Increasing Faculty Self-Efficacy in Mentoring through Training in Inclusive Mentoring and Course-based Undergraduate Research.

Encouraging diversity in biomedical fields is especially important and begins at the undergraduate level. Culturally competent mentorship and high impact practices, like involvement in research, play important roles in fostering success among undergraduates from historically underrepresented groups. The current study followed 20 biomedical faculty as they completed two semester-long trainings, one in mentoring and one in course based undergraduate research (CUREs) as part of the NIH Diversity Program Consortium Dissemination and Translation Awards initiative. Comparisons of pre- and post-training survey data showed increased self-efficacy for mentoring biomedical research trainees and for mentoring diverse groups of biomedical trainees. These results suggest that focused, formal faculty training can be effective for improving mentoring, and consequently success of biomedical students.

Data-Driven Hypothesis Generation in Clinical Research: What We Learned from a Human Subject Study?

Hypothesis generation is an early and critical step in any hypothesis-driven clinical research project. Because it is not yet a well-understood cognitive process, the need to improve the process goes unrecognized. Without an impactful hypothesis, the significance of any research project can be questionable, regardless of the rigor or diligence applied in other steps of the study, e.g., study design, data collection, and result analysis. In this perspective article, the authors provide a literature review on the following topics first: scientific thinking, reasoning, medical reasoning, literature-based discovery, and a field study to explore scientific thinking and discovery. Over the years, scientific thinking has shown excellent progress in cognitive science and its applied areas: education, medicine, and biomedical research. However, a review of the literature reveals the lack of original studies on hypothesis generation in clinical research. The authors then summarize their first human participant study exploring data-driven hypothesis generation by clinical researchers in a simulated setting. The results indicate that a secondary data analytical tool, VIADS-a visual interactive analytic tool for filtering, summarizing, and visualizing large health data sets coded with hierarchical terminologies, can shorten the time participants need, on average, to generate a hypothesis and also requires fewer cognitive events to generate each hypothesis. As a counterpoint, this exploration also indicates that the quality ratings of the hypotheses thus generated carry significantly lower ratings for feasibility when applying VIADS. Despite its small scale, the study confirmed the feasibility of conducting a human participant study directly to explore the hypothesis generation process in clinical research. This study provides supporting evidence to conduct a larger-scale study with a specifically designed tool to facilitate the hypothesis-generation process among inexperienced clinical researchers. A larger study could provide generalizable evidence, which in turn can potentially improve clinical research productivity and overall clinical research enterprise.

The quality of data-driven hypotheses generated by inexperienced clinical researchers: A case study.

Objectives: We invited inexperienced clinical researchers to analyze coded health datasets and develop hypotheses. We recorded and analyzed their hypothesis generation process. All the hypotheses generated in the process were rated by the same group of seven experts by using the same metrics. This case study examines the higher quality (i.e., higher ratings) and lower quality of hypotheses and participants who generated them. We characterized the contextual factors associated with the quality of hypotheses. Methods: All participants (i.e., clinical researchers) completed a 2-hour study session to analyze data and generate scientific hypotheses using the think-aloud method. Participants' screen activity and audio were recorded and transcribed. These transcriptions were used to measure the time used to generate each hypothesis and to code cognitive events (i.e., cognitive activities used when generating hypotheses, for example, "Seeking for Connection" describes an attempt to draw connections between data points). The hypothesis ratings by the expert panel were used as the quality of the hypotheses during the analysis. We analyzed the factors associated with (1) the five highest and (2) five lowest rated hypotheses and (3) the participants who generated them, including the number of hypotheses per participant, the validity of those hypotheses, the number of cognitive events used for each hypothesis, as well as the participant's research experience and basic demographics. Results: Participants who generated the five highest-rated hypotheses used similar lengths of time (difference 3:03), whereas those who generated the five lowest-rated hypotheses used more varying lengths of time (difference 7:13). Participants who generated the five highest-rated hypotheses also utilized slightly fewer cognitive events on average compared to the five lowest-rated hypotheses (4 per hypothesis vs. 4.8 per hypothesis). When we examine the participants (who generated the five highest and five lowest hypotheses) and their total hypotheses generated during the 2-hour study sessions, the participants with the five highest-rated hypotheses again had a shorter range of time per hypothesis on average (0:03:34 vs. 0:07:17). They (with the five highest ratings) used fewer cognitive events per hypothesis (3.498 vs. 4.626). They (with the five highest ratings) also had a higher percentage of valid rate (75.51% vs. 63.63%) and generally had more experience with clinical research. Conclusion: The quality of the hypotheses was shown to be associated with the time taken to generate them, where too long or too short time to generate hypotheses appears to be negatively associated with the hypotheses' quality ratings. Also, having more experience seems to positively correlate with higher ratings of hypotheses and higher valid rates. Validity is a quality dimension used by the expert panel during rating. However, we acknowledge that our results are anecdotal. The effect may not be simply linear, and future research is necessary. These results underscore the multi-factor nature of hypothesis generation.

