scholarly journals Structural Dynamics and Perspectives of Vitamin B6 Biosynthesis Enzymes in Plasmodium: Advances and Open Questions

2021 ◽  
Vol 11 ◽  
Author(s):  
Angélica Luana C. Barra ◽  
Najeeb Ullah ◽  
Luana G. Morão ◽  
Carsten Wrenger ◽  
Christian Betzel ◽  
...  
Keyword(s):  
De Novo ◽  
Sub Saharan Africa ◽  
Catalytic Center ◽  
Design And Optimization ◽  
Substrate Analogs ◽  
Drug Candidates ◽  
Treatment And Prevention ◽  
Open Questions ◽  
Sub Saharan ◽  
Suicide Inhibitors

Malaria is still today one of the most concerning diseases, with 219 million infections in 2019, most of them in Sub-Saharan Africa and Latin America, causing approx. 409,000 deaths per year. Despite the tremendous advances in malaria treatment and prevention, there is still no vaccine for this disease yet available and the increasing parasite resistance to already existing drugs is becoming an alarming issue globally. In this context, several potential targets for the development of new drug candidates have been proposed and, among those, the de novo biosynthesis pathway for the B6 vitamin was identified to be a promising candidate. The reason behind its significance is the absence of the pathway in humans and its essential presence in the metabolism of major pathogenic organisms. The pathway consists of two enzymes i.e. Pdx1 (PLP synthase domain) and Pdx2 (glutaminase domain), the last constituting a transient and dynamic complex with Pdx1 as the prime player and harboring the catalytic center. In this review, we discuss the structural biology of Pdx1 and Pdx2, together with and the understanding of the PLP biosynthesis provided by the crystallographic data. We also highlight the existing evidence of the effect of PLP synthesis inhibition on parasite proliferation. The existing data provide a flourishing environment for the structure-based design and optimization of new substrate analogs that could serve as inhibitors or even suicide inhibitors.

Sub-Saharan Africa's orphan crisis

2008 ◽  
Vol 51 (5) ◽  
pp. 682-698 ◽  
Author(s):  
Margaret Lombe ◽  
Alex Ochumbo
Keyword(s):  
Community Capacity ◽  
Sub Saharan Africa ◽  
Institutional Characteristics ◽  
Vulnerable Children ◽  
Multifaceted Approach ◽  
Number Of Children ◽  
Current Discussion ◽  
Treatment And Prevention ◽  
Sub Saharan

English The dramatic increase in the number of children made vulnerable by AIDS in sub-Saharan Africa has necessitated research in treatment and prevention. We contribute to the current discussion on the orphan crisis by proposing a multifaceted approach utilizing institutional characteristics, with greater potential to strengthen community capacity and empower vulnerable children. French L'accroissement phénoménal des enfants vulnérabilisés par le SIDA en Afrique sub-saharienne a eu pour effet de stimuler la recherche en matière de traitements et de prévention. Cette étude s'inscrit dans la réflexion courante sur la crise des orphelinats et propose une approche multidimensionnelle qui tire parti des caractéristiques institutionnelles tout en renforçant les capacités des communautés et en redonnant davantage du pouvoir aux enfants vulnérables. Spanish El dramático incremento en el número de niños que se han hecho vulnerables por el SIDA, en el África Subsahariana, ha hecho necesaria la investigación en tratamiento y prevención. Nosotros aportamos a la discusión actual sobre la crisis de huérfanos, proponiendo un acercamiento multifacético, utilizando las características institucionales con mayor potencial para fortalecer la capacidad comunitaria y empoderar a los niños vulnerables.

scholarly journals Phylogenetic relationships of endornaviruses in common bean from the western highlands of Kenya and global sequences

2018 ◽  
Author(s):  
James M Wainaina ◽  
Elijah Ateka ◽  
Timothy Makori ◽  
Monica A Kehoe ◽  
Laura M Boykin
Keyword(s):  
Phaseolus Vulgaris ◽  
Complete Genome ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Evolutionary Relationship ◽  
Sub Saharan Africa ◽  
Complete Genomes ◽  
Sub Saharan

