The Role of Clustered Organization and Generation of Mixed Properties in Macaque V2

Throughout the mammalian cortex, neurons of similar response characteristics group together into topographic functional domains. The genesis and role of this organization remains in question, but it has been proposed to affect the mixed properties of neurons. These types of neurons possess multiple receptive field preferences, such as a cell responding to a color and an oriented stimulus. To examine the functionality of clustered organization and their effect in generation of neurons possessing mixed properties, this dissertation examined the secondary visual cortex (V2) of the Macaca fasicularis. This particular cortex is comprised of domains organized according to distinct visual stimulus components, specifically clusters of neurons partitioned by color and orientation preferences within a close proximity. In the first series of experiments (Chapter 3), a computer model of a cortical area based upon macaque V2 investigated the effect of clusters of like-preferring neurons on the probability of two different preference terminals synapsing on a particular cell. These results indicate that presence of at least one cluster significantly increases the probability of multiple preferences arriving at a neuron. The second series of experiments (Chapter 4) used single unit electrophysiology to investigate the temporal properties of V2 neurons in response to achromatic and colored oriented stimuli. With the addition of color to the stimulus, an increase in latency, an increase to the time point of the maximum rate of firing, and a decreased initial-phase response with a sustained later-phase response were observed. These studies indicate that functional clusters of neurons significantly increase the joint probability of the co-localization of differing preference terminals, potentially yielding neurons with mixed preferences through these intra-areal connections. Furthermore, the temporal characteristics of V2 neurons, as seen in observed latency and time of maximum spiking, support this idea of domain-enhanced intra-areal integration

Influence of transnational economic alliances on the IFRS convergence decision in India - institutional perspectives

This study contributes to the literature on global governance by highlighting the importance of not losing sight of the nation state as an important player in the transnational governance arena. Specifically, literature on global (accounting) regulation devotes a great deal of attention to the roles of organisations and agencies with transnational remit (such as global standard setters, donor agencies) while often downplaying the significant impacts of the more traditional cross-country links forged through economic relationships and resource dependencies between national and transnational institutional fields. This was specially noted in the case of the indirect influences of the US’s decision to delay IFRS convergence. While being interpreted as an indirect source of influence, such a decision played a very significant role on the convergence negotiations in India. The study shows how the US influence was channelled through Japan with which India has significant trade and economic relations and, most importantly, holds a joint forum specifically to discuss convergence issues. The consequences of India’s links with countries such as US and Japan in the decision-making process provide a vivid indication of the important roles of cross-governmental relationships in the global governance arena, and also question the position of transnational organisations as pervasive powers in such governance. The study’s findings clearly demonstrate that the pursuit of full IFRS convergence strongly favoured by the transnational forces was invariably challenged in the Indian context by the influences of powerful nation states advocating a more cautious approach

Loci influencing blood pressure identified using a cardiovascular gene-centric array

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.</p

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Preparedness of the CTSA's Structural and Scientific Assets to Support the Mission of the National Center for Advancing Translational Sciences (NCATS)

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic and discoveries to clinical practice, ultimately improving the health of the nation. The CTSA sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to C&T science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support

The ion transporter superfamily

AbstractWe define a novel superfamily of secondary carriers specific for cationic and anionic compounds, which we have termed the ion transporter (IT) superfamily. Twelve recognized and functionally defined families constitute this superfamily. We provide statistical sequence analyses demonstrating that these families were in fact derived from a common ancestor. Further, we characterize the 12 families in terms of (1) the known substrates transported, (2) the modes of transport and energy coupling mechanisms used, (3) the family sizes (in numbers of sequenced protein members in the current NCBI database), (4) the organismal distributions of the members of each family, (5) the size ranges of the constituent proteins, (6) the predicted topologies of these proteins, and (7) the occurrence of non-homologous auxiliary proteins that may either facilitate or be required for transport. No member of the superfamily is known to function in a capacity other than transport. Proteins in several of the constituent families are shown to have arisen by tandem intragenic duplication events, but topological variation has resulted from a variety of dissimilar genetic fusion, splicing and insertional events. The evolutionary relationships between the members of each family are defined, leading to predictions of functionally relevant orthologous relationships. Some but not all of the families include functionally dissimilar paralogues that arose by early extragenic duplication events