13 research outputs found
Etude structurale des aptamères peptidiques anti-Fur et de leur interaction avec leur cible
No full textFur (Ferric Uptake Regulator) is a transcriptional regulator involved in the control of iron homeostasis. Specific to bacteria, Fur is an attractive antibacterial target. Before my arrival in the laboratory, four inhibitors interacting specifically with Fur had been isolated. The active part of these inhibitors consists of peptides of 13 amino acids. In this thesis I have used both theoretical and experimental approaches to study interactions of these peptides with Fur in order to understand the inhibition mechanism. I have synthesized several peptide sequences, shown through biochemical assays that some of them could inhibit Fur and I have identified residues important to the inhibitory activity. I‘ve obtained theoretical models of Fur/peptide complexes consistent with experimental results, which reveal an inhibition pocket in Fur. Small molecules have then been selected though In silico screening of this pocket, that could potentially inhibit Fur, and thus be interesting for therapeutic applications.Fur (Ferric Uptake Regulator) est un régulateur transcriptionnel spécifique des bactéries qui intervient dans le contrôle de l'homéostasie du fer, ce qui en fait une cible antibactérienne intéressante. Avant mon arrivée au laboratoire, quatre inhibiteurs interagissant spécifiquement avec Fur avaient été isolés. La partie active de ces inhibiteurs consiste en des peptides de 13 acides aminés. Au cours de cette thèse, j'ai utilisé une double-approche : théorique et expérimentale pour étudier l'interaction de ces peptides avec Fur afin de comprendre le mécanisme d'inhibition. J'ai synthétisé plusieurs séquences peptidiques, montré par des tests biochimiques que certaines inhibaient Fur et déterminé les interactions importantes à l'activité inhibitrice. J'ai obtenu des modèles théoriques des complexes Fur/peptides par amarrage moléculaire, cohérents avec les résultats expérimentaux, qui ont mis en évidence une zone d'inhibition de Fur. Des criblages in silico dans cette zone ont permis de sélectionner de petites molécules, inhibitrices potentielles de Fur et donc intéressantes pour des applications thérapeutiques
Structural study of anti-Fur peptide aptamers and their interactions with their target
No full textFur (Ferric Uptake Regulator) est un régulateur transcriptionnel spécifique des bactéries qui intervient dans le contrôle de l'homéostasie du fer, ce qui en fait une cible antibactérienne intéressante. Avant mon arrivée au laboratoire, quatre inhibiteurs interagissant spécifiquement avec Fur avaient été isolés. La partie active de ces inhibiteurs consiste en des peptides de 13 acides aminés. Au cours de cette thèse, j'ai utilisé une double-approche : théorique et expérimentale pour étudier l'interaction de ces peptides avec Fur afin de comprendre le mécanisme d'inhibition. J'ai synthétisé plusieurs séquences peptidiques, montré par des tests biochimiques que certaines inhibaient Fur et déterminé les interactions importantes à l'activité inhibitrice. J'ai obtenu des modèles théoriques des complexes Fur/peptides par amarrage moléculaire, cohérents avec les résultats expérimentaux, qui ont mis en évidence une zone d'inhibition de Fur. Des criblages in silico dans cette zone ont permis de sélectionner de petites molécules, inhibitrices potentielles de Fur et donc intéressantes pour des applications thérapeutiques.Fur (Ferric Uptake Regulator) is a transcriptional regulator involved in the control of iron homeostasis. Specific to bacteria, Fur is an attractive antibacterial target. Before my arrival in the laboratory, four inhibitors interacting specifically with Fur had been isolated. The active part of these inhibitors consists of peptides of 13 amino acids. In this thesis I have used both theoretical and experimental approaches to study interactions of these peptides with Fur in order to understand the inhibition mechanism. I have synthesized several peptide sequences, shown through biochemical assays that some of them could inhibit Fur and I have identified residues important to the inhibitory activity. I‘ve obtained theoretical models of Fur/peptide complexes consistent with experimental results, which reveal an inhibition pocket in Fur. Small molecules have then been selected though In silico screening of this pocket, that could potentially inhibit Fur, and thus be interesting for therapeutic applications
Etude structurale des aptamères peptidiques anti-Fur et de leur interaction avec leur cible
