Professional Development within Bachelors Programs: Addressing the Needs of a Diverse Student Population Entering Health Care

Following graduation from an undergraduate institution, students have the perception that they have the skills necessary to be successful in the workforce and/or graduate studies, however employers and professors do not agree. Professional development during undergraduate studies may help bridge the gap between student and employer/professor perceptions. Based on the discrepancies in post-graduation readiness perception and the number underrepresented minorities in health care and post-graduate studies, the Bachelor of Health Sciences (BSHS) program at Rush University established a professional development program with the goal of providing students seminars that  enhance their professional and social skills. Offering a professional development program ensures that students gain and maintain relevant academic and non-academic competencies that will support them in their academics and prepare them for their professional careers, which can be particularly effective for students from diverse racial and ethnic backgrounds and students studying within a diverse cohort. Surveys were conducted to determine the perception of effective and usefulness of each seminar as well as utility of the tools provided to students in each seminar during their academic and professional career. Overall, the professional development seminar series improved student utilization and application of tools provided at each seminar to improve student perception of readiness and gain confidence in their academic and professional development. The seminars also positively influenced formation of diverse relationships, as many of the tools provided were used in personal and social situations. A dynamic professional development program can provide useful tools and improve readiness perception in a diverse student population within an undergraduate program. As graduate programs and companies across the country continue to expand their diversity initiatives, professional development during undergraduate studies becomes even more relevant as it addresses their ability to be successful and resilient. Keywords: Professional Development, Diversity, Bachelors, Health Care DOI: 10.7176/JEP/11-29-02 Publication date:October 31st 202

Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction

Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction

Localized conformational change in the hinge region of human p38αMAPK when a non-selective inhibitor is bound.

<p><b>A.</b> Electron density maps (2mFo-Dfc; colored in light gray) contoured at 1.5 rmsd for the hinge region of p38αMAPK near Gly110 for 4F9W (in complex with MW108) and for 4FA2 (in complex with SB239063) are shown. Differences in the electron density path are seen in the area around Gly110, indicated by arrows. <b>B.</b> A superposition of 4F9W and 4FA2 reveals the differences around the peptide bond at Met109-Gly110, referred to as a glycine flip for structures such as 4FA2.</p

Data collection and phasing statistics. Values in parentheses are for highest resolution shell.

<p>Data collection and phasing statistics. Values in parentheses are for highest resolution shell.</p

Characterization of selective p38αMAPK inhibitors MW108 (panel A) and MW181 (panel B).

<p>The title compounds were characterized in terms of their physical characteristics, target selectivity, and pharmacological properties.</p

Synthesis of p38αMAPK inhibitor analogs and initial screens for differential p38αMAPK vs CK1δ inhibition and for improvement in high dose tolerance.

<p>The affinity of compounds for p38αMAPK and CK1δ is shown, as well as the highest dose at which no adverse events are observed in dose escalation studies.</p

Discovery synthetic scheme for title compounds.

<p>Reagents and conditions: i) Hydrazine sulphate, H₂O, 100°C; ii) Pyridin-4-ylboronic acid; 1,2-dimethoxyethane (DME)/water, Na₂CO₃, Pd(PPh₃)₄, 110°C; iii) phosphorus oxychloride/acetonitrile, 90°C; iv) Ethanol, amine, reflux; v) 1- or 2- Naphthylboronic acid, DME/water, Na₂CO₃, Pd(PPh₃)₄, 110°C; vi) concentrated HCl, anhydrous isopropanol, 80°C.</p

Attenuation of Aβ₄₂-induced synaptic and cognitive dysfunction by MW108 administration.

<p><b>A.</b> MW108 ameliorated the LTP deficit in Aβ₄₂-treated slices (n = 7–8 slices/group; F(1,13) = 17.25, p = 0.0011, compared to slices treated only with Aβ₄₂). Horizontal bar = time of application of Aβ₄₂ and MW108. <b>B.</b> MW108 ameliorated the reference memory deficit in Aβ₄₂-infused mice (n = 10–14 mice/group; F(1,24) = 1.827, p = 0.0001 comparing Aβ-infused vs. Aβ-infused+compound). <b>C.</b> MW108 ameliorated the contextual fear memory deficit in Aβ₄₂-infused mice (n = 16-18 mice/group; p = 0.009 comparing Aβ-infused vs. Aβ-infused+compound). <b>D-E.</b> No difference was detected between groups when tested for visual-motor-motivational deficits with the visible platform test; speed and time to the platform are shown in D and E, respectively (n = 10–14 mice/group). <b>F.</b> The same animals that underwent contextual fear conditioning testing were assessed for cued learning 24 hrs after the contextual learning. No difference was detected between groups (n = 16–18 mice/group). <b>G.</b> Sensory threshold was not affected regardless of treatment (n = 13–17 mice/group). <b>H-I.</b> No differences in exploratory behavior, as shown by a similar percentage of time spent in the center compartment (H) and the number of entries into the center compartment (I), were observed (n = 13–17 mice/group).</p