Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p<10-3) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.1 (rs3846329, p=0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.

The aim of this study was to investigate the diversity and prevalence of non-tuberculous mycobacteria (NTM) in cattle, African buffaloes and their environments in South Africa and the potential of these NTM to elicit cross- reactive immune responses in these animal species which may in turn lead to false diagnosis of bovine tuberculosis. A total of 40 NTM species were identified during a countrywide survey. Mycobacterium terrae, Mycobacterium nonchromogenicum, Mycobacterium vaccae/ Mycobacterium vanbaalenii and a group of isolates closely related to Mycobacterium moriokaense (M. moriokaense-like isolates) were the four most frequently isolated species. Further characterization of M. moriokaense- like isolates revealed two novel NTM species which were named Mycobacterium malmesburii sp.nov. and Mycobacterium komanii sp.nov. respectively. Genomes of M. nonchromogenicum, M. malmesburii sp. nov., M. komanii sp. nov., and M. fortuitum ATCC 6841 were elucidated and investigated for genes encoding homologues of M. bovis predominant immunogenic proteins. These included genes encoding for the Esx family proteins (esx genes), mpb70, mpb63, mpb64, hspX, tpx, Rv1120c, canA and dnaK. The esx gene orthologs encoded in ESX-1 (esxA and esxB), ESX-3 (esxH and esxG), esxR, and ESX-4 (esxT and esxU) loci were identified in the NTM genomes while those encoded in ESX-2 locus were absent in all the four NTM genomes and only esxN (encoded in the ESX-5 locus) and its homologue, esxK were present in M. nonchromogenicum. Gene orthologs encoding for MPB70 (M. malmesburii sp.nov. and M. komanii sp.nov.), DnaK (all four NTM species), CanA (all four NTM species), MPB64 (all four NTM species), Rv1120c (in all four NTM species), TpX, MBP63 and HspX (all in M. nonchromogenicum and M. fortuitum), were found in the NTM genomes. In contrast orthologs of mpb83 and espC were not detected in any of the four NTM. We could not judge just based on the overall protein sequence homologies of the antigens whether the NTM homologues will give rise to cross-reactive immune responses. We consequently checked the existence in NTM of epitopes shown to be immunogenic in M. bovis and M. tuberculosis. Amino acid sequence alignment of the EsxA and EsxB of the NTM sequenced in this study as well as M. smegmatis, M. bovis and M. tuberculosis respectively was done to investigate their similarities at “immunogenic” epitope level. In this analysis, we found that the six bovine T-cell recognized epitopes of M. bovis ESAT-6 described by Vordermeier et al., 2003 and 2007 had similarities to those of M. fortuitum and M. nonchromogenicum (showing sequence similarity of as high as 81.28% and as low as 52.9% ). Likewise a certain degree of sequence similarity between the six M. bovis CFP 10 immunogenic epitopes and those of the NTM species (highest similarity of 75% observed between all NTM and M. bovis and lowest similarity of 50% between M. komanii sp.nov, M. malmesburii sp.nov and M. bovis.) was observed. Still, with sequence homologies of less than 100% between the M. bovis immunogenic epitopes and those of the NTM, it was difficult to unambiguously predict T-cell cross-recognition. Comparison of the EsxR and EsxH amino acid sequences at immunogenic epitope level, revealed higher sequence similarities in the epitopes of NTM and those of M. bovis than the predicted protein sequences of EsxA and EsxB. A sequence similarity of 100% was observed between two of the five M. bovis immunogenic epitopes of EsxR and those of M. fortuitum, M. malmesburii sp. nov. and M. komanii sp.nov. Full cross- recognition of these NTM EsxR epitopes is therefore highly likely, and may lead to misdiagnosis of bovine Tuberculosis (BTB). The other three EsxR/EsxH epitopes shown to be immunogenic in M. bovis also exist in the three NTM showing similarity of as low as 77.7%. / Thesis (PhD)--University of Pretoria, 2015. / WOTRO Science for Global Development / Genomics Research Institute (GRI) / Veterinary Tropical Diseases / PhD / Unrestricted

