556 research outputs found

    A case-control analysis of common variants in GIP with type 2 diabetes and related biochemical parameters in a South Indian population

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    <p>Abstract</p> <p>Background</p> <p>Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in <it>GIP </it>in association with type 2 diabetes and related biochemical parameters.</p> <p>Method</p> <p>A total of 2000 subjects which includes 1000 (584M/416F) cases with type 2 diabetes and 1000 (470M/530F) normoglycemic control subjects belonging to Dravidian ethnicity from South India were recruited to assess the effect of single nucleotide polymorphisms (SNPs) in <it>GIP </it>(rs2291725, rs2291726, rs937301) on type 2 diabetes in a case-control manner. The SNPs were genotyped by using tetra primer amplification refractory mutation system-PCR (ARMS PCR). For statistical analysis, our study population was divided into sub-groups based on gender (male and female). Association analysis was carried out using chi-squared test and the comparison of biochemical parameters among the three genotypes were performed using analysis of covariance (ANCOVA).</p> <p>Result</p> <p>Initial analysis revealed that, out of the total three SNPs selected for the present study, two SNPs namely rs2291726 and rs937301 were in complete linkage disequilibrium (LD) with each other. Therefore, only two SNPs, rs2291725 and rs2291726, were genotyped for the association studies. No significant difference in the allele frequency and genotype distribution of any of the SNPs in <it>GIP </it>were observed between cases and controls (<it>P </it>> 0.05). Analysis of biochemical parameters among the three genotypes showed a significant association of total cholesterol (<it>P </it>= 0.042) and low density lipoprotein (LDL) with the G allele of the SNP rs2291726 in <it>GIP </it>(<it>P </it>= 0.004), but this was observed only in the case of female subjects. However this association does not remain significant after correction for multiple testing by Bonferroni's inequality method.</p> <p>Conclusion</p> <p>No statistically significant association was observed between any of the SNPs analysed and type 2 diabetes in our population. But the analysis of biochemical parameters indicates that the G allele in rs2291726 may be a putative risk allele for increased LDL cholesterol and further studies in other population needs to be carried out for ascertaining its role in cholesterol metabolism and subsequent cardiovascular risk.</p

    Case-Control Analysis of SNPs in GLUT4, RBP4 and STRA6: Association of SNPs in STRA6 with Type 2 Diabetes in a South Indian Population

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    BACKGROUND: The inverse relationship between GLUT4 and RBP4 expression is known to play a role in the pathogenesis of type 2 diabetes. Elevated levels of RBP4 were shown to cause insulin resistance in muscles and liver. Identification of STRA6 as a cell surface receptor for RBP4 provides further link in this axis and hence we analyzed SNPs in these three genes for association with type 2 diabetes in a South Indian population. METHODOLOGY/PRINCIPAL FINDINGS: Selected SNPs in the three genes were analyzed in a total of 2002 individuals belonging to Dravidian ethnicity, South India, by Tetra Primer ARMS PCR or RFLP PCR. Allele frequencies and genotype distribution were calculated in cases and controls and were analyzed for association by Chi-squared test and Logistic regression. Haplotype analysis was carried out for each gene by including all the markers in a single block. We observed a significant association of three SNPs, rs974456, rs736118, and rs4886578 in STRA6 with type 2 diabetes (P = 0.001, OR 0.79[0.69-0.91], P = 0.003, OR 0.81[0.71-0.93], and P = 0.001, OR 0.74[0.62-0.89] respectively). None of the SNPs in RBP4 and GLUT4 showed any association with type 2 diabetes. Haplotype analysis revealed that two common haplotypes H1 (111, P = 0.001, OR 1.23[1.08-1.40]) and H2 (222, P = 0.002 OR 0.73[0.59-0.89]) in STRA6, H6 (2121, P = 0.006, OR 1.69[1.51-2.48]) in RBP4 and H4 (2121, P = 0.01 OR 1.41[1.07-1.85]) in GLUT4 were associated with type 2 diabetes. CONCLUSION: SNPs in STRA6, gene coding the cell surface receptor for RBP4, were significantly associated with type 2 diabetes and further genetic and functional studies are required to understand and ascertain its role in the manifestation of type 2 diabetes