No full textFur (Ferric Uptake Regulator) is a transcriptional regulator involved in the control of iron homeostasis. Specific to bacteria, Fur is an attractive antibacterial target. Before my arrival in the laboratory, four inhibitors interacting specifically with Fur had been isolated. The active part of these inhibitors consists of peptides of 13 amino acids. In this thesis I have used both theoretical and experimental approaches to study interactions of these peptides with Fur in order to understand the inhibition mechanism. I have synthesized several peptide sequences, shown through biochemical assays that some of them could inhibit Fur and I have identified residues important to the inhibitory activity. I‘ve obtained theoretical models of Fur/peptide complexes consistent with experimental results, which reveal an inhibition pocket in Fur. Small molecules have then been selected though In silico screening of this pocket, that could potentially inhibit Fur, and thus be interesting for therapeutic applications.Fur (Ferric Uptake Regulator) est un régulateur transcriptionnel spécifique des bactéries qui intervient dans le contrôle de l'homéostasie du fer, ce qui en fait une cible antibactérienne intéressante. Avant mon arrivée au laboratoire, quatre inhibiteurs interagissant spécifiquement avec Fur avaient été isolés. La partie active de ces inhibiteurs consiste en des peptides de 13 acides aminés. Au cours de cette thèse, j'ai utilisé une double-approche : théorique et expérimentale pour étudier l'interaction de ces peptides avec Fur afin de comprendre le mécanisme d'inhibition. J'ai synthétisé plusieurs séquences peptidiques, montré par des tests biochimiques que certaines inhibaient Fur et déterminé les interactions importantes à l'activité inhibitrice. J'ai obtenu des modèles théoriques des complexes Fur/peptides par amarrage moléculaire, cohérents avec les résultats expérimentaux, qui ont mis en évidence une zone d'inhibition de Fur. Des criblages in silico dans cette zone ont permis de sélectionner de petites molécules, inhibitrices potentielles de Fur et donc intéressantes pour des applications thérapeutiques
Etude structurale des aptamères peptidiques anti-Fur et de leur interaction avec leur cible
No full textFur (Ferric Uptake Regulator) est un régulateur transcriptionnel spécifique des bactéries qui intervient dans le contrôle de l'homéostasie du fer, ce qui en fait une cible antibactérienne intéressante. Avant mon arrivée au laboratoire, quatre inhibiteurs interagissant spécifiquement avec Fur avaient été isolés. La partie active de ces inhibiteurs consiste en des peptides de 13 acides aminés. Au cours de cette thèse, j'ai utilisé une double-approche : théorique et expérimentale pour étudier l'interaction de ces peptides avec Fur afin de comprendre le mécanisme d'inhibition. J'ai synthétisé plusieurs séquences peptidiques, montré par des tests biochimiques que certaines inhibaient Fur et déterminé les interactions importantes à l'activité inhibitrice. J'ai obtenu des modèles théoriques des complexes Fur/peptides par amarrage moléculaire, cohérents avec les résultats expérimentaux, qui ont mis en évidence une zone d'inhibition de Fur. Des criblages in silico dans cette zone ont permis de sélectionner de petites molécules, inhibitrices potentielles de Fur et donc intéressantes pour des applications thérapeutiques.Fur (Ferric Uptake Regulator) is a transcriptional regulator involved in the control of iron homeostasis. Specific to bacteria, Fur is an attractive antibacterial target. Before my arrival in the laboratory, four inhibitors interacting specifically with Fur had been isolated. The active part of these inhibitors consists of peptides of 13 amino acids. In this thesis I have used both theoretical and experimental approaches to study interactions of these peptides with Fur in order to understand the inhibition mechanism. I have synthesized several peptide sequences, shown through biochemical assays that some of them could inhibit Fur and I have identified residues important to the inhibitory activity. I ve obtained theoretical models of Fur/peptide complexes consistent with experimental results, which reveal an inhibition pocket in Fur. Small molecules have then been selected though In silico screening of this pocket, that could potentially inhibit Fur, and thus be interesting for therapeutic applications.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF
Understanding and evaluating environmental costs of manufacturing: The industrial management perspectives
No full textIt is noted that the collection, processing, recycling, and disposal of manufacturing-generated waste presents a significant engineering problem and a new major challenge to industrial engineers and managers. The author attempts to make industrial engineers and managers recognize that, in today\u27s manufacturing, environmental-related waste avoidance and other considerations are very much among the key determinants of the success and failure of an enterprise. Thus, an effort is made to improve the thinking of these professionals and to provide a first step toward an integrated approach based on IE and EM principles in dealing with environmental costs and related problems, and for including these in a manufacturing program for actions
Pathways, outputs and impact of NIH-supported bioinformatics and genomics graduate trainees in Africa