Background: Endornaviruses are non-pathogenic viruses infecting multiple agricultural important crops including legumes, with global distribution. However, there is an absence on the complete genome of endornaviruses from legumes in particular with the sub-Saharan region. In this study, we report the first complete genomes of PvEV1 and PvEV2, and the evolutionary relationship of these genomes. Methods: Viral symptomatic common beans (Phaseolus vulgaris) showing Bean common mosaic necrosis virus (BCMNV) symptoms from Vihiga county, in the western highlands of Kenya were collected during field survey’s in the region. High throughput sequencing (RNA-Seq) was carried out on total RNA isolated from symptomatic leaf samples. Subsequently, de novo assembly and reference mapping was carried out to obtain the complete genomes of PvEV-1 and PvEV-2. Results: We identified the complete genome of Phaseolus vulgaris endornavirus 1 and 2 (PvEV-1 and PvEV-2) from sub-Saharan Africa (SSA). The average genome size of PvEV-1 was ~13,890 nucleotides (nt) while PvEV-2 was ~14,698 nt, encoding a single open reading frame (ORF). Single ORFs ranged from 4,632 to 4,633 aa in PvEV-1 and from 4,899 – to 4,954 aa in PvEV-2. Both ORFs encoded for the RNA-dependent RNA polymerase (RdRP) gene. The percentage sequence similarity between PvEV-1, PvEV-2 from this study GenBanks sequences was 29 % to 99 %. Bayesian phylogenetic analysis resolved in two well-supported monophyletic clades, with isolates from this study clustering with those from Brazil sequences. Discussion: This study provides the first insights into the evolutionary relationships of PvEV from SSA diverse and contributes towards filling the current knowledge gaps on endornaviruses

scholarly journals Phylogenetic relationships of endornaviruses in common bean from the western highlands of Kenya and global sequences

2018 ◽  
Author(s):  
James M Wainaina ◽  
Elijah Ateka ◽  
Timothy Makori ◽  
Monica A Kehoe ◽  
Laura M Boykin
Keyword(s):  
Phaseolus Vulgaris ◽  
Complete Genome ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Evolutionary Relationship ◽  
Sub Saharan Africa ◽  
Complete Genomes ◽  
Sub Saharan

Background: Endornaviruses are non-pathogenic viruses infecting multiple agricultural important crops including legumes, with global distribution. However, there is an absence on the complete genome of endornaviruses from legumes in particular with the sub-Saharan region. In this study, we report the first complete genomes of PvEV1 and PvEV2, and the evolutionary relationship of these genomes. Methods: Viral symptomatic common beans (Phaseolus vulgaris) showing Bean common mosaic necrosis virus (BCMNV) symptoms from Vihiga county, in the western highlands of Kenya were collected during field survey’s in the region. High throughput sequencing (RNA-Seq) was carried out on total RNA isolated from symptomatic leaf samples. Subsequently, de novo assembly and reference mapping was carried out to obtain the complete genomes of PvEV-1 and PvEV-2. Results: We identified the complete genome of Phaseolus vulgaris endornavirus 1 and 2 (PvEV-1 and PvEV-2) from sub-Saharan Africa (SSA). The average genome size of PvEV-1 was ~13,890 nucleotides (nt) while PvEV-2 was ~14,698 nt, encoding a single open reading frame (ORF). Single ORFs ranged from 4,632 to 4,633 aa in PvEV-1 and from 4,899 – to 4,954 aa in PvEV-2. Both ORFs encoded for the RNA-dependent RNA polymerase (RdRP) gene. The percentage sequence similarity between PvEV-1, PvEV-2 from this study GenBanks sequences was 29 % to 99 %. Bayesian phylogenetic analysis resolved in two well-supported monophyletic clades, with isolates from this study clustering with those from Brazil sequences. Discussion: This study provides the first insights into the evolutionary relationships of PvEV from SSA diverse and contributes towards filling the current knowledge gaps on endornaviruses

scholarly journals A systematic review of Hepatitis B virus (HBV) drug and vaccine escape mutations in Africa: a call for urgent action

2018 ◽  
Author(s):  
Jolynne Mokaya ◽  
Anna L McNaughton ◽  
Martin J Hadley ◽  
Apostolos Beloukas ◽  
Anna-Maria Geretti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Sub Saharan Africa ◽  
Prevention Strategies ◽  
Diagnostic Screening ◽  
Treatment And Prevention ◽  
B Virus ◽  
High Prevalence ◽  
Sub Saharan

ABSTRACTInternational sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with compensatory mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.Author’s summaryThe Global Hepatitis Health Sector Strategy is aiming for the elimination of viral hepatitis as a public health threat by 2030. However, mutations associated with drug resistance and vaccine escape may reduce the success of existing treatment and prevention strategies. In the current literature, the prevalence, distribution and impact of hepatitis B virus (HBV) mutations in many settings in Africa are neglected, despite the high prevalence of HBV and co-endemic HIV infection. This systematic review describes the frequency, prevalence and co-occurrence of mutations associated with HBV drug resistance and vaccine escape mutations in Africa. The findings suggest a high prevalence of these mutations in some populations in sub-Saharan Africa. Scarce resources have contributed to the lack of HBV diagnostic screening, inconsistent supply of drugs, and poor access to clinical monitoring, all of which contribute to drug and vaccine resistance. Sustainable long-term investment is required to expand consistent drug and vaccine supply, to provide screening to diagnose infection and to detect drug resistance, and to provide appropriate targeted clinical monitoring for treated patients.

scholarly journals Schistosoma and Other Relevant Helminth Infections in HIV-Positive Individuals—an Overview

