Effect of oxidative stress on ABC transporters: contribution to epilepsy pharmacoresistance

Epilepsy is a neurological disorder affecting around 1%-2% of population worldwide and its treatment includes use of antiepileptic drugs to control seizures. Failure to respond to antiepileptic drug therapy is a major clinical problem and over expression of ATP-binding cassette transporters is considered one of the major reasons for pharmacoresistance. In this review, we have summarized the regulation of ABC transporters in response to oxidative stress due to disease and antiepileptic drugs. Further, ketogenic diet and antioxidants were examined for their role in pharmacoresistance. The understanding of signalling pathways and mechanism involved may help in identifying potential therapeutic targets and improving drug response

Multimodal Classification of Urban Micro-Events

In this paper we seek methods to effectively detect urban micro-events. Urban micro-events are events which occur in cities, have limited geographical coverage and typically affect only a small group of citizens. Because of their scale these are difficult to identify in most data sources. However, by using citizen sensing to gather data, detecting them becomes feasible. The data gathered by citizen sensing is often multimodal and, as a consequence, the information required to detect urban micro-events is distributed over multiple modalities. This makes it essential to have a classifier capable of combining them. In this paper we explore several methods of creating such a classifier, including early, late, hybrid fusion and representation learning using multimodal graphs. We evaluate performance on a real world dataset obtained from a live citizen reporting system. We show that a multimodal approach yields higher performance than unimodal alternatives. Furthermore, we demonstrate that our hybrid combination of early and late fusion with multimodal embeddings performs best in classification of urban micro-events

Synthesis of Silver Nanostructures and their Application in Highly Sensitive SERS Sensors

A comparison of Surface Enhanced Raman Scattering (SERS) activity of chemically synthesised silver nanostructures with different shapes is reported. The silver nanostructures of cubical, prism and wire like morphology were synthesised using chemical synthesis route and utilised as SERS substrates. The sensors were fabricated by spin coating these materials over a Silicon or glass substrate. The fabricated sensors were used to analyse response with two different analytes, 4-Mercaptobenzoic acid and Rhodamine 6G under different concentrations. The signal enhancement was compared with a silver coated thin film over glass substrate and it was observed that the enhancement of the order of 103 is achieved. The nanowire performed better than the other forms of silver and gave a higher signal enhancement for all the analytes as compared to other nanostructures. The fabricated sensors may be useful for various applications including explosive and biowarfare agent detection

Enhancement in production of recombinant two-chain Insulin Glargine by over-expression of Kex2 protease in Pichia pastoris

Glargine is an analog of Insulin currently being produced by recombinant DNA technology using two different hosts namely Escherichia coli and Pichia pastoris. Production from E. coli involves the steps of extraction of inclusion bodies by cell lysis, refolding, proteolytic cleavage and purification. In P. pastoris, a single-chain precursor with appropriate disulfide bonding is secreted to the medium. Downstream processing currently involves use of trypsin which converts the precursor into two-chain final product. The use of trypsin in the process generates additional impurities due to presence of Lys and Arg residues in the Glargine molecule. In this study, we describe an alternate approach involving overexpression of endogenous Kex2 proprotein convertase, taking advantage of dibasic amino acid sequence (ArgArg) at the end of B-chain of Glargine. KEX2 gene overexpression in Pichia was accomplished by using promoters of varying strengths to ensure production of greater levels of fully functional two-chain Glargine product, confirmed by HPLC and mass analysis. In conclusion, this new production process involving Kex2 protease over-expression improves the downstream process efficiency, reduces the levels of impurities generated and decreases the use of raw material

Indigenous approaches of pest management in vegetables with special reference to coriander in southern Rajasthan, India

The present survey based study was conducted to record the indigenous pest management practices which were prepared by the use of various ethnobotanical plant parts, animal bi-products etc., for vegetable pest control by the farmers of tribal community in four tribal districts of southern Rajasthan. Data revealed that nowadays, indigenous knowledge of insect-pests management is being alive in age old people of few communities, amongst tribes of southern Rajasthan is one of the community in which some farmers are still practicing indigenous tactics for controlling pests on vegetables. 28 indigenous practices constituted by locally available wild plants constituents, animal byproducts, natural resource and few spiritual mean were applied with age old knowledge of farmers recorded effective management of various insect-pests infesting vegetables including coriander. The highest Fic value was recorded for aphids followed by thrips and jassids. The used value was recorded in the range of 0.09 to 0.69 for all locations. The highest UV secured for indigenous practices of Neem leaf extract; cow butter milk + cow dung ash + chilli seed powder; Neem seed kernel extract and ker plant + neem leaf + negadi leaf extract. These practices were easy in preparation, cost effective, eco-friendly and widely acceptable by the community in region need to be documented for future reference