No full textGlobal biomedical and health research is increasingly relying on genomic and computational approaches, largely driven by the increasing volumes of nucleic acid sequencing. Concurrently, epidemiological studies and clinical records are generating enormous amounts of data amenable to disease modeling, machine learning, and artificial intelligence techniques. Bioinformatics and data science expertise is therefore essential for improved population health. Accordingly, in 2012, the US National Institutes of Health (NIH) in partnership with the Wellcome Trust, and with support from the African Society for Human Genetics, initiated the H3Africa (Human Heredity and Health in Africa) consortium. One of its key goals was to build capacity among African scientists to lead research on genetic and environmental contributors to health and disease across the continent. In 2017, the NIH provided funding to support the establishment of four graduate bioinformatics training programs across five African universities. Over seven years, these programs enrolled multiple trainees (n > 270), with >110 earning Master’s degrees and >20 completing PhDs in Bioinformatics. It is thus timely to evaluate the outcomes and impact of these programs, particularly regarding graduation rates, career trajectories, and the institutions and research domains their alumni are serving. We also assess employment outcomes and the nature of the research they are enabling (n > 110 peer-reviewed articles). We additionally include the progress and outputs of the programs’ instructors, which were partially enabled by program resources, networks, and trainees. Overall, this review paints valuable insights into the pioneering role of NIH extramural support in shaping Africa’s biomedical research landscape
PfDHFR Resistance Mutations in Mali: Impact on Protein Structure and Identification of Novel Natural Inhibitors
No full textMalaria drug resistance remains one of the greatest challenges to the malaria control program in Mali. Mutation in the Plasmodium falciparum Dihydrofolate Reductase (PfDHFR), a key enzyme in the folate biosynthesis pathway and primary target of antifolate drugs, are knows to induces resistance to pyrimethamine and Proguanil. Four-point mutations: N51I, C59R, S108N, and I164L are particularly associated with antifolate resistance. This study aims to characterize resistance-associated PfDHFR mutations circulating in three sentinel sites in Mali (Dioro, Missira, and Sélingué) and identify potential inhibitors effective against mutant PfDHFR variants through virtual screening of African natural compound libraries.
A total of 47 Pfdhfr were analyzed to identify Single-Nucleotide Polymorphisms (SNPs) using Geneious Prime. Homology-based 3D protein structures of mutant PfDHFR using PRIMO server, and structural visualization as well as molecular analyses were performed using UCSF Chimera and AutoDock vina.
Among the 47 PfDHFR sequences analyzed, 22 exhibited the triple mutations N51I, C59R, and S108N, will the I164L mutation was absent in all samples across the three sentinel sites. Structural modeling of these mutants revealed restricted access and crowding in the PfDHFR active site, consistent with known antifolate resistance mechanisms. Virtual screening identified several promising inhibitors, among which compound SANC00747 exhibiting exceptional binding affinity (-14.046 kcal/mol), highlighting the potential of African natural products as resistance-breaking candidates.
This study demonstrates the prevalence of key antifolate-resistance mutations in Mali and reveals promising natural compounds capable of effectively targeting mutant PfDHFR. These findings underscore the value of African natural products as a rich reservoir for developing next-generation antimalarial therapies
Microbiome Responses to RYMV Infection: Insights from Rice Cultivation in Mali
No full textBackground: The Rice Yellow Mottle Virus (RYMV) is one of the most significant viral pathogens affecting rice production in Sub-Saharan Africa, leading to yield losses as high as 100% in severely affected areas. In Mali, particularly in the Office du Niger region, RYMV poses a constant threat to rice cultivation. This study aimed to explore the microbiome diversity associated with RYMV-infected and non-infected rice plants, using next-generation sequencing (NGS) and metagenomics approaches. The presence of RYMV was confirmed by RT-PCR, and microbial DNA was extracted for sequencing.
Results: A total of 40 samples (leaves and roots) were collected from both infected and non-infected plants. The results revealed alterations in bacterial community composition between infected and non-infected plants. Alpha diversity indices, such as Shannon and Simpson indicated reduced microbial diversity in infected plants. Notably, certain bacterial genera, including Bacillus, Pseudomonas, and Kaistobacter, were statistically more abundant in non-infected plants, suggesting their potential role in conferring resistance to RYMV.
