-acetyl GD3, which promotes tumor survival. Thus, we have demonstrated for the first time in primary glioblastoma that cleaving the acetyl group restores GD3, resulting in a reduction in tumor cell viability while normal astrocytes remain unaffected. Additionally, we have shown that glioblastoma viability is reduced due to the induction of mitochondrially mediated apoptosis and that this occurs after mitochondrial membrane depolarization. Three methods of cleaving the acetyl group using hemagglutinin esterase were investigated, and we have shown that the baculovirus vector transduces glioma cells as well as normal astroctyes with a relatively high efficacy. A recombinant baculovirus containing hemagglutinin esterase could be developed for the clinic as an adjuvant therapy for glioma.     

探讨BV三项在阴道分泌物检测中的临床价值

目的：探讨细菌性阴道病（Backrial Vagimsis,BV）三项实验在阴道分泌物检测中诊断细菌性阴道病的临床价值。方法：对门诊210例来诊妇产科患者做过氧化氢酶、唾液酸苷酶、白细胞脂酶三项实验和显微镜检查。结果：BV的患病率为41．4％,滴虫性阴道炎4.3％,霉菌性阴道炎23.8％,BV的患病率明显高于其他的阴道炎。结论：门诊就医的妇产科患者BV的患病率很高,应该把BV三项作为妇产科常规的筛选实验。     

血小板活化因子乙酰水解酶基因多态性与缺血性脑卒中患者血小板活化和预后关系的研究

目的 探讨血小板活化因子乙酰水解酶(PAF-AH)基因多态性与缺血性脑卒中的关系.方法 应用PCR技术,分析205例缺血性脑卒中患者(脑卒中组)及114例健康体检者(对照组)的基因型.并测定血浆血小板活化因子(PAF)、α颗粒膜糖蛋白140(GMP-140)、β-血小板球蛋白(β-TG)和血小板第4因子(PF4)水平.结果 脑卒中组PAF-AH.基因突变率和血浆PAF、GMP-140、β-TG和PF4水平[分别为42.44%、(91.08±39.10)ng/L、(36.46±13.10)μg/L、(41.75±11.18)μg/L、(29.05±9.16)μg/L]均显著高于对照组[分别为21.05%、(64.30±18.81)ng/L、(18.27±7.68)μg/L、(30.94±8.47)μg/L、(18.75±6.06)μg/L](P<0.01)脑卒中组基因突变者血浆PAF、GMP-140水平显著高于无基因突变者(P<0.01)结论 缺血性脑卒中患者急性期血小板活化增强,且与PAF-AH基因多态性相关.PAF-AH基因突变可能是缺血性脑卒中的一种遗传危险标志.     

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte, and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes, and brain remain to be defined.     

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Mara...     

Efficacy of Fumonisin Esterase in Piglets as Animal Model for Fumonisin Detoxification in Humans: Pilot Study Comparing Intraoral to Intragastric Administration

Fumonisins, a group of highly prevalent and toxic mycotoxins, are suspected to be causal agents of several diseases in animals and humans. In the animal feed industry, fumonisin esterase is used as feed additive to prevent mycotoxicosis caused by fumonisins. In humans, a popular dosage form for dietary supplements, with high patient acceptance for oral intake, is capsule ingestion. Thus, fumonisin esterase provided in a capsule could be an effective strategy against fumonisin intoxication in humans. To determine the efficacy of fumonisin esterase through capsule ingestion, two modes of application were compared using piglets in a small-scale preliminary study. The enzyme was administered intraorally (in-feed analogue) or intragastrically (capsule analogue), in combination with fumonisin B1 (FB1). Biomarkers for FB1 exposure; namely FB1, hydrolysed FB1 (HFB1) and partially hydrolysed forms (pHFB1a and pHFB1b), were measured both in serum and faeces using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and toxicokinetic parameters were calculated. Additionally, the serum sphinganine/sphingosine (Sa/So) ratio, a biomarker of effect, was determined using LC-MS/MS. A significantly higher Sa/So ratio was shown in the placebo group compared to both esterase treatments, demonstrating the efficacy of the esterase. Moreover, a significant decrease in serum FB1 area under the concentration-time curve (AUC) and an increase of faecal HFB1 AUC were observed after intraoral esterase administration. However, these effects were not observed with statistical significance after intragastric esterase administration with the current sample size.     

NONLINEAR DETERMINISM IN THE IMMUNE SYSTEM. IN VIVO INFLUENCE OF ELECTROMAGNETIC FIELDS ON DIFFERENT FUNCTIONS OF MURINE LYMPHOCYTE SUBPOPULATIONS*

Animal studies of the effects of low-frequency electromagnetic fields (EMFs) on the immune system appear inconsistent and recent evidence indicates that inconspicuous experimental problems are not responsible. We hypothesized that the inconsistencies resulted from use of linear methods and models to study inherently nonlinear input-output relationships. Using a novel analytical method, we found that exposure of mice to 5 G, 60 Hz, for 1–105 days in 6 independent experiments consistently affected a broad panel of immune variables when and only when the reaction of the immune system was modeled to allow the possibility of nonlinearity in the relationship between the field and the immune variables. It was possible to mimic the pattern observed in the immune data by sampling from a known chaotic system, suggesting the possibility that the observed pattern was the result of intrinsic nonlinear regulatory mechanisms in the immune system. Overall, the results suggested that lymphoid sub-populations were vulnerable to the physiological consequences of EMF transduction, that it may never be possible to predict specific changes in particular immune-system variables, and that the underlying behavior of the immune system (that which occurs in the absence of specific inputs) may be governed by laws that manifest extreme sensitivity to prior states.     

枳术饮对功能性消化不良大鼠肠动力的影响

目的探讨枳术饮对功能性消化不良（FD）大鼠肠道动力的影响。方法将Wistar大鼠随机分为正常对照组、模型对照组、枳术饮组和西沙比利组,每组10只。复制大鼠胃电节律失常模型,药物干预后分别以葡聚糖蓝-2000为胃肠内标记物,观察大鼠肠道传输速率的变化及十二指肠病理组织学改变。免疫组织化学法观察十二指肠组织乙酰胆碱酯酶（AchE）、胃动素（MTL）阳性神经分布的变化。结果模型对照组大鼠肠道传输速率显著降低（P〈0.01）,十二指肠组织AchE、MTL阳性神经分布显著减少（P〈0.01）。枳术饮可明显促进模型大鼠肠道传输速率（P〈0.01）,明显增加十二指肠组织AchE、MTL阳性神经分布（P〈0.05,P〈0.01）。结论枳术饮能够改善FD大鼠肠动力障碍,其作用机制可能与十二指肠AchE、MTL阳性神经分布增加有关。