Data-driven hypothesis generation among inexperienced clinical researchers: A comparison of secondary data analyses with visualization (VIADS) and other tools.

Objectives: To compare how clinical researchers generate data-driven hypotheses with a visual interactive analytic tool (VIADS, a visual interactive analysis tool for filtering and summarizing large datasets coded with hierarchical terminologies) or other tools. Methods: We recruited clinical researchers and separated them into "experienced" and "inexperienced" groups. Participants were randomly assigned to a VIADS or control group within the groups. Each participant conducted a remote 2-hour study session for hypothesis generation with the same study facilitator on the same datasets by following a think-aloud protocol. Screen activities and audio were recorded, transcribed, coded, and analyzed. Hypotheses were evaluated by seven experts on their validity, significance, and feasibility. We conducted multilevel random effect modeling for statistical tests. Results: Eighteen participants generated 227 hypotheses, of which 147 (65%) were valid. The VIADS and control groups generated a similar number of hypotheses. The VIADS group took a significantly shorter time to generate one hypothesis (e.g., among inexperienced clinical researchers, 258 s versus 379 s, p = 0.046, power = 0.437, ICC = 0.15). The VIADS group received significantly lower ratings than the control group on feasibility and the combination rating of validity, significance, and feasibility. Conclusion: The role of VIADS in hypothesis generation seems inconclusive. The VIADS group took a significantly shorter time to generate each hypothesis. However, the combined validity, significance, and feasibility ratings of their hypotheses were significantly lower. Further characterization of hypotheses, including specifics on how they might be improved, could guide future tool development.

How do clinical researchers generate data-driven scientific hypotheses? Cognitive events using think-aloud protocol.

Objectives: This study aims to identify the cognitive events related to information use (e.g., "Analyze data", "Seek connection") during hypothesis generation among clinical researchers. Specifically, we describe hypothesis generation using cognitive event counts and compare them between groups. Methods: The participants used the same datasets, followed the same scripts, used VIADS (a visual interactive analysis tool for filtering and summarizing large data sets coded with hierarchical terminologies) or other analytical tools (as control) to analyze the datasets, and came up with hypotheses while following the think-aloud protocol. Their screen activities and audio were recorded and then transcribed and coded for cognitive events. Results: The VIADS group exhibited the lowest mean number of cognitive events per hypothesis and the smallest standard deviation. The experienced clinical researchers had approximately 10% more valid hypotheses than the inexperienced group. The VIADS users among the inexperienced clinical researchers exhibit a similar trend as the experienced clinical researchers in terms of the number of cognitive events and their respective percentages out of all the cognitive events. The highest percentages of cognitive events in hypothesis generation were "Using analysis results" (30%) and "Seeking connections" (23%). Conclusion: VIADS helped inexperienced clinical researchers use fewer cognitive events to generate hypotheses than the control group. This suggests that VIADS may guide participants to be more structured during hypothesis generation compared with the control group. The results provide evidence to explain the shorter average time needed by the VIADS group in generating each hypothesis.