    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∌99% of the euchromatic genome and is accurate to an error rate of ∌1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

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    Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

    Effect of climate on Enteric Fever incidence in Ahmedabad, India

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    ObjectiveThis study is an attempt to explore the relationship of EF incidence with climate variables and ENSO events in the seventh most populous city in India.IntroductionEnteric fever (EF) is a grave systemic infection, which has been controlled quite effectively in developed countries, but continues to be a grave public health concern for India. Environmental drivers such as rainfall, temperature, relative humidity and El Niño-Southern Oscillations (ENSO) are known to influence the transmission of Salmonella typhi and paratyphi. India possesses the largest population burden of EF, yet very few studies have explored its climatic associations.MethodsWe analyzed address-confirmed widal positive, monthly EF cases reported by Ahmedabad Municipal Corporation and local climate data recorded by the Meteorology Office from 1986-2017. EF incidence trend in the city was cross validated using EF monthly reports from one large public hospital and from private reports. We also collected data for Temperature, Humidity and Rainfall from Meteorological Centre of Ahmedabad, population data from Census department, and identified IOD and ENSO events from National Oceanic and Atmospheric Administration (NOAA) for the same period.ResultsOur study recorded 29,808 Widal positive cases for 32 years. EF incidence trend over last 32 years showed a decadal pattern. Initial study period (1986-1995) showed higher and erratic case rates, while cases were more restrained during the last decade (1995-2005), although a steady rise is persisting. We also observed a consistent rise in EF cases in the last 8 years (Fig 1).Analysis of annual pattern of monthly-normalized EF cases revealed a bimodal distribution of peaks, in the month of June and September. Peaks of EF cases showed a lag and lead of one month with Tmax and Tmin. The first EF peak in June lagged the Tmax peak in May by a month and the second EF peak in September led the Tmax peak in October by a month. The second peak of EF cases in September coincided with the peak humidity in the same month. The dip between the two EF peaks coincided with maximum rainfall peak in July (Fig 2 a,b,c). Spearman’s rank correlation showed a small positive but significant correlation between monthly EF case rates and climate variables (Tab 1). A Poisson model showed significant but weak association between EF incidence and all climate variables - Tmin, RH and Rainfall. In our study T max had the strongest association with EF cases, wherein an increase of one case was accompanied by a 0.1°C increase of the Tmax (Tab 2).Over the 32 years, there were 4 strong and 4 moderate El Nino years, 5 strong and 2 moderate La Nina years and 17 neutral years. Figure 3 shows that except for the two El Nino years which coincided with positive IOD events, the remaining six El Nino years experienced a subdued rainfall. Six out of seven La Nina years experienced high rainfall. The early El Nino events of 1986, 1987, 1991 and the most recent one of 2015 exhibit a trend of low rainfall and high cases. This trend is diluted in the middle El Nino years, 1994, 1997, 2002 and 2009 showing high and low rainfall and relatively lesser annual case rates. Although the highest case rate was recorded in a La Nina year - 59/100,000 in 1988, average case rates were highest for El Nino years (25.5), lower for La Nina (20.5) and lowest for Neutral years (17.6). However, we were unable to establish any statistical significance between average EF case rates during each of these periods. A spearman correlation between EF cases and rainfall was small but significant for El Nino (rs= 0.35, p=0.001) and for neutral years (rs= 0.20, p= 0.004), but not for La Nina years. A repeated measures ANOVA analysis showed no significant difference in average EF cases during the three ENSO categories, however visual profile plot (Fig 4) of estimated marginal monthly means over the year showed distinct differences – early rise and peaking of cases in the El Nino and La Nina years, and a much more restrained rise without conspicuous peaks in Neutral years.The 2 positive IOD events that occurred along with the strong El Nino events in 1994 and 1997 may have led to lowering of case rates during El Nino years, and thus the lack of a significant increase in EF incidence rates. But this could also be due to the fact that our analysis, unlike a time series analysis, has used an El Nino year as a variable, which does not accommodate the fact that El Nino does not run by a calendar year. We were unable to conduct a geospatial analysis which may have better correlated our data with temperature and rainfall intensity during the three ENSO phases in our region. Uneven development of urban infrastructure would also influence rates of illness. Furthermore, the cases reported to the epidemic cell were based on Slide and/or Tube Widal positive tests which is considered a poor diagnostic test. Despite these numerous and at times opposing factors influencing trends of EF, the upswing in case incidence rate early in the El Nino and La Nina years, when the weather is still balmy and water shortages haven’t yet begun in the city, merits deeper investigation.ConclusionsFuture control strategies for EF need to consider the influence of local environment, geographical climate variation and seasonal patterns. This relationship between ENSO events and EF cases needs to be investigated with larger and longer data sets from different cities and towns in the sub-continent. One of the limitation of our study is we need longer and larger, spatially distributed dataset of EF incidences to associate it better with climate phenomena