Conclusions: This study provided new insights into the microbial dynamics associated with RYMV infection and highlights the potential for leveraging the rice microbiome in developing biocontrol strategies to manage viral diseases. Future research should focus on isolating and characterizing the functional roles of these beneficial microorganisms in enhancing rice resistance to RYMV. That will serve for sustainable agriculture strategies development
Prioritisation of Promising Therapeutic Targets in Plasmodium falciparum Using in Silico Multi Criteria Scoring
No full textBackground: Malaria remains one of the deadliest infectious diseases globally, causing over 597,000 deaths each year, with Plasmodium falciparum (Pf) responsible for the most severe cases. Sub-Saharan Africa remains the most affected region of the world, the region hosting more than 90% of the global burden of P. falciparum. Despite years of research, drug resistance continues to emerge, underscoring the urgent need for new therapeutic targets.
Aim: The aim of this study is to identify promising therapeutic targets in Plasmodium falciparum using advanced in silico approaches. This study focuses particularly on the intraerythrocytic stage of the parasite\u27s life cycle, which is critical for its survival and proliferation.
Methodology: A comprehensive bioinformatics approach was employed, integrating data mining and extensive database analyses to efficiently streamline the drug discovery pipeline and pinpoint vital therapeutic targets in Plasmodium falciparum. Analyses were carried out from January to June 2022 at the African Centre of Excellence in Bioinformatics (ACE-Mali), using data from the TDR Targets database and advanced bioinformatics tools. The WHO validated TDR Targets database was used to extract Plasmodium falciparum proteins likely to be therapeutic targets, applying strict criteria such as strong expression during the intra-erythrocytic stage, lack of human orthologs, essentiality, druggability score and bibliographic support. This candidate list has been refined using an in-house scoring system combining bioinformatics analyses, taking into account criteria such as the presence of transmembrane helices, sequence identity, and conservation. Each criterion was scored from 0 to 3 and summed into an overall prioritisation score to systematically rank proteins.
Results: The study identified sixteen potential therapeutic targets, with five of them: Adenylate kinase, P. falciparum Chloroquine Resistance Transporter (PfCRT), AdenyloSuccinate Lyase (ADSL), PhosphatidylSerine Decarboxylase (PSD), and Protein Disulfide Isomerase (PDI), highlighted as highly promising. These key proteins are involved in essential processes such as invasion, replication, and immune evasion of the malaria parasite.
Conclusion: This study identified sixteen potential therapeutic targets against malaria, with Adenylate kinase, PfCRT, ADSL, PSD, and PDI standing out as particularly promising. These targets may contribute to overcoming drug resistance and support global eradication efforts. The findings highlight the power of in silico approaches in accelerating drug discovery and target validation
Meta-Analysis and Multivariate GWAS Analyses in 80,950 Individuals of African Ancestry Identify Novel Variants Associated with Blood Pressure Traits
No full textHigh blood pressure (HBP) has been implicated as a major risk factor for cardiovascular diseases in several populations, including individuals of African ancestry. Despite the elevated burden of HBP-induced cardiovascular diseases in Africa and other populations of African descent, limited genetic studies have been carried out to explore the genetic mechanism driving this phenomenon. We performed genome-wide association univariate and multivariate analyses of both systolic (SBP) and diastolic blood pressure (DBP) traits in 80,950 individuals of African ancestry. We used summary statistics data from six independent cohorts, including the African Partnership for Chronic Disease Research (APCDR), the UK Biobank, and the Million Veteran Program (MVP). FUMA was used to annotate, prioritize, visualize, and interpret our findings to gain a better understanding of the molecular mechanism(s) underlying the genetics of BP traits. Finally, we undertook a Bayesian fine-mapping analysis to identify potential causal variants. Our meta-analysis identified 10 independent variants associated with SBP and 9 with DBP traits. Whilst our multivariate GWAS method identified 21 independent signals, 18 of these SNPs have been previously identified. SBP was linked to gene sets involved in biological processes such as synapse assembly and cell–cell adhesion via plasma membrane adhesion. Of the 19 independent SNPs identified in the BP meta-analysis, only 11 variants had posterior probability (PP) of > 50%, including one novel variant: rs562545 (MOBP, PP = 77%). To facilitate further research and fine-mapping of high-risk loci/variants in highly susceptible groups for cardiovascular disease and other related traits, large-scale genomic datasets are needed. Our findings highlight the importance of including ancestrally diverse populations in large GWASs and the need for diversity in genetic research