Data-driven hypothesis generation among inexperienced clinical researchers: A comparison of secondary data analyses with visualization (VIADS) and other tools.

Objectives: To compare how clinical researchers generate data-driven hypotheses with a visual interactive analytic tool (VIADS, a visual interactive analysis tool for filtering and summarizing large data sets coded with hierarchical terminologies) or other tools. Methods: We recruited clinical researchers and separated them into "experienced" and "inexperienced" groups. Participants were randomly assigned to a VIADS or control group within the groups. Each participant conducted a remote 2-hour study session for hypothesis generation with the same study facilitator on the same datasets by following a think-aloud protocol. Screen activities and audio were recorded, transcribed, coded, and analyzed. Hypotheses were evaluated by seven experts on their validity, significance, and feasibility. We conducted multilevel random effect modeling for statistical tests. Results: Eighteen participants generated 227 hypotheses, of which 147 (65%) were valid. The VIADS and control groups generated a similar number of hypotheses. The VIADS group took a significantly shorter time to generate one hypothesis (e.g., among inexperienced clinical researchers, 258 seconds versus 379 seconds, p = 0.046, power = 0.437, ICC = 0.15). The VIADS group received significantly lower ratings than the control group on feasibility and the combination rating of validity, significance, and feasibility. Conclusion: The role of VIADS in hypothesis generation seems inconclusive. The VIADS group took a significantly shorter time to generate each hypothesis. However, the combined validity, significance, and feasibility ratings of their hypotheses were significantly lower. Further characterization of hypotheses, including specifics on how they might be improved, could guide future tool development.

A Visual Analytic Tool (VIADS) to Assist the Hypothesis Generation Process in Clinical Research: Mixed Methods Usability Study.

BACKGROUND: Visualization can be a powerful tool to comprehend data sets, especially when they can be represented via hierarchical structures. Enhanced comprehension can facilitate the development of scientific hypotheses. However, the inclusion of excessive data can make visualizations overwhelming. OBJECTIVE: We developed a visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS). In this study, we evaluated the usability of VIADS for visualizing data sets of patient diagnoses and procedures coded in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). METHODS: We used mixed methods in the study. A group of 12 clinical researchers participated in the generation of data-driven hypotheses using the same data sets and time frame (a 1-hour training session and a 2-hour study session) utilizing VIADS via the think-aloud protocol. The audio and screen activities were recorded remotely. A modified version of the System Usability Scale (SUS) survey and a brief survey with open-ended questions were administered after the study to assess the usability of VIADS and verify their intense usage experience with VIADS. RESULTS: The range of SUS scores was 37.5 to 87.5. The mean SUS score for VIADS was 71.88 (out of a possible 100, SD 14.62), and the median SUS was 75. The participants unanimously agreed that VIADS offers new perspectives on data sets (12/12, 100%), while 75% (8/12) agreed that VIADS facilitates understanding, presentation, and interpretation of underlying data sets. The comments on the utility of VIADS were positive and aligned well with the design objectives of VIADS. The answers to the open-ended questions in the modified SUS provided specific suggestions regarding potential improvements for VIADS, and the identified problems with usability were used to update the tool. CONCLUSIONS: This usability study demonstrates that VIADS is a usable tool for analyzing secondary data sets with good average usability, good SUS score, and favorable utility. Currently, VIADS accepts data sets with hierarchical codes and their corresponding frequencies. Consequently, only specific types of use cases are supported by the analytical results. Participants agreed, however, that VIADS provides new perspectives on data sets and is relatively easy to use. The VIADS functionalities most appreciated by participants were the ability to filter, summarize, compare, and visualize data. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/39414.

Development, validation, and usage of metrics to evaluate the quality of clinical research hypotheses.