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

1,2,3-Triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzodisoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 of 2 μM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells (C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as the potential protein target of those compounds in silico, and the predicted target was next experimentally validated by measuring the variations in the levels of p21, cyclin D and acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds with the second deacetylase domain of HDAC6 displayed high degree of shape complementarity to the binding site of the enzyme, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active ligands against histone deacetylases which deserve to be further evaluated in their applications in the cancer field. © 2015 Elsevier Ltd. All rights reserved

Chandipura virus: a major cause of acute encephalitis in children in North Telangana, Andhra Pradesh, India

A hospital-based surveillance was undertaken between May 2005 and April 2006 to elucidate the contribution of Chandipura virus (CHPV) to acute viral encephalitis cases in children, seroconversion in recovered cases and to compare the seroprevalences of anti-CHPV IgM and N antibodies in areas reporting cases with those without any case of acute viral encephalitis. During this period, 90 cases of acute encephalitis were hospitalized in the pediatric wards of Mahatma Gandhi Memorial (MGM) Hospital, Warangal. There were 49 deaths (Case Fatality Rate, i.e., CFR of 54.4%). Clinical samples and records were obtained from 52 suspected cases. The cases were below 15 years, majority in 0-4 years (35/52, 67.3%). Computerized tomography (CT) scans and cerebro-spinal fluid (CSF) picture favored viral etiology. No neurological sequelae were observed. CHPV etiology was detected in 25 cases (48.1%, n = 52; RNA in 20, IgM in 3 and N antibody seroconversion in 2). JEV etiology was detected in 5 cases (IgM in 4 cases and seroconversion in 1 case). Anti-CHPV IgM seroprevalence in contacts (26/167, 15.6%) was significantly higher (P < 0.05) than in non-contacts (11/430, 2.6%); which was also observed in children < 15 years (19/90, 21.1% vs. 3/109, 2.7%). Anti-CHPV N antibody seroprevalence in <15 years contacts (66/90, 73.3%) and non-contacts (77/109, 70.6%) was significantly lower (P < 0.05) than in contacts (75/77, 97.4%) and non-contacts (302/321, 94.1%) more than 15 years respectively. CHPV appears to be the major cause of acute viral encephalitis in children in endemic areas during early monsoon months

Cigarette smoke exposure impairs β-cell function through activation of oxidative stress and ceramide accumulation

Objectives Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models. Methods Beginning at 8 weeks of age, C57BL/6 J mice were concurrently fed a high-fat diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured INS-1 β-cells and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide accumulation in the lung and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry. Results Compared to HFD-fed, ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and had accelerated worsening of their glucose tolerance. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p = 0.017), reduced β-cell proliferation (p = 0.006), and increased islet ceramide content compared to non-smoking control mice. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide levels, which was correlated with reduced insulin gene expression and glucose-stimulated insulin secretion, and increased β-cell oxidative and endoplasmic reticulum (ER) stress. Treatment with the antioxidant N-acetylcysteine markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress. Conclusions Our results indicate that CS exposure leads to impaired insulin production, processing, secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of the mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers

Identifying sources, pathways and risk drivers in ecosystems of Japanese Encephalitis in an epidemic-prone north Indian district

Japanese Encephalitis (JE) has caused repeated outbreaks in endemic pockets of India. This study was conducted in Kushinagar, a highly endemic district, to understand the human-animal-ecosystem interactions, and the drivers that influence disease transmission. Utilizing the ecosystems approach, a cross-sectional, descriptive study, employing mixed methods design was employed. Four villages (two with pig-rearing and two without) were randomly selected from a high, a medium and a low burden (based on case counts) block of Kushinagar. Children, pigs and vectors were sampled from these villages. A qualitative arm was incorporated to explain the findings from the quantitative surveys. All human serum samples were screened for JE-specific IgM using MAC ELISA and negative samples for JE RNA by rRT-PCR in peripheral blood mononuclear cells. In pigs, IgG ELISA and rRT-PCR for viral RNA were used. Of the 242 children tested, 24 tested positive by either rRT-PCR or MAC ELISA; in pigs, 38 out of the 51 pigs were positive. Of the known vectors, Culex vishnui was most commonly isolated across all biotopes. Analysis of 15 blood meals revealed human blood in 10 samples. Univariable analysis showed that gender, religion, lack of indoor residual spraying of insecticides in the past year, indoor vector density (all species), and not being vaccinated against JE in children were significantly associated with JE positivity. In multivariate analysis, only male gender remained as a significant risk factor. Based on previous estimates of symptomatic: asymptomatic cases of JE, we estimate that there should have been 618 cases from Kushinagar, although only 139 were reported. Vaccination of children and vector control measures emerged as major control activities; they had very poor coverage in the studied villages. In addition, lack of awareness about the cause of JE, lack of faith in the conventional medical healthcare system and multiple referral levels causing delay in diagnosis and treatment emerged as factors likely to result in adverse clinical outcomes