Modeling Human Genetic Variation in Non-Coding DNA in Humanized Mice

The increasing availability of sequencing data from genome-wide association studies and whole genome sequencing of the human genome has enabled rapid identification of genetic variations—mainly single nucleotide polymorphisms (SNPs)— in non-coding DNA of the human genome. However, it has been difficult to find the biological functions of the numerous SNPs in the genome. This gap in knowledge can be explained in part by our poor understanding of the function of non-coding DNA, and by the challenge of experimentally assigning function to SNPs that map to these non-coding regions. To clearly define the function of non-coding SNPs, we created genetically humanized mice to model human genetic variation in non-coding DNA in vivo. To generate the mice, we used a bacterial artificial chromosome (BAC) system harboring two genetically different human IL10 SNP haplotypes. The IL10 SNP haplotypes are “ATA” and “GCC,” which have been associated with differential IL-10 levels and disease susceptibility in humans. We found a robust allele-specific human IL-10 expression in both macrophages and CD4+ T cells. Specifically, GCC-hIL10BAC encodes for a high human IL-10 level relative to ATA-hIL10BAC in CD4+ T cells both in vitro and in vivo. The reverse was observed in macrophages. Accordingly, by complementing Il10 null mice with the GCC-hIL10BAC, namely Il10-/-/GCC-hIL10BAC mice, we were able to completely reverse disease outcome. The Il10-/-/GCC-hIL10BAC mice were susceptible to persistent leishmania infection as evidenced by a high parasite burden in the liver and spleen. In contrast, like Il10 null mice, the Il10-/-/ATA-hIL10BAC mice were refractory to disease. Therefore, our data demonstrate that human IL10 promoter SNP haplotypes alone can modulate IL-10 levels and disease risk. In the second part of this dissertation, we examined the regulation of IL-10 and its homolog, IL-24, as a means to indirectly demonstrate that we are not missing important regulatory elements within the hIL10BAC. We chose IL-24 from the remaining cytokines within the Il10 gene cluster because the gene encoding for IL-24 is localized at the extreme end of the Il10 locus in both mouse and man and also human IL24 gene is not included in the hIL10BAC. Thus, finding co-regulation of IL-10 and IL-24 expression would suggest that the two homologs share common regulatory elements. Interestingly, we found that IL-10 and IL-24 are regulated by distinct cell-type-specific regulatory pathways. Optimal IL-24 expression requires Stat6 and Stat4 in macrophages and NK cells; meanwhile, IL-10 expression is independent of Stat6 and dependent on Stat4 only in IL-12-treated NK cells. We also discovered an unexpected role for Type-I Interferons in mediating differential regulation of IL-10 and IL-24 expression in macrophages and NK cells. Thus, our results suggest that IL-24 and IL-10 are unlikely to share common regulatory elements within the Il10 locus. Altogether, our results undoubtedly demonstrate that we can model human genetic variation in non-coding DNA in vivo using genetically humanized hIL10BAC mice. In the future, the hIL10BAC approach can be extended to other human genes to accelerate rational development of safe and efficient personalized therapies, including vaccines

Poverty Trends and Determinants in Mali from 2001 to 2006

This paper analyzes the trend in, and determinants of poverty in Mali from 2001 and 2006. Thanks to strong economic growth, poverty has been reduced. Yet due to demographic growth, the number of the poor is still increasing. Households working in agriculture, especially in the cotton producing area of Sikasso, suffer from higher rates of poverty. Other household characteristics also affect consumption levels and thereby poverty.Poverty; Mali

Tendance, profil et déterminants de la pauvreté au Mali de 2001 à 2006

This paper analyzes the trend in, and determinants of poverty in Mali from 2001 and 2006. Thanks to strong economic growth, poverty has been reduced. Yet due to demographic growth, the number of the poor is still increasing. Households working in agriculture, especially in the cotton producing area of Sikasso, suffer from higher rates of poverty. Other household characteristics also affect consumption levels and thereby poverty

Tendance, profil et déterminants de la pauvreté au Mali de 2001 à 2006

This paper analyzes the trend in, and determinants of poverty in Mali from 2001 and 2006. Thanks to strong economic growth, poverty has been reduced. Yet due to demographic growth, the number of the poor is still increasing. Households working in agriculture, especially in the cotton producing area of Sikasso, suffer from higher rates of poverty. Other household characteristics also affect consumption levels and thereby poverty

A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali.