Objectives: Metrics and instruments can provide guidance for clinical researchers to assess their potential research projects at an early stage before significant investment. Furthermore, metrics can also provide structured criteria for peer reviewers to assess others' clinical research manuscripts or grant proposals. This study aimed to develop, test, validate, and use evaluation metrics and instruments to accurately, consistently, and conveniently assess the quality of scientific hypotheses for clinical research projects. Materials and Methods: Metrics development went through iterative stages, including literature review, metrics and instrument development, internal and external testing and validation, and continuous revisions in each stage based on feedback. Furthermore, two experiments were conducted to determine brief and comprehensive versions of the instrument. Results: The brief version of the instrument contained three dimensions: validity, significance, and feasibility. The comprehensive version of metrics included novelty, clinical relevance, potential benefits and risks, ethicality, testability, clarity, interestingness, and the three dimensions of the brief version. Each evaluation dimension included 2 to 5 subitems to evaluate the specific aspects of each dimension. For example, validity included clinical validity and scientific validity. The brief and comprehensive versions of the instruments included 12 and 39 subitems, respectively. Each subitem used a 5-point Likert scale. Conclusion: The validated brief and comprehensive versions of metrics can provide standardized, consistent, and generic measurements for clinical research hypotheses, allow clinical researchers to prioritize their research ideas systematically, objectively, and consistently, and can be used as a tool for quality assessment during the peer review process.

The Roles of a Secondary Data Analytics Tool and Experience in Scientific Hypothesis Generation in Clinical Research: Protocol for a Mixed Methods Study.

BACKGROUND: Scientific hypothesis generation is a critical step in scientific research that determines the direction and impact of any investigation. Despite its vital role, we have limited knowledge of the process itself, thus hindering our ability to address some critical questions. OBJECTIVE: This study aims to answer the following questions: To what extent can secondary data analytics tools facilitate the generation of scientific hypotheses during clinical research? Are the processes similar in developing clinical diagnoses during clinical practice and developing scientific hypotheses for clinical research projects? Furthermore, this study explores the process of scientific hypothesis generation in the context of clinical research. It was designed to compare the role of VIADS, a visual interactive analysis tool for filtering and summarizing large data sets coded with hierarchical terminologies, and the experience levels of study participants during the scientific hypothesis generation process. METHODS: This manuscript introduces a study design. Experienced and inexperienced clinical researchers are being recruited since July 2021 to take part in this 2×2 factorial study, in which all participants use the same data sets during scientific hypothesis-generation sessions and follow predetermined scripts. The clinical researchers are separated into experienced or inexperienced groups based on predetermined criteria and are then randomly assigned into groups that use and do not use VIADS via block randomization. The study sessions, screen activities, and audio recordings of participants are captured. Participants use the think-aloud protocol during the study sessions. After each study session, every participant is given a follow-up survey, with participants using VIADS completing an additional modified System Usability Scale survey. A panel of clinical research experts will assess the scientific hypotheses generated by participants based on predeveloped metrics. All data will be anonymized, transcribed, aggregated, and analyzed. RESULTS: Data collection for this study began in July 2021. Recruitment uses a brief online survey. The preliminary results showed that study participants can generate a few to over a dozen scientific hypotheses during a 2-hour study session, regardless of whether they used VIADS or other analytics tools. A metric to more accurately, comprehensively, and consistently assess scientific hypotheses within a clinical research context has been developed. CONCLUSIONS: The scientific hypothesis-generation process is an advanced cognitive activity and a complex process. Our results so far show that clinical researchers can quickly generate initial scientific hypotheses based on data sets and prior experience. However, refining these scientific hypotheses is a much more time-consuming activity. To uncover the fundamental mechanisms underlying the generation of scientific hypotheses, we need breakthroughs that can capture thinking processes more precisely. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39414.

Age of Peak Performance Differs by Functional Task in Mice Tracked Over 2 Years.