This dissertation investigates how agricultural trade frictions, such as tariffs and non-tariff measures (NTMs), impact trade competitiveness and globalization in the agricultural sector. The dissertation consists of three chapters. The first chapter argues that agricultural trade cost evolution differs from other sectors due to frequent regulations, standards, and the unique physical characteristics of agricultural products. We measure agricultural trade costs in the 21st century using a three-step estimation procedure based on structural gravity models. Our findings reveal unequal integration of world economies into agricultural trade, with heterogeneous trade costs among countries. Only high-income countries have achieved lower agricultural trade costs between 2001 to 2018. The chapter concludes by demonstrating that while standard country characteristics are important, trade policy tools such as agricultural tariff rates, trade agreements, provisions in deep trade agreements, as well as logistics and infrastructure systems, significantly impact agricultural trade costs. In the second chapter, we assess the impact of non-tariff measures on U.S. agricultural exports as these measures have become increasingly important in global agricultural trade. Despite a vast empirical literature, the universe of NTMs is large and diverse, making it difficult to understand trade and export survival in the face of restrictive non-tariff regulatory measures. Moreover, the sheer number of NTMs collected and notified makes it difficult for researchers to disentangle and quantify measures that are burdensome for exporters from those that are largely inconsequential. In this chapter, we follow a different approach and create an NTM dataset consisting of sanitary and phytosanitary (SPS) measures and technical barriers to trade (TBT) measures from the National Trade Estimate Report of the United States Trade Representative. Using this dataset, we quantify the impact of SPS and TBT measures on U.S. agricultural exports. We find that the existence of NTM measures reduces U.S. agricultural exports by 34%, an effect equivalent to an 8% ad-valorem tariff. Furthermore, we find that these NTMs do not increase the probability of U.S. agricultural exports stopping. In the third chapter, we employ a recently developed method to estimate the border effects of the USA and competitive agricultural exporters to Sub-Saharan Africa (SSA). We use recent advances in structural gravity modeling to estimate international border effects, incorporating intra-national trade. We present the differences in border effects relative to USA exports to the North American Free Trade Agreement (NAFTA) in ad valorem equivalent (AVE) tariffs. Our findings reveal substantial differences in USA agricultural border effects between relatively more integrated NAFTA partners and the SSA region, equivalent to a 43% AVE tariff, while for competitive suppliers, these AVEs range from 3% to 46%. The chapter concludes with a general equilibrium experiment stimulating a 20% reduction in border effects. Results indicate significant increases in SSA's imports, as well as welfare gains for both SSA and partner countries subject to border liberalization, with larger effects observed in SSA countries. / Doctor of Philosophy / This dissertation investigates how agricultural trade frictions, such as tariffs and non-tariff measures (NTMs), impact trade competitiveness and globalization in the agricultural sector. The dissertation consists of three chapters. In the first chapter, we estimate a trade costs dataset and document how agricultural trade costs have evolved in the 21st century. Using this newly created trade costs dataset, we argue that there is an unequal integration of world economies into agricultural trade. We show that trade costs are heterogeneous among countries, with only high-income countries achieving lower agricultural trade costs between 2001 to 2018. In the last section of this chapter, we demonstrate that while standard country characteristics play a significant role, trade policy tools such as agricultural tariff rates, trade agreements, and provisions in deep trade agreements, as well as logistics and infrastructure systems, significantly impact agricultural trade costs. In the second chapter, we assess the impact of non-tariff measures on U.S. agricultural exports. Specifically, we created an NTM dataset consisting of sanitary and phytosanitary (SPS) measures and technical barriers to trade (TBT) measures from the National Trade Estimate Report of the United States Trade Representative. Using this dataset, we quantified the impact of SPS and TBT measures on U.S. agricultural exports. We find that the existence of NTM measures reduces U.S. agricultural exports by 34%, an effect equivalent to an 8% ad-valorem tariff. Furthermore, we find that these NTMs do not increase the probability of U.S. agricultural exports stopping. In the third chapter, we employ a recently developed method to estimate the border effects of the USA and competitive agricultural exporters to Sub-Saharan Africa (SSA). We use recent advances in the structural gravity model to estimate international border effects, incorporating intra-national trade. We present the differences in border effects relative to USA exports to the North American Free Trade Agreement (NAFTA) in ad valorem equivalent (AVE) tariffs. Our findings reveal substantial differences in USA agricultural border effects between relatively more integrated NAFTA partners and the SSA region, equivalent to a 43% AVE tariff, while for competitive suppliers, these AVEs range from 3% to 46%. The chapter concludes with a general equilibrium experiment of a 20% reduction in border effects. Results indicate significant increases in SSA's imports, as well as welfare gains for both SSA and partner countries subject to border liberalization, with larger effects observed in SSA countries.

