Kathy K. Griendling

Introduction: Mentoring is an important developmental tool for academic scientists. The match between mentor and mentee is a critical factor than can influence outcomes for mentees. However, we know little about what factors should be considered when matching mentors and mentees. We draw on person-environment fit theory to examine how different factors related to the fit between mentors and mentees may influence outcomes for mentees in health-related scientific disciplines. Methods: Data were collected from 76 mentor-mentee pairs who participated in a nine-month mentoring program for scientists interested in clinical and translational research. An index of supplementary fit was calculated to reflect mentor-mentee similarity in terms of race/ethnicity, gender, academic discipline, professional track, percent time allocated to research, and type of research. Complementary fit reflected the proportion of skills mentees identified as needs that their mentor felt comfortable providing. Mentee outcomes assessed included satisfaction with one’s mentor, learning and development experiences, and short-term research output. Results: As predicted, we found that supplementary fit was positively related to mentee satisfaction with the mentor. We found no support for the expected relationship between complementary fit and mentee learning development experiences or short-term research output. Supplementary analyses explored other non-hypothesized relationships among study variables. Conclusions: This research underscores the need to consider different types of fit when matching academic mentors and mentees in clinical and translational science-related disciplines. Our results can be leveraged during the matching process in academic mentoring programs to maximize the success of mentoring relationships for scientists in health-related fields.

The importance of mentoring for professional development in Science, Technology, Engineering, Mathematics and Medicine (STEMM) fields is well established. With the increasing prevalence of team science, mentoring that incorporates team science skills is essential. Here, we describe a novel mentoring program designed to develop technical and relational/interpersonal skills for working in multi-disciplinary team science environments and to develop networks to improve collaboration in multi-disciplinary team science. The Georgia Clinical and Translational Science Alliance Translational Education and Mentoring in Science program is a nine-month program consisting of one-on-one mentoring, peer mentoring groups, mentoring resources, and shared learning experiences. Mentees (fellows) are exposed to a wide range of learning opportunities related to the goals of the program. This multi-institutional effort, in its fifth year, has been well received by participants. To date, 95 faculty, post-doctoral fellows, and research scientists have participated in the program as mentees. Participants indicated that they enjoyed the program, identified new networking opportunities, and would recommend it to others. In addition, fellows reported improved relational, technical, and networking skills over the duration of the program. Mentor ratings were also quite favorable. The multi-institutional nature of the program enriched learning and its unique structure combining traditional one-on-one mentoring with peer learning communities has been beneficial to those participating.

NADPH oxidases (Nox) are one of the main sources of reactive oxygen species (ROS) in the central nervous system (CNS). While these enzymes have been shown to be involved in physiological regulation of cerebral vascular tone, excessive ROS produced by Nox1-5 play a critical role in blood–brain barrier (BBB) dysfunction in numerous neuropathologies. Nox-derived ROS have been implicated in mediating matrix metalloprotease (MMP) activation, downregulation of junctional complexes between adjacent brain endothelial cells and brain endothelial cell apoptosis, leading to brain microvascular endothelial barrier dysfunction and consequently, increases in BBB permeability. In this review, we will highlight recent findings on the role played by these enzymes in BBB disruption induced by ischemic stroke.

Background: Lung injury, a severe adverse outcome of lipopolysaccharide‐induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ‐interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that myeloid Poldip2 is involved in neutrophil recruitment to inflamed lungs. Methods and Results: After characterizing myeloid‐specific Poldip2 knockout mice, we showed that at 18 hours post‐lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2‐deficient mice contained fewer inflammatory cells (8 [4–16] versus 29 [12–57]×10 ⁴ /mL in wild‐type mice) and a smaller percentage of neutrophils (30% [28%–34%] versus 38% [33%–41%] in wild‐type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2‐deficient neutrophils responded as well as wild‐type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor‐α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115–272] wild‐type [myePoldip2 ^+/+ ] versus 133 [62–178] myeloid‐specific Poldip2 knockout [myePoldip2 ^‐/‐ ] neutrophils) as was transmigration (1.7 [1.3–2.1] versus 1.1 [1.0–1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2‐integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2‐integrins was not affected by Poldip2 deletion, whereas β2‐integrins and Pyk2 were less activated in Poldip2‐deficient neutrophils. Conclusions: These results suggest that myeloid Poldip2 is involved in β2‐integrin activation during the inflammatory response, which in turn mediates neutrophil‐to‐endothelium adhesion in lipopolysaccharide‐induced acute respiratory distress syndrome.

Background: Reactive oxygen species (ROS) and calcium ions (Ca ²⁺ ) are among the major effectors of Ang II (angiotensin II) in vascular smooth muscle cells. ROS are related to Ca ²⁺ signaling or contraction induced by Ang II, but little is known about their detailed functions. Here, NOX (NADPH oxidase), a major ROS source responsive to Ang II, was investigated regarding its contribution to Ca ²⁺ signaling. Methods: Vascular smooth muscle cells were primary cultured from rat aorta. Ca ²⁺ and ROS were monitored mainly using fura-2 and HyPer family probes‚ respectively. Signals activating NOX were examined with relevant pharmacological inhibitors and genetic manipulation techniques. Results: Ang II–induced ROS generation was found to be biphasic: the first phase of ROS production, which was mainly mediated by NOX1, was small and transient, preceding a rise in Ca ²⁺ , and the second phase of ROS generation, mediated by NOX1 and NOX4, was slow but sizeable, continuing over tens of minutes. NOX1-derived superoxide in the first phase is required for Ca ²⁺ influx through nonselective cation channels. AT1R (Ang II type 1 receptor)-G _βγ -PI3K _γ (phosphoinositide 3-kinase γ) signaling pathway was responsible for the rapid activation of NOX1 in the first phase, while in the second phase, NOX1 was further activated by a separate AT1R-Gα _q/11 -PLC (phospholipase C)-PKC _β (protein kinase C β) signaling axis. Consistent with these observations, aortas from NOX1-knockout mice exhibited reduced contractility in response to Ang II, and thus the acute pressor response to Ang II was also attenuated in NOX1-knockout mice. Conclusions: NOX1 mediates Ca ²⁺ signal generation and thereby contributes to vascular contraction and blood pressure elevation by Ang II.

POLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from three limitations: perinatal lethality in homozygotes, constitutivePoldip2inactivation and inadvertent downregulation of the adjacentTmem199gene. To overcome these limitations, we developed a new conditional floxedPoldip2model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication aroundPoldip2with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxedPoldip2mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects ofPoldip2ablation in the vasculature, RNA-seq and RT-qPCR experiments were performed in constitutive knockout arteries. Results show that POLDIP2 inactivation affects multiple cellular processes and provide new opportunities for future in-depth study of its functions.