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TRANSCRIPTIONAL CONTROL OF MITOCHONDRIAL GENE EXPRESSION IN TRYPANOSOMES by BOSTON UNIVERSITY MEDICAL CAMPUS (The Research University TRU)

AFASIZHEV, RUSLAN

 

ABSTRACTParasitic protist Trypanosoma brucei causes African human and animal trypanosomiasis, a spectrum of diseasesaffecting the population and economy in sub-Saharan Africa. These digenetic hemoflagellates belong toKinetoplastea, a taxonomic class distinguished by possession of a kinetoplast. This nucleoprotein body containsmitochondrial DNA (kDNA) of two kinds: ~25 maxicircles (each ~23 kb) encoding rRNAs, ribosomal proteins andsubunits of respiratory complexes, and approximately 5000 of ~1 kb minicircles bearing guide RNA genes.Relaxed maxicircles and minicircles are interlinked and packed into a dense disc-shaped network by associationwith histone-like proteins. Decades of kDNA studies have unraveled fascinating phenomena of general biologicalsignificance, such as DNA bending and mRNA editing, and revealed exquisite details of replication and RNAprocessing. However, the molecular mechanisms of transcription remain virtually unexplored and arguablyconstitute the most critical gap in understanding mitochondrial gene expression. The historically enduring viewof polycistronic RNA synthesis has abridged efforts to investigate transcription’s contribution to regulatinggenome activity. In contrast, this proposal presents evidence that maxicircle and minicircle genes are individuallytranscribed into 3? extended precursors. The transcription start site defines pre-mRNA 5? terminus, which issubsequently converted into monophosphorylated state by a pyrophosphohydrolase complex, termed thePPsome. Most guide RNAs lack PPsome recognition sites and remain triphosphorylated. Furthermore, weestablish that antisense transcripts delimit the 3? boundaries of mature RNAs by blocking 3?-5? degradation ofprecursors by the 3? processome (MPsome). It follows that transcription start sites on sense and antisensestrands define 5? and 3? mRNA termini, respectively. These findings support a concept of mitochondrial gene-specific transcriptional control with broad implications in parasite development and pathogenesis. We posit thatelucidating transcription complex composition, DNA template requirements and functions of specific factors willbuild a foundation for this nascent research area. We propose to: 1) Characterize RNA polymerase complexfrom bloodstream and insect parasite forms, and assess transcription factors’ contributions to RNA synthesis; 2)Map maxicircle and minicircle promoters; and 3) Reconstitute the active transcription complex.

 

"Zimbabwe
AfricaUniversity Affairs

Harnessing Data Science for Health Discovery and Innovation in Africa: NIH joins Africa Movement Thinking initiative

We are experiencing an explosion of data relevant to human health, from both biological and non-health sources, that currently exceeds our ability to capture and interpret. This gap applies to every field of biomedical and behavioral research. If we don’t invest in the data itself, applying known and developing new Data Science (DS) approaches, we are wasting an incredible opportunity to improve Human Health. This set of initiatives addresses that gap for Global Health research and Public Health application in low resource settings.

In the next decade, rapid advances in DS, including new approaches to the description, collection, storage, integration, and analysis of large, heterogeneous, structured and unstructured data sets, and new computational methods such as advanced deep learning, digital phenotypes, machine/artificial intelligence, and 3D imaging are expected to transform biomedical and behavioral research and lead to improved health for individuals and populations. Traditional datasets (e.g. national health systems, surveillance, surveys) are becoming deeper and richer while new sources of data based on new technologies and sensors (e.g. social media, geospatial data, mobile phones, wearables, electronic medical records, bioimaging, and genomics) are emerging that may be of greatest value when linked to DS. Progress in development of huge new data sets and advanced methods for mining them underpin advances in diagnostics, technology development, and the potential for precision public health. This initiative examines whether advances in DS developed and/or applied in the African context can be used to spur discoveries and innovations that ultimately promote significant improvements in health for African individuals, communities, and populations. We define DS as “the interdisciplinary field of inquiry in which quantitative and analytical approaches, processes, and systems are developed and used to extract knowledge and insights from increasingly large and/or complex sets of data” (NIH Strategic Plan for Data Science).

While advances in the United States and other high-income countries (HICs) are being actively explored and increasingly supported in both the public and private sectors, applications that are relevant, affordable, acceptable, and scalable in low- and middle-income countries (LMICs) are largely undeveloped. Moreover, in most cases applications and tools cannot simply be adapted from HICs for use in LMICS as they are generated from data collections biased towards European ancestry populations and may not apply to other genetic backgrounds (this is true, for example, for GWAS studies, clinical imaging data used as a basis for machine learning, and major disease biomarkers). However, we can leverage the momentum and knowledge generated in this field in HICs to stimulate new investment, knowledge generation and innovations for LMIC populations.

What is InventXR is solving for?

While advances in the United States and other high-income countries (HICs) are being actively explored and increasingly supported in both the public and private sectors, applications that are: relevant, affordable, acceptable, and scalable in low- and middle-income countries (LMICs) are largely undeveloped. 

  • We focus this initiative in Africa for several reasons: 
    • First, despite recent progress, Africa carries a disproportionate share of the global burden of disease. DS has the potential to significantly impact both quantitative and qualitative research and health on the continent. 
    • Second, the African population is growing faster than other world regions and some African leaders are eager to transition to knowledge-based economies that InventXR infrastructure is well designed for. Extensive mobile phone coverage in Africa has led to major innovations in banking, agriculture, and other sectors and has the potential to “leopard frog” in health care delivery systems, bringing the clinic to the patient through Point of Care (POC) technologies and self-management systems, with applications to rural and underserved populations worldwide. 
    • Third, this initiative is synergistic with and leverages the substantial investments NIH has already made in research and research training in Africa.
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