Genetic Insights Into Latent Autoimmune Diabetes In Adults

‘Latent autoimmune diabetes in adults’ (LADA) is a controversial subtype of diabetes characterized by initial insulin independency and the presence of diabetes associated autoantibodies. As a result, LADA is often misclassified and can represent 5-10% of apparent type 2 diabetes (T2D) cases and is potentially more prevalent than childhood-onset type 1 diabetes (T1D). Despite LADA sharing features with the two better characterized classic diabetes subtypes, the genetic etiology of LADA remains largely unknown. Once there is a more accurate definition of LADA, there will be an improvement in diabetes classification and consequently better treatment and therapeutic interventions. The objective of this thesis is to understand the genetic basis of LADA in order to bring clarity to the current definition of LADA by being the first to leverage genome-wide genotype data from a LADA cohort and the subsequent application of statistical genetics approaches. These investigations can be divided into three parts: 1) the role of T1D and T2D loci in LADA 2) the first genome-wide association study (GWAS) of LADA, and 3) searching for genetic discrepancies between LADA and childhood-onset T1D in the human leukocyte antigen (HLA) region. Four out of the five strongest associations from the candidate locus study were known T1D loci (HLA, PTPN22, INS and SH2B3) and reached genome-wide significance in the GWAS meta-analysis. However, a novel independent signal at a known T1D locus was also observed to be genome-wide significant, near the PFKFB3 gene, which had not been implicated in previous T1D or T2D GWAS. Additionally, major T1D-susceptibility HLA haplotypes were observed to be less frequent in LADA. Furthermore, contrary to observations in childhood-onset T1D studies, HLA-B and HLA-A, were not significantly associated with LADA, independent of HLA-DQB1 and HLA-DRB1 haplotypes. Overall, the genetics of LADA point to a strong T1D component, but a positive genetic correlation between LADA and T2D is also evident, strongly suggesting LADA has both a T1D and T2D component. However, it remains unresolved whether LADA is at the genetic intersection of T1D and T2D or simply a mixture of relatively poorly phenotyped individuals who have either T1D or T2D

Preparing educators for inclusive classrooms

Although in our country the law provides for access to equal quality education, the reality is replete with examples of uneven access and dismal educational outcomes. There are a large number of children in the system who suffer the consequences of disability, poverty and social exclusion. Academic achievement in the school system has been elusive, especially, for first-generation school-goers. Teachers in these schools have the hardest job of all. They have to ensure that all the academic learning happens within the school, as these children do not receive any academic support at home. The circumstances that the children live in are so fragile that teachers are not sure whether, for familial or cultural or socio-economic reasons, they will turn up at school the next day because their lives are in a constant state of uncertainty and ambiguity. They need teachers and an overall supportive system, that consistently believes that all children are capable of learning and achievement. The belief that poverty, caste, religion and other social differences account neither for intelligence nor for inquiry ought to be central to the philosophy and practice of schooling

Novel Insights into the Role of the Smoothened Cysteine Rich Domain in Hedgehog Signalling

The Hedgehog (Hh) signal transduction pathway functions as one of the key developmental pathways and deranged Hh signalling is associated with numerous cancer and tumor conditions. The Smoothened (Smo) G protein coupled receptor (GPCR) functions as the signal transducer of the Hh pathway and is the most attractive drug target of the pathway. The structure of the Smo receptor includes seven membrane spanning domains, extracellular and intracellular loops connecting the membranous domains and the extracellular cysteine rich domain (CRD). The extracellular CRD of the Smo receptor is homologous to the Frizzled (FzD) CRD. The FzD CRD interacts with the physiological ligand of the FzD receptor: Wnt, but the function of the Smo CRD is not clearly elucidated. In the present dissertation we determined the first structure of the Drosophila Smo CRD by solution Nuclear Magnetic Resonance (NMR) spectroscopy. The structure of the Smo CRD comprises primarily of four helices and is stabilized by disulfide bonds between the conserved cysteine residues. The tertiary structure of the Smo CRD is similar to the structure of the FzD CRD. Additionally, we showed that both the Drosophila and the human Smo CRD interact with the glucocorticoid: Budesonide (Bud), albeit with different binding affinities. We identified the key residues in both species that are important for this interaction and generated the complex structure of the Drosophila Smo CRD with Bud using computational methodologies. The binding pocket in the Smo CRD can be targeted for the development of novel anti-cancer therapeutics. The Smo receptor possesses a binding cavity located in the transmembrane domains and we determined that the Smo CRD also possesses ligand binding capabilities. This finding enabled us to propose a novel mechanism of Hh signalling. We speculate that certain Smo ligands bind to the Smo CRD and membrane spanning domains simultaneously to regulate intracellular signalling. Phosphatidylinositol-4-phosphate (PI(4)P) has been shown to regulate Smo activation. We determined that the fatty-acid side chains of the phosphatidylinositols interact with Smo CRD, and PI(4)P specifically enhances activator induced Hh signalling. Therefore, we speculated that PI(4)P may function to bridge the Smo extracellular and the membrane spanning domains, wherein the fatty-acid side chains of PI(4)P docks in the Smo CRD and the inositol head with the fourth position phosphate is necessary for anchoring in the cavity in the transmembrane domains; however, PI(4)P may not necessarily function as endogenous Smo ligand because in the cell-based luciferase reporter assays PI(4)P could only enhance signalling in the presence of an activator of Hh signalling. This suggests that PI(4)P binding to Smo is either a prerequisite and renders Smo active to further induce downstream signalling or PI(4)P acts as an allosteric activator of Hh signalling