2019 ◽  
Vol 4 (2) ◽  
pp. 65 ◽  
Author(s):  
Amrei von Braun ◽  
Henning Trawinski ◽  
Sebastian Wendt ◽  
Christoph Lübbert
Keyword(s):  
Neglected Tropical Diseases ◽  
Sub Saharan Africa ◽  
World Health ◽  
Cross Sectional ◽  
Treatment And Prevention ◽  
Helminth Infections ◽  
Helminthic Infections ◽  
Sub Saharan ◽  
Health Organization ◽  
Hiv Acquisition

For many years, researchers have postulated that helminthic infections may increase susceptibility to HIV, and that immune activation may have contributed to the extensive spread of HIV in sub-Saharan Africa. In the meantime, immunological studies have provided some evidence in support of this hypothesis, while cross-sectional clinical studies were able to further support the assumed association between HIV infection and selected helminthic co-infections. However, as many of the helminthic infections relevant to HIV-infected patients belong to the group of “neglected tropical diseases”, as defined by the World Health Organization, a certain lack of attention has inhibited progress in fully scaling up treatment and prevention efforts. In addition, despite the fact that the challenges of co-infections have preoccupied clinicians for over two decades, relevant research questions remain unanswered. The following review aims to provide a concise overview of associations between HIV and selected helminthic co-infections concerning aspects of HIV acquisition and transmission, clinical and immunological findings in co-infected individuals, as well as treatment and prevention efforts.

scholarly journals Hepatitis B Virus Infection in Tanzania: Current Status and Challenges

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Semvua B. Kilonzo ◽  
Daniel W. Gunda ◽  
Bonaventura C. T. Mpondo ◽  
Fatma A. Bakshi ◽  
Hyasinta Jaka
Keyword(s):  
Hepatitis B ◽  
Sub Saharan Africa ◽  
Current Status ◽  
Hepatitis B Virus Infection ◽  
Treatment And Prevention ◽  
Resource Limited ◽  
B Virus ◽  
High Prevalence ◽  
Sub Saharan ◽  
Management Challenge

Hepatitis B is one of the most common infectious diseases in the world with high prevalence in most of sub-Saharan Africa countries. The complexity in its diagnosis and treatment poses a significant management challenge in the resource-limited settings including Tanzania, where most of the tests and drugs are either unavailable or unaffordable. This mini review aims at demonstrating the current status of the disease in the country and discussing the concomitant challenges in diagnosis, treatment, and prevention.

Characterization of the novelTrypanosoma bruceiinosine 5′-monophosphate dehydrogenase

Parasitology ◽  
2013 ◽  
Vol 140 (6) ◽  
pp. 735-745 ◽  
Author(s):  
TOMOAKI BESSHO ◽  
SHOKO MORII ◽  
TOSHIHIDE KUSUMOTO ◽  
TAKAHIRO SHINOHARA ◽  
MASANORI NODA ◽  
...  
Keyword(s):  
Analytical Ultracentrifugation ◽  
De Novo ◽  
Binding Mode ◽  
Nucleotide Metabolism ◽  
Sub Saharan Africa ◽  
Size Exclusion ◽  
Purine Nucleotides ◽  
Exclusion Chromatography ◽  
Sub Saharan ◽  
Monophosphate Dehydrogenase

SUMMARYThere is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy.Trypanosomalacks the enzymatic machinery for thede novosynthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5′-monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinantTrypanosoma bruceiIMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculatedKmvalues of 30 and 1300 μmfor IMP and NAD, respectively. The obtainedKmvalue of TbIMPDH for NAD is approximately 20–200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies showKivalues of 3·2 μm, 21 nM and 3·3 nM for ribavirin 5′-monophosphate, mycophenolic acid and mizoribine 5′-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs.

Contemporary Management and Prevention of Vaso-Occlusive Crises (VOCs) in Adults With Sickle Cell Disease

2021 ◽  
pp. 089719002110266
Author(s):  
Salome Bwayo Weaver ◽  
Dhakrit Rungkitwattanakul ◽  
Divita Singh
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
English Language ◽  
Sub Saharan Africa ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Treatment And Prevention ◽  
Sub Saharan ◽  
Contemporary Management ◽  
Sickle Cell Crises

Sickle cell disease (SCD) is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the mediterranean. The main complications leading to hospitalizations include vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). Therefore, the main objective of this paper was to identify and evaluate evidence-based management and prevention of VOCs in patients with SCD. A literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) was performed using the following search terms “vaso-occlusive crises”, “sickle cell disease”, “hydroxyurea”, “L-glutamine”, “voxelotor”, “crizanlizumab”, “treatment” and “prevention” as well as a combination of these terms. All English-language interventional studies assessing the efficacy and safety of VOC outcomes were evaluated. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and there were 7 articles that met the search criteria. Majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to first sickle cell crises, median rates of hospitalizations etc were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.

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