This thesis comprises a three papers. The chapters stand on their own. Each paper-chapter analyses a specific issue and contains introduction, theoretical framework, methods of analyses, results and findings. Each of the chapters offers new empirical, methodological and modelling contributions with new empirical evidence and findings, with new extensions and specifications for the gravity based and CGE based analytical tools. The thesis reflects my analysis of regional and international trade of Central Asia by analyzing the past economic ties of the CA with former Big Brother , Russia; the present heterogeneity of socio-economic environment of CA countries; and the future development of CA trade relations with the formation of the Eurasian (Re)Union. The Introductory Chapter binds together the other chapters by discussing the general background of the Central Asian institutional formation, transition and trade relations; the research motivations and methodology employed in this thesis. Afterwards come three substantive chapters. In the first chapter, the analysis of enhancing economic relations between Russia and CA in the post-Soviet period contradicts the post-colonial trade erosion theory. In the second chapter, how the open or isolationist policies followed by Central Asian countries affect the performance of local firms and MNEs, and linked to the economic performances of the countries, is investigated. In the third chapter, the impact of deeper Eurasian regional economic integration is assessed quantitatively in the context of asymmetry between the union members and the EU deeper integration project. The final chapter discusses the limitations and possible directions for future research.

Assortative Mating, the tendency for mate selection to occur on the basis of similar traits, plays an essential role in understanding the genetic variation on academic achievements and intelligence (IQ). It is an important mechanism explaining spousal concordance. We used principal component analysis (PCA) for spousal correlation. There is a significant positive correlation between spouses by the new variable PC1 (correlation coefficient=0.515, p<0.0001). We further research the genetic factor that affects IQ by using the same data. We performed a low density genome-wide association (GWA) analysis with a family-based association test to identify genetic variants that associated with intelligence as measured by WAIS full-score IQ (FSIQ). NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.23 (rs3846329, p=0.000675) were 2 novel genes that haven't been associated with IQ from other studies. This study may serve as a resource for replication in other populations and a foundation for future investigations.

The opportunistic environmental microbes, non-tuberculous Mycobacterium (NTM), pose an increasing risk of disease and death in both immunodeficient and immunocompetent individuals in the USA and across the world. NTM lung disease is particularly prevalent in Hawaii, although the modes of NTM acquisition and transport in Hawaii are not fully understood. This study evaluated 149 soil and 50 water samples across the Hawaiian Islands to determine geochemical factors controlling NTM. Non-metric multidimensional scaling (NMDS) and principal component analyses (PCA) of modern soils show variables such as Total Organic Carbon (TOC), pH, P, mafic silicate minerals, and Pb seem to control NTM presence and transition metals and oxides such as TiO2, Zr, and Nb seem to control the absence perhaps due to toxicity. Logistic regression modeling coupled with Kolmogorov-Smirnov testing supported that TOC and P could be used to explain the probability of NTM presence in modern soils. Kolmogorov-Smirnov, non-metric multidimensional scaling, and principal components analysis results suggest poor predictability of NTM presence in soils when evaluating mineralogy alone. The same statistical methods indicated that transition metals appeared to control NTM presence in stream water and major cations and anions seemed to control NTM absence. However, additional bacterial stream data is needed to strengthen this finding. Additionally, an Oahu source water assessment and protection groundwater model was refined by including stream discharge data, including losses to the aquifer. NTM inhabits many environmental niches, although little is understood regarding the transport of NTM from the environment to indoor plumbing. However, transport from surface water to water-supply aquifers is likely important. This study analyzes groundwater flow from stream losses as a mechanism of NTM transport to water supplies. An updated MODFLOW groundwater model was developed for the north-east Oahu, Waimea River drainage. Results show hundreds of meters of lateral and tens of meters of vertical transport of NTM in 1-3 months. Additionally, geochemical modeling with Geochemist’s Workbench showed Fe oxy/hydroxides oversaturated in 100% of streams. Fe oxy/hydroxide affixed to NTM would potentially satisfy NTM’s preference for attachment and allow for colloidal transport through the aquifer.

No description available.