Mouse models are often used to validate novel interventions prior to human testing, although biological differences between mice and humans limit the translatability of outcomes. A common assumption in animal research is that maximal physical performance will be present at a young age, and that differences in task performance between young and old can be attributed to the aging process. However, this may not be true for all physical function tasks, and leaving out intermediate time points could drastically alter data interpretation. Here, we document age-related changes in forelimb and hindlimb grip strength, balance and coordination, and body composition in mice (n = 43) collected at multiple time points between 4 and 24 months of age. Maximal forelimb grip strength was recorded at 4 months of age, but maximal hindlimb grip strength was recorded at 15 months of age. Balance performance was stable from 4 to 15 months of age, declining significantly at 18 months. Both lean and fat mass peaked at 18 months before declining steadily. We conclude that the inclusion of intermediate time points is essential for the accurate evaluation of physical function status in mice, particularly in the context of translating intervention outcomes into strategies to be tested in humans.

Sex differences in body composition but not neuromuscular function following long-term, doxycycline-induced reduction in circulating levels of myostatin in mice.

Age-related declines in muscle function result from changes in muscle structure and contractile properties, as well as from neural adaptations. Blocking myostatin to drive muscle growth is one potential therapeutic approach. While the effects of myostatin depletion on muscle characteristics are well established, we have very little understanding of its effects on the neural system. Here we assess the effects of long-term, post-developmental myostatin reduction on electrophysiological motor unit characteristics and body composition in aging mice. We used male (N = 21) and female (N = 26) mice containing a tetracycline-inducible system to delete the myostatin gene in skeletal muscle. Starting at 12 months of age, half of the mice were administered doxycycline (tetracycline) through their chow for one year. During that time we measured food intake, body composition, and hindlimb electromyographic responses. Doxycycline-induced myostatin reduction had no effect on motor unit properties for either sex, though significant age-dependent declines in motor unit number occurred in all mice. However, treatment with doxycycline induced different changes in body composition between sexes. All female mice increased in total, lean and fat mass, but doxycycline-treated female mice experienced a significantly larger increase in lean mass than controls. All male mice also increased total and lean mass, but administration of doxycycline had no effect. Additionally, doxycycline-treated male mice maintained their fat mass at baseline levels, while the control group experienced a significant increase from baseline and compared to the doxycycline treated group. Our results show that long-term administration of doxycycline results in body composition adaptations that are distinctive between male and female mice, and that the effects of myostatin reduction are most pronounced during the first three months of treatment. We also report that age-related changes in motor unit number are not offset by reduced myostatin levels, despite increased lean mass exhibited by female mice.

A visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS).

BACKGROUND: Vast volumes of data, coded through hierarchical terminologies (e.g., International Classification of Diseases, Tenth Revision-Clinical Modification [ICD10-CM], Medical Subject Headings [MeSH]), are generated routinely in electronic health record systems and medical literature databases. Although graphic representations can help to augment human understanding of such data sets, a graph with hundreds or thousands of nodes challenges human comprehension. To improve comprehension, new tools are needed to extract the overviews of such data sets. We aim to develop a visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS) as an online, and publicly accessible tool. The ultimate goals are to filter, summarize the health data sets, extract insights, compare and highlight the differences between various health data sets by using VIADS. The results generated from VIADS can be utilized as data-driven evidence to facilitate clinicians, clinical researchers, and health care administrators to make more informed clinical, research, and administrative decisions. We utilized the following tools and the development environments to develop VIADS: Django, Python, JavaScript, Vis.js, Graph.js, JQuery, Plotly, Chart.js, Unittest, R, and MySQL. RESULTS: VIADS was developed successfully and the beta version is accessible publicly. In this paper, we introduce the architecture design, development, and functionalities of VIADS. VIADS includes six modules: user account management module, data sets validation module, data analytic module, data visualization module, terminology module, dashboard. Currently, VIADS supports health data sets coded by ICD-9, ICD-10, and MeSH. We also present the visualization improvement provided by VIADS in regard to interactive features (e.g., zoom in and out, customization of graph layout, expanded information of nodes, 3D plots) and efficient screen space usage. CONCLUSIONS: VIADS meets the design objectives and can be used to filter, summarize, compare, highlight and visualize large health data sets that coded by hierarchical terminologies, such as ICD-9, ICD-10 and MeSH. Our further usability and utility studies will provide more details about how the end users are using VIADS to facilitate their clinical, research or health administrative decision making.

Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors.

Selective serotonin reuptake inhibitor medications (SSRIs) are prescribed to up to 10% of pregnant women to treat maternal mood disorders. Exposure to these medications in-utero has raised concerns about altered neurobehavioral outcomes; most recently those related to peer-to-peer social interactions and play. While clinical data show that both perinatal SSRIs (pSSRI) and maternal stress can contribute to social behavioral changes in children, minimal animal work has investigated the effects of pSSRIs in relevant models of maternal stress or the long-term implications of these effects. Therefore the aim of this work was to investigate the long-term effects of pSSRI exposure to fluoxetine on social behaviors, the hypothalamic pituitary adrenal system (HPA) and hippocampal plasticity in adult male and female rat offspring using a model of pre-gestational maternal stress. Adult Sprague-Dawley female and male rat offspring from the following four groups were utilized: 1. Control + Vehicle, 2. Control + Fluoxetine, 3. Pre-gestational Stress + Vehicle, 4. Pre-gestational Stress + Fluoxetine (n = 8-16/female/age groups, n = 8-14/male/age groups). Main findings show pSSRIs increased social investigation in adult females and increased social play (pouncing, nape attacks) in adult males. Perinatal SSRIs also had sexually differentiated effects on hippocampal neurogenesis and GR density. Pre-gestational stress had enduring effects by decreasing social investigation and hippocampal neurogenesis in adult males. Thus pSSRIs, as well as pre-gestational maternal stress, have significant long-term effects on social neurobehavioral outcomes which differ in males and females. This suggests that it would be valuable to consider fetal-sex specific treatments for maternal mental illness.

Relative Contributions of Myostatin and the GH/IGF-1 Axis in Body Composition and Muscle Strength.

Myostatin, a negative regulator of muscle growth, is considered a potential therapeutic agent for individuals suffering from various muscle wasting and strength declining diseases because inhibiting Mstn signaling leads to muscular hypertrophy. In this study we investigate the interaction between myostatin and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in muscle function and strength. To this end, we measured hind limb grip strength and myostatin levels in two mouse models of GH gene manipulation; GH receptor knockout (GHR-/-) mice which have reduced GH/IGF-1 action, and bovine GH transgenic (bGH) mice which have excess GH/IGF-1 action. We found that specific muscle force was significantly reduced in bGH mice, and significantly increased in GHR-/- mice, compared to their respective littermate wild type controls. The expression of the mature form of myostatin was significantly increased in bGH mice, and unchanged in GHR-/- mice. In the bGH mice, the high levels of mature myostatin were accompanied by increase body weight and lean mass, consistent with other published results indicating that the IGF-1 signaling pathway is dominant over that of Mstn. Our results also suggest that in these mouse models there is an inverse relationship between muscle strength and levels of myostatin and GH, since constitutive overexpression of GH resulted in elevated levels of mature myostatin in muscle, accompanied by a reduction in strength. By contrast, in the GHR-/- mice with reduced levels of IGF-1, mature myostatin levels were unchanged and muscle strength was increased.

Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress.

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring.

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning.

Effect of Postnatal Myostatin Inhibition on Bite Mechanics in Mice.

