Despite efforts to promote diversity in the biomedical workforce, there remains a lower rate of funding of National Institutes of Health R01 applications submitted by African-American/black (AA/B) scientists relative to white scientists. To identify underlying causes of this funding gap, we analyzed six stages of the application process from 2011 to 2015 and found that disparate outcomes arise at three of the six: decision to discuss, impact score assignment, and a previously unstudied stage, topic choice. Notably, AA/B applicants tend to propose research on topics with lower award rates. These topics include research at the community and population level, as opposed to more fundamental and mechanistic investigations; the latter tend to have higher award rates. Topic choice alone accounts for over 20% of the funding gap after controlling for multiple variables, including the applicant’s prior achievements. Our findings can be used to inform interventions designed to close the funding gap.
Abstract. Nearly all of the known activities required for mitochondrial DNA (mtDNA) replication and expression are nuclear-encoded gene products, necessitating communication between these two physically distinct intracellular compartments. A significant amount of both general and specific biochemical information about mtDNA replication in mammalian cells has been known for almost two decades. Early studies achieved selective incorporation of the thymidine analog 5-Bromo-2-deoxy-Uridine (BrdU) into mtDNA of thymidine kinase-deficient (TK [-]) cells. We have revisited this approach from a cellular perspective to determine whether there exist spatiotemporal constraints on mtDNA replication. Laser-scanning confocal microscopy was used to selectively detect mtDNA synthesis in situ in cultured mammalian cells using an immunocytochemical double-labeling approach to visualize the incorporation of BrdU into mtDNA of dye-labeled mitochondria. In situ detection of BrdU-incorporated mtDNA was feasible after a minimum of 1-2 h treatment with BrdU, consistent with previous biochemical studies that determined the time required for completion of a round of mtDNA replication. Interestingly, the pattern of BrdU incorporation into the mtDNA of cultured mammalian cells consistently radiated outward from a perinuclear position, suggesting that mtDNA replication first occurs in the vicinity of nuclear-provided materials. Newly replicated mtDNA then appears to rapidly distribute throughout the dynamic cellular mitochondrial network.
MITOCHONDRIA are semiautonomous organelles that have a resident genome but rely heavily upon the nucleus to encode both proteins and nucleic acids for replication and transcription of mitochondrial DNA (mtDNA). t The important discovery that mammalian mitochondria have a genetically distinct (from the major cellular [soluble]) thymidine kinase (TK) enzyme (Berk and Clayton, 1973) greatly facilitated quantitative biochemical studies of mtDNA replication in cultured cells. Early studies showed that cell lines could be developed that are devoid of the cellular TK (Kit et al., 1963); however, these TK(-) cell lines still incorporate the thymidine analog 5-Bromo-2-deoxy-Uridine (BrdU) into mtDNA (Clayton and Teplitz, 1972;Berk and Clayton, 1973). As a result, the mtDNA in these cells can be labeled to a high specific activity to the relative exclusion of nuclear DNA.
Mitochondria are essential organelles in all eukaryotic cells where cellular ATP is generated through the process of oxidative phosphorylation. Protein components of the respiratory assembly are gene products of both mitochondrial and nuclear genes. The mitochondrial genome itself encodes several protein and nucleic acid components required for such oxidative phosphorylative processes, but the vast majority of genes encoding respiratory chain components are nuclear. Similarly, the processes of replication and transcription of mitochondrial DNA rely exclusively upon RNA and protein species encoded by nuclear genes. We have analyzed two key nuclear-encoded proteins involved in mitochondrial DNA replication and transcription as a function of the presence or absence of mitochondrial DNA. Mitochondrial DNA polymerase (DNA polymerase gamma), the nuclear-encoded enzyme which synthesizes mtDNA, is expressed and translated in cells devoid of mitochondrial DNA itself. In contrast, mitochondrial transcription factor A protein levels are tightly linked to the mtDNA status of the cell. These results demonstrate that the DNA polymerase gamma protein is stable in the absence of mitochondrial DNA, and that there appears to be no regulatory mechanism present in these cells to alter levels of this protein in the complete absence of mitochondrial DNA. Alternatively, it is possible that this enzyme plays an additional, as yet undefined, role in the cell, thereby mandating its continued production.
One thousand two hundred thirty seven smokers responding to lung association announcements in five geographic areas were randomly assigned to one of four groups and mailed American Lung Association materials: 1) leaflets (L); 2) leaflets plus maintenance manual (L+M); 3) cessation manual (C); and 4) cessation and maintenance manuals (C+M). Five telephone interviews over one year achieved a 95 per cent follow-up completion rate. Nonrespondents as well as exclusive cigar and pipe users were classified as smokers. Twenty per cent quit initially, with 5 per cent continually abstinent in (C +M) at 12 months vs 2 per cent in (L) (p < .05). Nonsmoking prevalence rates (no tobacco smoking in the past
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