Yes / Background: Tuberculosis (TB) is the highest-mortality infectious disease in the world and the main cause of death related to antimicrobial resistance, yet its surveillance is still paper-based. Rifampicin-resistant TB (RR-TB) is an urgent public health crisis. The World Health Organization has, since 2010, endorsed a series of rapid diagnostic tests (RDTs) that enable rapid detection of drug-resistant strains and produce large volumes of data. In parallel, most high-burden countries have adopted connectivity solutions that allow linking of diagnostics, real-time capture, and shared repository of these test results. However, these connected diagnostics and readily available test results are not used to their full capacity, as we have yet to capitalize on fully understanding the relationship between test results and specific rpoB mutations to elucidate its potential application to real-time surveillance. Objective: We aimed to validate and analyze RDT data in detail, and propose the potential use of connected diagnostics and associated test results for real-time evaluation of RR-TB transmission. Methods: We selected 107 RR-TB strains harboring 34 unique rpoB mutations, including 30 within the rifampicin resistance–determining region (RRDR), from the Belgian Coordinated Collections of Microorganisms, Antwerp, Belgium. We subjected these strains to Xpert MTB/RIF, GenoType MTBDRplus v2.0, and Genoscholar NTM + MDRTB II, the results of which were validated against the strains’ available rpoB gene sequences. We determined the reproducibility of the results, analyzed and visualized the probe reactions, and proposed these for potential use in evaluating transmission. Results: The RDT probe reactions detected most RRDR mutations tested, although we found a few critical discrepancies between observed results and manufacturers’ claims. Based on published frequencies of probe reactions and RRDR mutations, we found specific probe reactions with high potential use in transmission studies: Xpert MTB/RIF probes A, Bdelayed, C, and Edelayed; Genotype MTBDRplus v2.0 WT2, WT5, and WT6; and Genoscholar NTM + MDRTB II S1 and S3. Inspection of probe reactions of disputed mutations may potentially resolve discordance between genotypic and phenotypic test results. Conclusions: We propose a novel approach for potential real-time detection of RR-TB transmission through fully using digitally linked TB diagnostics and shared repository of test results. To our knowledge, this is the first pragmatic and scalable work in response to the consensus of world-renowned TB experts in 2016 on the potential of diagnostic connectivity to accelerate efforts to eliminate TB. This is evidenced by the ability of our proposed approach to facilitate comparison of probe reactions between different RDTs used in the same setting. Integrating this proposed approach as a plug-in module to a connectivity platform will increase usefulness of connected TB diagnostics for RR-TB outbreak detection through real-time investigation of suspected RR-TB transmission cases based on epidemiologic linking. / KCN was supported by Erasmus Mundus Joint Doctorate Fellowship grant 2016-1346, and BCdJ, LR, and CJM were supported by European Research Council-INTERRUPTB starting grant 311725.

The treatment of tuberculosis (TB) is currently a challenge due to multi- and extensively drug resistant strains of Mycobacterium tuberculosis. Mycobacterium bovis and M. tuberculosis cause clinically indistinguishable tuberculosis in humans. Both M. bovis and M. tuberculosis have been isolated from humans and animals. Plant species contain antimicrobial compounds that may lead to new anti-TB drugs. To conduct in vitro antimycobacterial assays, it is important to include current clinical isolates as new strains of bacteria might be circulating under the ongoing climate change environment. The overall goal and objectives of this study were to isolate and characterize mycobacteria species from South Africa, to test some selected plant species of the Anacardiaceae family for antimycobacterial activity using some of the newly isolated and reference strains of mycobacteria followed by cytotoxicity evaluation of the most active plant species, and finally the isolation and characterization of at least one compound from the most active and least toxic plant. This study led to the discovery of a new isolate of Mycobacterium Avium Complex species from black wildebeest. Other non-tuberculous mycobacteria and M. bovis isolates were identified from other animal species. Five out of 15 plant species screened showed good activity against Mycobacterium species. Five antimycobacterial compounds were isolated from Searsia undulata, the most active plant species. Two out of the five compounds were identified, and one compound appears to be novel, but both compounds have been isolated for the first time from Searsia undulata. An incidental finding was the potential anticancer property of extracts of Searsia undulata. Recommended future activities include isolation and identification of more active compounds from Searsia undulata which were visible in bioautography analysis, as well as synergy evaluation of antimycobacterial activities of the different compounds with current anti-tubercular drugs. / Environmental Sciences / Ph. D. (Environmental Science)