Perspectives on Cognitive Phenotypes and Models of Vascular Disease.

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Divergent natural selection alters male sperm competition success in Drosophila melanogaster.

Sexually selected traits may also be subject to non-sexual selection. If optimal trait values depend on environmental conditions, then "narrow sense" (i.e., non-sexual) natural selection can lead to local adaptation, with fitness in a certain environment being highest among individuals selected under that environment. Such adaptation can, in turn, drive ecological speciation via sexual selection. To date, most research on the effect of narrow-sense natural selection on sexually selected traits has focused on precopulatory measures like mating success. However, postcopulatory traits, such as sperm function, can also be under non-sexual selection, and have the potential to contribute to population divergence between different environments. Here, we investigate the effects of narrow-sense natural selection on male postcopulatory success in Drosophila melanogaster. We chose two extreme environments, low oxygen (10%, hypoxic) or high CO2 (5%, hypercapnic) to detect small effects. We measured the sperm defensive (P1) and offensive (P2) capabilities of selected and control males in the corresponding selection environment and under control conditions. Overall, selection under hypoxia decreased both P1 and P2, while selection under hypercapnia had no effect. Surprisingly, P1 for both selected and control males was higher under both ambient hypoxia and ambient hypercapnia, compared to control conditions, while P2 was lower under hypoxia. We found limited evidence for local adaptation: the positive environmental effect of hypoxia on P1 was greater in hypoxia-selected males than in controls. We discuss the implications of our findings for the evolution of postcopulatory traits in response to non-sexual and sexual selection.

Portfolio Analysis of Research Grants in Data Science Funded by the National Heart, Lung, and Blood Institute.

Leveraging emerging opportunities in data science to open new frontiers in heart, lung, blood, and sleep research is one of the major strategic objectives of the National Heart, Lung, and Blood Institute (NHLBI), one of the 27 Institutes/Centers within the National Institutes of Health (NIH). To assess NHLBI's recent funding of research grants in data science and to identify its relative areas of focus within data science, a portfolio analysis from fiscal year 2008 to fiscal year 2017 was performed. In this portfolio analysis, an efficient and reliable methodology was used to identify data science research grants by utilizing several NIH databases and search technologies (iSearch, Query View Reporting system, and IN-SPIRE [Pacific Northwest National Laboratory, Richland, WA]). Six hundred thirty data science-focused extramural research grants supported by NHLBI were identified using keyword searches based primarily on NIH's working definitions of bioinformatics and computational biology. Further analysis characterized the distribution of these grants among the heart, lung, blood, and sleep disease areas as well as the subtypes of data science projects funded by NHLBI. Information was also collected for data science research grants funded by other NIH institutes/centers using the same search and analysis methodology. The funding comparison among different NIH institutes/centers highlighted relative data science areas of emphasis and further identified opportunities for potential data science areas in which NHLBI could foster research advances.

Shifting Demographics among Research Project Grant Awardees at the National Heart, Lung, and Blood Institute (NHLBI).

The present study was initiated because of concerns expressed by NHLBI-funded mid-career investigators regarding perceived difficulties in the renewal of their grant awards. This led us to ask: "Are mid-career investigators experiencing disproportionate difficulties in the advancement of their professional careers?" Our portfolio analysis indicates that there has been a significant and evolving shift in the demographics of research project grant (RPG) awardees at NHLBI. In 1998, mid-career (ages 41-55) investigators constituted approximately 60% of all investigators with the remaining 40% being equally divided between early-stage (ages 24-40) investigators and established (ages 56 to 70 and older) investigators. However, since 1998, the proportion of established RPG awardees has been increasing in a slowly progressive and strikingly linear fashion. At the same time the proportion of early-stage awardees fell precipitously until 2006 and then stabilized. During the same period, the proportion of mid-career awardees, which had been relatively stable through 2006, began to fall significantly. In examining potential causes of these demographic shifts we have identified certain inherent properties within the RPG award system that appear to promote an increasingly more established awardee population and a persistent decrease in the proportion of mid-career investigators. A collateral result of these demographic shifts, when combined with level or declining funding, is a significant reduction in the number of RPG awards received by NHLBI mid-career investigators and a corresponding decrease in the number of independent research laboratories.

Evolutionary consequences of altered atmospheric oxygen in Drosophila melanogaster.

Twelve replicate populations of Drosophila melanogaster, all derived from a common ancestor, were independently evolved for 34+ generations in one of three treatment environments of varying PO(2): hypoxia (5.0-10.1 kPa), normoxia (21.3 kPa), and hyperoxia (40.5 kPa). Several traits related to whole animal performance and metabolism were assayed at various stages via "common garden" and reciprocal transplant assays to directly compare evolved and acclimatory differences among treatments. Results clearly demonstrate the evolution of a greater tolerance to acute hypoxia in the hypoxia-evolved populations, consistent with adaptation to this environment. Greater hypoxia tolerance was associated with an increase in citrate synthase activity in fly homogenate when compared to normoxic (control) populations, suggesting an increase in mitochondrial volume density in these populations. In contrast, no direct evidence of increased performance of the hyperoxia-evolved populations was detected, although a significant decrease in the tolerance of these populations to acute hypoxia suggests a cost to adaptation to hyperoxia. Hyperoxia-evolved populations had lower productivity overall (i.e., across treatment environments) and there was no evidence that hypoxia or hyperoxia-evolved populations had greatest productivity or longevity in their respective treatment environments, suggesting that these assays failed to capture the components of fitness relevant to adaptation.

Osteogenic Protein-1: gene expression and treatment in rat remnant kidney model.

Osteogenic Protein-1 (OP-1) is a bone morphogen involved in tissue repair and development. We have shown that OP-1 is downregulated during acute ischemic renal injury. Here we report the use of the rat remnant kidney model (RRKM) to evaluate changes in kidney OP-1 expression during chronic injury, and determine if treatment with recombinant human OP-I (rhOP-1) aids in recovery from injury. Sprague-Dawley rats were subjected to kidney decapsulation (Cx) or 5/6 nephrectomy (Nx). Serum for BUN and creatinine and tissue for histology and mRNA analysis were collected at: 2, 10. and 12-14 wks post Nx. We show kidney OP-1 mRNA levels were downregulated at 2 and 12-14 wks post Nx. To determine the effect of rhOP-1 in the RRKM, rhOP-1 (0.25, 2.5 or 25 microg/kg) or vehicle (V) was injected in a second set of rats, 2 weeks after 2/3 left Nx for a total of six doses. Nx rats treated with rhOP-1 showed significantly increased tubular regeneration (increased mitotic figures, polyoid infolding, and tubular epithelialhyperplasia) in a dose dependent manner without changes in glomerular or tubular damage. rhOP-1 stimulates tubular epithelial cell regeneration,early in the repair process in a chronic renal failure model, before significant fibrosis is established.