    Synthesis, characterization, cytotoxicity and antibacterial studies of chitosan, O-carboxymethyl and N,O-carboxymethyl chitosan nanoparticles

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    Chitosan (CS) is a naturally occurring biopolymer. It has important biological properties such as biocompatibility, antifungal and antibacterial activity, wound healing ability, anticancerous property, anticholesteremic properties, and immunoenhancing effect. Recently, CS nanoparticles have been used for biomedical applications. However, due to the limited solubility of CS in water its water-soluble derivatives are preferred for the above said applications. In this work, the nanoparticles of CS and its water-soluble derivatives such as O-carboxymethyl chitosan (O-CMC) and N,O-carboxymethyl chitosan (N,O-CMC) was synthesized and characterized. In addition, cytotoxicity and antibacterial activity of the prepared nanoparticles was also evaluated for biomedical applications

    Challenges affecting the implementation of e-procurement in the Malawi Public Sector: - The Case of Malawi Housing Corporation, Lilongwe City Council, Kamuzu Central Hospital, Immigration Department and Malawi Defence Force.

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    As part of e-government initiative, the public sector is encouraged to adopt e-procurement systems and some initiatives are currently underway in Malawi public sector. Despite the numerous benefits of e-procurement and goals set by the Government of Malawi (GoM) to reduce costs, improve service delivery, enhance transparency and efficiency, the public sector is reluctant to move procurement to the Internet and government ministries or departments have not yet implemented e-procurement. This study aimed at assessing the challenges that affect the implementation of e-procurement, perceived benefits, and critical success factors for effective implementation. Both Qualitative and Quantitative research methodologies were used as a guide to achieve the research objectives and the Questionnaire was used to collect data from government ministries and departments. Systematic Random sampling was used to select the government offices to be included in the study then purposive sampling was used to obtain the required primary data from respondents that are knowledgeable with the subject area. Out of the 113 questionnaires distributed, only 91 were received and analyzed, representing 81 percent response rate. Data was analyzed using thematic areas for qualitative (descriptive data) and excel for quantitative data. The results indicate that all the public entities in this study currently do not use any form of e-procurement but they are ready to adopt some. However, the respondents were able to identify the benefits that include, reduced maverick buying and reduced lead time. Challenges for implementation include lack of trained personnel, organizational culture that does not embrace technology, lack of managerial support and cost for setting up the system. The respondents further identified some critical success factors for e-procurement implementation and these include enhanced managerial support and end user training as the major ones. While system integration, users and supplier involvement are the secondary factors for consideration too. The researcher concluded that e-procurement requires resources, training and enactment of law within the public procurement framework for improved efficiency and service delivery. Hence, recommendations have been made to various stakeholders to enhance the implementation process. For instance, the Government of Malawi (GoM) to reduce taxes on ICT equipment and develop curriculum on e-procurement in institutions of higher learning. Executive management of public institutions to involve staff during implementation and train staff on e-procurement systems and tools usage. Lastly, recommendations to employees to acquire the necessary skills through attendance of short term or long term learning from institutions such as Malawi institute of Management (MIM) to enhance computer skills capacity especially in e-procurement
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