Analysis of Electrical Parameters of Ge/Si Heterojunction GeOI FinFETs

AbstractThis paper proposes for the first time three heterojunction structures of FinFET, each structurally different from the other. The first structure is a heterojunction FinFET with Germanium fin, dual gate material and dual gate dielectric, where a Silicon layer near the source end creates a heterojunction. The second structure is a modification of the first one with the Silicon layer placed near the source and drain ends. The second structure further modifies into the third with the introduction of a gate-drain underlap. The third heterojunction FinFET having a gate-drain underlap on the drain shows the improved ION/IOFF and low leakage current compared to the other two structures. Therefore, a further detailed analysis is done for the third geometry, that is, dual gate material dual dielectric gate-drain underlap heterojunction FinFET. Analysis of the transfer characteristics are carried out for this structure for variations in gate-drain underlap length, concentration of both Silicon layers on source and drain ends, and fin width

EDIBLE VACCINES: AN ADVANCEMENT IN ORAL IMMUNIZATION

Vaccines represent a useful contribution to the field of biotechnology as they supply protection against various diseases. But, the major obstacle to oral vaccination is the digestion of macromolecule antigenic protein within the stomach due to extremely acidic pH. To address this issue, scientist Arntzen introduced the concept of edible vaccines. Edible vaccines are prepared by using the science of genetic engineering in which the selected genes are introduced into the plants by means of various methods. The transgenic plant is then induced to manufacture the encoded protein which acts as a vaccine. Owing to its low cost, it will be affordable for developing countries like India. Edible vaccines are used to treat various diseases like malaria, measles, hepatitis B, stopping autoimmunity in type-1 diabetes, cholera, enterotoxicogenic E.coli (ETEC), HIV and anthrax. This review comprises mechanism of action, methods of development, candidate plants, applications, clinical trials and patents of edible vaccines.Keywords: Edible vaccines, Antigens, Oral immunization, Immunity

India’s Law School Legal Aid Clinics: The Gaps Between Aspiration and Practice

The law schools legal aid activities conducted through its clinics has come a long way in India especially since its inception in the early 1970’s. Its evolution has been gradual, intermittent and varied. Although The Bar Council of India (BCI) has mandated, establishing legal aid clinics as a pre-requisite for granting the necessary permissions before law schools start functioning, there are limited ideas of its purpose and objectives. An inherent lack of understanding its importance in terms of teaching, learning and research, the legal aid practices are largely left to the discretion of the individual law schools and interpretations of the individual faculty members. Combined with ideas heavily borrowed from the law schools in the US and individual experiences of the faculty members, legal aid practices in India are diversified. In the backdrop of this, the author intends to explore and map the aspiration of legal aid through an analysis of the key policy documents of legal education since India’s independence through an ontological framework. The ontology maps the aspirations of the legal aid clinics that was intended through these documents. Additionally, a case study of two important institutions have been taken as the case in point in order to verify whether the practices match such aspirations. Thereby, putting forth arguments that are critical for understanding the gaps between the aspiration and the state of reality. Key words: Legal aid Clinics, Law schools, Clinical, Legal education, Social justic

Distribution of mercury in a tropical estuary (India) situated near a chloro-alkali plant

The distribution of mercury in water, sediment and some biological samples of the Rushikulya estuary, east coast of India were assessed during Jan-Dec. 1989. Both the dissolved plus acid leachable mercury contents in water and the sediment mercury discerned conspicuous spatial and seasonal fluctuations. Adsorption on to the suspended particulates was found to be the most likely mechanism for removal of mercury from the water column. Exchange of mercury from sediments to water was observed at high salinities (20-30x10-3). The residual mercury contents in the biological samples revealed that bio-accumulation by bottom-dwelling organisms are higher than the pelagic components

A CLINICAL EVALUATION OF JATIPHALA CHURNA LEPA IN VYANGA WSR TO MELASMA

Vyanga is the one of the Kshudra Roga, characterised by Niruja (painless), Shyava Varna Mandalas (bluish black patches) occurring especially on the face. While considering the pathogenesis of Vyanga, involvement of Pitta is more and it is Rakta Pradoshaja vyadhi. On the basis of clinical features it is correlated with melasma, or facial melanosis, one of the hyper pigmented disorders. Melasma is a common acquired hypermelanosis that affects sun- exposed areas of skin. This study is important since melasma is a disease causing mental side effects in patients, due to darkness and opacity of the skin; therefore, the treatment of melasma in terms of its psychological complication is of particular importance. Jatiphala (Myristica fragrans Houtt.) is an important drug which has got various medicinal uses. The seed and aril of Jatiphala (Myristica fragrans Houtt.) of family myristicaceae have the utilized therapeutically as medicine as well as a spice. Acharya Bhavamishra have mentioned Jatiphala (Myristica fragrans Houtt.) as a single herbal remedy for its action on Vyanga. Intervention and duration: 30 patients having hyperpigmentation on face with clinical manifestations, fulfilling the diagnostic criteria of Vyanga, the prepared Lepa churna was applied over the affected area, once a day for 60 days. Pre test assessment was done on 15th day, 30th and 60thday. Results: The subjective and objective parameters of the study were graded and the results of the study were analysed statistically using descriptive statistics where the study has shown statistically significant in the subjective and objective parameters. Conclusion: This clinical study of Jatiphala churna lepa showed the result in 50-60% of people in the group of Vyanga