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Nurturing the development of cardiovascular physician-scientist investigators is critical for sustained progress in cardiovascular science and improving human health. The transition from an inexperienced trainee to an independent physician-scientist is a multifaceted process requiring a sustained commitment from the trainee, mentors, and institution. A cornerstone of this training process is a career development (K) award from the National Institutes of Health (NIH). These awards generally require 75% of the awardee's professional effort devoted to research aims and diverse career development activities carried out in a mentored environment over a 5-year period. We report on recent success rates for obtaining NIH K awards, provide strategies for preparing a successful application and navigating the early career period for aspiring cardiovascular investigators, and offer cardiovascular division leadership perspectives regarding K awards in the current era. Our objective is to offer practical advice that will equip trainees considering an investigator path for success.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Youth identified before age 13 (N = 320) as having profound mathematical or verbal reasoning abilities (top 1 in 10,000) were tracked for nearly three decades. Their awards and creative accomplishments by age 38, in combination with specific details about their occupational responsibilities, illuminate the magnitude of their contribution and professional stature. Many have been entrusted with obligations and resources for making critical decisions about individual and organizational well-being. Their leadership positions in business, health care, law, the professoriate, and STEM (science, technology, engineering, and mathematics) suggest that many are outstanding creators of modern culture, constituting a precious human-capital resource. Identifying truly profound human potential, and forecasting differential development within such populations, requires assessing multiple cognitive abilities and using atypical measurement procedures. This study illustrates how ultimate criteria may be aggregated and longitudinally sequenced to validate such measures.
In cell biology, subcellular locale is critical for the action of signaling molecules, for regulation of gene expression, and for proper cell division. In simple terms, everything must be in the right place at the right time. For my research, I have focused on understanding the role the nuclear pore complex (NPC) plays in maintaining this balance. With eukaryotic transcription in the nucleus and translation in the cytoplasm, highly selective import and export events at the NPC connect these spatially separated processes to allow gene expression. In a similar way, spatial and temporal events have repeatedly impacted my scientific career. In different places and times, interactions with mentors, collaborators, colleagues, and trainees have shaped my research and mentoring philosophies: aim high, fuel your passions, collaborate, and take risks to find supportive environments and challenging projects that impact scientific discovery.
STUDY DESIGN - Analysis of the effect of antifibrinolytics on in vitro bone formation.
OBJECTIVE - As the direct effect of antifibrinolytics on bone formation is unknown, we examined whether antifibrinolytics routinely used in spine surgery, namely, aprotinin and aminocaproic acid, affect osteoblast function in vitro.
SUMMARY OF BACKGROUND DATA - Antifibrinolytics are used in spine surgery to prevent intraoperative blood loss and decrease the need for transfusion. They are either delivered systemically or included as a component of most tissue sealants. Although the role of the fibrinolytic system in wound healing is well established, reports of indirect effects on normal bone biology are emerging. This suggests that the pharmacological targeting of this system may also influence skeletal mass and integrity.
METHODS - Osteoblast progenitor cells were cultured with therapeutic doses of aprotinin and aminocaproic acid. The effect of the antifibrinolytics on osteoblast development was determined by measuring cellular viability and proliferation, quantification of matrix mineralization, and genetic analysis of osteoblast differentiation markers. Protease inhibition profiles of the antifibrinolytics were determined by amidolytic chromogenic assays.
RESULTS - Therapeutic concentrations of aprotinin dose-dependently inhibited plasmin's proteolytic activity, stimulated osteoblast proliferation, and inhibited osteoblast differentiation and matrix mineralization. Aprotinin inhibition of osteoblast differentiation and matrix mineralization could be recovered by removing aprotinin from culture or stimulating cells with bone morphogenetic protein-2 or plasmin. Conversely, aminocaproic acid inhibited plasmin's proteolytic activity significantly less than aprotinin and had no effect on osteoblast proliferation, differentiation, or matrix mineralization in its therapeutic range.
CONCLUSION - These findings demonstrate that the antifibrinolytics have drastically different effects on osteoblasts due in part to different efficacies of protease inhibition. Further, this work suggests that the fibrinolytic proteases and their inhibitors have great potential to regulate bone by affecting the processes that control osteoblast growth and differentiation.
Top down proteomics in a TOF-TOF instrument was further explored by examining the fragmentation of multiply charged precursors ions generated by matrix-assisted laser desorption ionization. Evaluation of sample preparation conditions allowed selection of solvent/matrix conditions and sample deposition methods to produce sufficiently abundant doubly and triply charged precursor ions for subsequent CID experiments. As previously reported, preferential cleavage was observed at sites C-terminal to acidic residues and N-terminal to proline residues for all ions examined. An increase in nonpreferential fragmentation as well as additional low mass product ions was observed in the spectra from multiply charged precursor ions providing increased sequence coverage. This enhanced fragmentation from multiply charged precursor ions became increasingly important with increasing protein molecular weight and facilitates protein identification using database searching algorithms. The useable mass range for MALDI TOF-TOF analysis of intact proteins has been expanded to 18.2 kDa using this approach.