Widespread association of the Argonaute protein AGO2 with meiotic chromatin suggests a distinct nuclear function in mammalian male reproduction.

Argonaute 2 (AGO2) is a ubiquitously expressed protein critical for regulation of mRNA translation and vital to animal development. AGO2 protein is found in both cytoplasmic and nuclear compartments, and although its cytoplasmic role is well studied, the biological relevance of nuclear AGO2 is unclear. Here, we address this problem in vivo using spermatogenic cells as a model. We find that AGO2 transiently binds both chromatin and nucleus-specific mRNA transcripts of hundreds of genes required for sperm production during male meiosis in mice, and that germline conditional knockout (cKO) of Ago2 causes depletion of the encoded proteins. Correspondingly, Ago2 cKO males show abnormal sperm head morphology and reduced sperm count, along with reduced postnatal viability of offspring. Together, our data reveal an unexpected nuclear role for AGO2 in enhancing expression of developmentally important genes during mammalian male reproduction.

Postdocs' lab engagement predicts trajectories of PhD students' skill development.

The doctoral advisor-typically the principal investigator (PI)-is often characterized as a singular or primary mentor who guides students using a cognitive apprenticeship model. Alternatively, the "cascading mentorship" model describes the members of laboratories or research groups receiving mentorship from more senior laboratory members and providing it to more junior members (i.e., PIs mentor postdocs, postdocs mentor senior graduate students, senior students mentor junior students, etc.). Here we show that PIs' laboratory and mentoring activities do not significantly predict students' skill development trajectories, but the engagement of postdocs and senior graduate students in laboratory interactions do. We found that the cascading mentorship model accounts best for doctoral student skill development in a longitudinal study of 336 PhD students in the United States. Specifically, when postdocs and senior doctoral students actively participate in laboratory discussions, junior PhD students are over 4 times as likely to have positive skill development trajectories. Thus, postdocs disproportionately enhance the doctoral training enterprise, despite typically having no formal mentorship role. These findings also illustrate both the importance and the feasibility of identifying evidence-based practices in graduate education.

Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.

Catalytic enantioselective O-nitrosocarbonyl aldol reaction of ß-dicarbonyl compounds.

The first example of a Cu-catalyzed asymmetric O-nitrosocarbonyl aldol reaction is described. This novel protocol allows convenient access to highly enantioenriched α-hydroxy-ß-ketoesters including the antibacterial natural product kjellmanianone (up to 99% ee). MnO(2) was introduced as a mild efficient oxidant for the in situ generation of nitrosocarbonyl species from hydroxamic acid derivatives.

Career Development among American Biomedical Postdocs.

Recent biomedical workforce policy efforts have centered on enhancing career preparation for trainees, and increasing diversity in the research workforce. Postdoctoral scientists, or postdocs, are among those most directly impacted by such initiatives, yet their career development remains understudied. This study reports results from a 2012 national survey of 1002 American biomedical postdocs. On average, postdocs reported increased knowledge about career options but lower clarity about their career goals relative to PhD entry. The majority of postdocs were offered structured career development at their postdoctoral institutions, but less than one-third received this from their graduate departments. Postdocs from all social backgrounds reported significant declines in interest in faculty careers at research-intensive universities and increased interest in nonresearch careers; however, there were differences in the magnitude and period of training during which these changes occurred across gender and race/ethnicity. Group differences in interest in faculty careers were explained by career interest differences formed during graduate school but not by differences in research productivity, research self-efficacy, or advisor relationships. These findings point to the need for enhanced career development earlier in the training process, and interventions sensitive to distinctive patterns of interest development across social identity groups.

Biomedical Science Ph.D. Career Interest Patterns by Race/Ethnicity and Gender.

Increasing biomedical workforce diversity remains a persistent challenge. Recent reports have shown that biomedical sciences (BMS) graduate students become less interested in faculty careers as training progresses; however, it is unclear whether or how the career preferences of women and underrepresented minority (URM) scientists change in manners distinct from their better-represented peers. We report results from a survey of 1500 recent American BMS Ph.D. graduates (including 276 URMs) that examined career preferences over the course of their graduate training experiences. On average, scientists from all social backgrounds showed significantly decreased interest in faculty careers at research universities, and significantly increased interest in non-research careers at Ph.D. completion relative to entry. However, group differences emerged in overall levels of interest (at Ph.D. entry and completion), and the magnitude of change in interest in these careers. Multiple logistic regression showed that when controlling for career pathway interest at Ph.D. entry, first-author publication rate, faculty support, research self-efficacy, and graduate training experiences, differences in career pathway interest between social identity groups persisted. All groups were less likely than men from well-represented (WR) racial/ethnic backgrounds to report high interest in faculty careers at research-intensive universities (URM men: OR 0.60, 95% CI: 0.36-0.98, p = 0.04; WR women: OR: 0.64, 95% CI: 0.47-0.89, p = 0.008; URM women: OR: 0.46, 95% CI: 0.30-0.71, p<0.001), and URM women were more likely than all other groups to report high interest in non-research careers (OR: 1.93, 95% CI: 1.28-2.90, p = 0.002). The persistence of disparities in the career interests of Ph.D. recipients suggests that a supply-side (or "pipeline") framing of biomedical workforce diversity challenges may limit the effectiveness of efforts to attract and retain the best and most diverse workforce. We propose incorporation of an ecological perspective of career development when considering strategies to enhance the biomedical workforce and professoriate through diversity.

What do I want to be with my PhD? The roles of personal values and structural dynamics in shaping the career interests of recent biomedical science PhD graduates.

Interest in faculty careers decreases as graduate training progresses; however, the process underlying career-interest formation remains poorly defined. To better understand this process and whether/how it differs across social identity (i.e., race/ethnicity, gender), we conducted focus groups with 38 biomedical scientists who received PhDs between 2006 and 2011, including 23 women and 18 individuals from underrepresented minority (URM) backgrounds. Objective performance and quality of advisor relationships were not significantly different between scientists with high versus low interest in faculty careers. Career interests were fluid and formed in environments that generally lacked structured career development. Vicarious learning shaped similar outcome expectations about academic careers for all scientists; however, women and URMs recounted additional, distinct experiences and expectations. Scientists pursuing faculty careers described personal values, which differed by social identity, as their primary driver. For scientists with low interest in faculty careers, a combination of values, shared across social identity, and structural dynamics of the biomedical workforce (e.g., job market, grant funding, postdoc pay, etc.) played determinative roles. These findings illuminate the complexity of career choice and suggest attracting the best, most diverse academic workforce requires institutional leaders and policy makers go beyond developing individual skill, attending to individuals' values and promoting institutional and systemic reforms.