As a negative regulator of muscle size, myostatin (Mstn) impacts the force-production capabilities of skeletal muscles. In the masticatory system, measures of temporalis-stimulated bite forces in constitutive myostatin KOs suggest an absolute, but not relative, increase in jaw-muscle force. Here, we assess the phenotypic and physiologic impact of postnatal myostatin inhibition on bite mechanics using an inducible conditional KO mouse in which myostatin is inhibited with doxycycline (DOX). Given the increased control over the timing of gene inactivation in this model, it may be more clinically-relevant for developing interventions for age-associated changes in the musculoskeletal system. DOX was administered for 12 weeks starting at age 4 months, during which time food intake was monitored. Sex, age and strain-matched controls were given the same food without DOX. Bite forces were recorded just prior to euthanasia after which muscle and skeletal data were collected. Food intake did not differ between control or DOX animals within each sex. DOX males were significantly larger and had significantly larger masseters than controls, but DOX and control females did not differ. Although there was a tendency towards higher absolute bite forces in DOX animals, this was not significant, and bite forces normalized to masseter mass did not differ. Mechanical advantage for incisor biting increased in the DOX group due to longer masseter moment arms, likely due to a more anteriorly-placed masseter insertion. Despite only a moderate increase in bite force in DOX males and none in DOX females, the increase in masseter mass in males indicates a potentially positive impact on jaw muscles. Our data suggest a sexual dimorphism in the role of mstn, and as such investigations into the sex-specific outcomes is warranted.

The value of partnerships in science education: a win-win situation.

An editorial in Science (Alberts, 2012) has expressed the need to teach "real science," firmly based on hands-on and inquiry methodology. Also in a recent article, Stevens (2011) highlighted the contrast between the emphasis that federal agencies and professional associations place on science outreach, and the scarcity of support for such activities at the classroom level. To bridge this gap, we have developed a way to redefine science education by involving college students and faculty in "real science" outreach. Incorporating outreach activities into a college science curriculum is an efficient means to affect not only future scientists but also the world at large with which scientists need to communicate. In this paper we describe a Science Education Partnership Award (SEPA) project. The project has been implemented in a minority setting, at a small college of allied health located in one of the most underserved areas of Los Angeles. Some of its outcomes were presented at two Society for Neuroscience meetings (Gizerian et al., 2009; Ayers and de Lacalle, 2010), before being also discussed as an example of outreach program during the FUN summer workshop in Pomona (California) in 2011. This project entails the development of a working partnership between K-12 institutions and college science students and faculty. Participation was voluntary (but college students could request community service credit) and most importantly built on student interests and connections with the community. The three components are described in terms of efficacy (i.e., impact on college students' communication skills) and community value (i.e., impact on educational outcomes for the partner K-12 institution).

Astrocytic reaction to a lesion, under hormonal deprivation.

Gonadal hormones can influence the morphology and function of glial cells, particularly astrocytes. Here we explore the hypothesis that 17beta-estradiol (E2) exerts a positive effect on astrocytes within the region of the cholinergic neurons of the basal forebrain, an area heavily implicated in memory and attentional processes. Female rats were ovariectomized at 3 months of age and lesioned with the immunotoxin 192 IgG-saporin before receiving a subcutaneous pellet containing 0.25mg of estrogen or placebo, released over 60 days. The control, non-ovariectomized group was treated identically. At the end of the treatment, we used image analysis procedures to evaluate changes in the levels of glial fibrillary acidic protein (GFAP) expression in the area of the lesion. Infusion of the immunotoxin induced a slight increase in GFAP expression in some subjects, compared to the contralateral side. However, when differences within animals where factored in, GFAP expression in ovariectomized animals treated with E2 was undistinguishable from intact controls. By contrast, in ovariectomized animals treated with placebo, GFAP expression was significantly higher. These results suggest that E2 deprivation may exacerbate the effects of an immunotoxic lesion, and, more importantly, that E2 administration may contribute to structural recovery of lesioned cholinergic neurons by blocking GFAP expression in the area. These results are particularly relevant in the context of female aging and postmenopausal dementia, and further highlight other potential levels at which to design interventions to preserve an intact cholinergic system, which may be crucial to prevent Alzheimer's disease.