BACKGROUND: Drug resistance is one of the greatest challenges of malaria control programme in Mali. Recent advances in next-generation sequencing (NGS) technologies provide new and effective ways of tracking drug-resistant malaria parasites in Africa. The diversity and the prevalence of Plasmodium falciparum drug-resistance molecular markers were assessed in Dangassa and Nioro-du-Sahel in Mali, two sites with distinct malaria transmission patterns. Dangassa has an intense seasonal malaria transmission, whereas Nioro-du-Sahel has an unstable and short seasonal malaria transmission. METHODS: Up to 270 dried blood spot samples (214 in Dangassa and 56 in Nioro-du-Sahel) were collected from P. falciparum positive patients in 2016. Samples were analysed on the Agena MassARRAY® iPLEX platform. Specific codons were targeted in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps, Pfarps10, Pfferredoxin, Pfexonuclease and Pfmdr2 genes. The Sanger's 101-SNPs-barcode method was used to assess the genetic diversity of P. falciparum and to determine the parasite species. RESULTS: The Pfcrt_76T chloroquine-resistance genotype was found at a rate of 64.4% in Dangassa and 45.2% in Nioro-du-Sahel (p = 0.025). The Pfdhfr_51I-59R-108N pyrimethamine-resistance genotype was 14.1% and 19.6%, respectively in Dangassa and Nioro-du-Sahel. Mutations in the Pfdhps_S436-A437-K540-A581-613A sulfadoxine-resistance gene was significantly more prevalent in Dangassa as compared to Nioro-du-Sahel (p = 0.035). Up to 17.8% of the isolates from Dangassa vs 7% from Nioro-du-Sahel harboured at least two codon substitutions in this haplotype. The amodiaquine-resistance Pfmdr1_N86Y mutation was identified in only three samples (two in Dangassa and one in Nioro-du-Sahel). The lumefantrine-reduced susceptibility Pfmdr1_Y184F mutation was found in 39.9% and 48.2% of samples in Dangassa and Nioro-du-Sahel, respectively. One piperaquine-resistance Exo_E415G mutation was found in Dangassa, while no artemisinin resistance genetic-background were identified. A high P. falciparum diversity was observed, but no clear genetic aggregation was found at either study sites. Higher multiplicity of infection was observed in Dangassa with both COIL (p = 0.04) and Real McCOIL (p = 0.02) methods relative to Nioro-du-Sahel. CONCLUSIONS: This study reveals high prevalence of chloroquine and pyrimethamine-resistance markers as well as high codon substitution rate in the sulfadoxine-resistance gene. High genetic diversity of P. falciparum was observed. These observations suggest that the use of artemisinins is relevant in both Dangassa and Nioro-du-Sahel

Expanding Research Capacity in Sub-Saharan Africa Through Informatics, Bioinformatics, and Data Science Training Programs in Mali

Bioinformatics and data science research have boundless potential across Africa due to its high levels of genetic diversity and disproportionate burden of infectious diseases, including malaria, tuberculosis, HIV and AIDS, Ebola virus disease, and Lassa fever. This work lays out an incremental approach for reaching underserved countries in bioinformatics and data science research through a progression of capacity building, training, and research efforts. Two global health informatics training programs sponsored by the Fogarty International Center (FIC) were carried out at the University of Sciences, Techniques and Technologies of Bamako, Mali (USTTB) between 1999 and 2011. Together with capacity building efforts through the West Africa International Centers of Excellence in Malaria Research (ICEMR), this progress laid the groundwork for a bioinformatics and data science training program launched at USTTB as part of the Human Heredity and Health in Africa (H3Africa) initiative. Prior to the global health informatics training, its trainees published first or second authorship and third or higher authorship manuscripts at rates of 0.40 and 0.10 per year, respectively. Following the training, these rates increased to 0.70 and 1.23 per year, respectively, which was a statistically significant increase (p < 0.001). The bioinformatics and data science training program at USTTB commenced in 2017 focusing on student, faculty, and curriculum tiers of enhancement. The program’s sustainable measures included institutional support for core elements, university tuition and fees, resource sharing and coordination with local research projects and companion training programs, increased student and faculty publication rates, and increased research proposal submissions. Challenges reliance of high-speed bandwidth availability on short-term funding, lack of a discounted software portal for basic software applications, protracted application processes for United States visas, lack of industry job positions, and low publication rates in the areas of bioinformatics and data science. Long-term, incremental processes are necessary for engaging historically underserved countries in bioinformatics and data science research. The multi-tiered enhancement approach laid out here provides a platform for generating bioinformatics and data science technicians, teachers, researchers, and program managers. Increased literature on bioinformatics and data science training approaches and progress is needed to provide a framework for establishing benchmarks on the topics

Tendance, profil et déterminants de la pauvreté au Mali de 2001 à 2006

Cette étude analyse les tendances récentes de la pauvreté au Mali sur la période 2001-2006 et présente un profil de la pauvreté et une analyse de ses déterminants pour 2006. Grâce à la croissance économique enregistrée au cours des dernières années, la pauvreté recule. Cependant, suite à la croissance démographique, le nombre de personnes pauvres augmente. Les ménages engagés dans l’agriculture et notamment dans la production de coton dans la région de Sikasso sont parmi les plus pauvres. A l’opposé, les ménages dirigés par un salarié (surtout du secteur public) et les indépendants (employeurs et chefs de ménage travaillant pour compte propre) sont moins pauvres. La composition du ménage, le niveau d’éducation du chef de ménage et du conjoint, les caractéristiques de l’emploi du chef de ménage sont autant de variables corrélées à la dépense par tête du ménage et ayant donc un impact sur la probabilité d’être pauvre.