Integrins are cell adhesion receptors that mediate cell-tocell, or cell-to-extracellular matrix adhesion. They represent an attractive target for treatment of multiple diseases. Two classes of small molecule integrin inhibitors have been developed. Competitive antagonists bind directly to the integrin ligand binding pocket and thus disrupt the ligand-receptor interaction. Allosteric antagonists have been developed primarily for ␣ L  2 -integrin (LFA-1, lymphocyte function-associated antigen-1). Here we present the results of screening the Prestwick Chemical Library using a recently developed assay for the detection of ␣ 4  1 -integrin allosteric antagonists. Secondary assays confirmed that the compounds identified: 1) do not behave like competitive (direct) antagonists; 2) decrease ligand binding affinity for VLA-4 ϳ2 orders of magnitude; 3) exhibit antagonistic properties at low temperature. In a cell based adhesion assay in vitro, the compounds rapidly disrupted cellular aggregates. In accord with reports that VLA-4 antagonists in vivo induce mobilization of hematopoietic progenitors into the peripheral blood, we found that administration of one of the compounds significantly increased the number of colony-forming units in mice. This effect was comparable to AMD3100, a well known progenitor mobilizing agent. Because all the identified compounds are structurally related, previously used, or currently marketed drugs, this result opens a range of therapeutic possibilities for VLA-4-related pathologies.
Proline metabolism in mammals involves two other amino acids, glutamate and ornithine, and five enzymatic activities, Δ 1 -pyrroline-5-carboxylate (P5C) reductase (P5CR), proline oxidase, P5C dehydrogenase, P5C synthase and ornithine-δ-aminotransferase (OAT). With the exception of OAT, which catalyzes a reversible reaction, the other 4 enzymes are unidirectional, suggesting that proline metabolism is purpose-driven, tightly regulated, and compartmentalized. In addition, this tri-aminoacid system also links with three other pivotal metabolic systems, namely the TCA cycle, urea cycle, and pentose phosphate pathway. Abnormalities in proline metabolism are relevant in several diseases: six monogenic inborn errors involving metabolism and/or transport of proline and its immediate metabolites have been described. Recent advances in the Human Genome Project, in silico database mining techniques, and research in dissecting the molecular basis of proline metabolism prompted us to utilize functional genomic approaches to analyze human genes which encode proline metabolic enzymes in the context of gene structure, regulation of gene expression, mRNA variants, protein isoforms, and single nucleotide polymorphisms.
Background Shortly after the World Health Organization declared the SARS-CoV-2 outbreak a worldwide pandemic, medical school governing bodies issued guidance recommending pausing clinical rotations. Prior to the availability of COVD-19 vaccines, many schools implemented exclusively online curriculums in the didactic and clinical years. These unprecedented events and paradigm changes in medical education could contribute to trainee burnout, wellness, and mental health. Methods This single-institution study interviewed first, second, and third-year medical students from a medical school in the southwestern United States. A semi-structured interview was conducted with paper-based Likert scale questions rating perceived happiness were administered both at the time of the interview and one year later in order to understand how their student experience and happiness were impacted. In addition, we asked participants to describe any major life events they experienced since the first interview. Results Twenty-seven volunteers participated in the original interview. Twenty-four from the original cohort participated in the one-year follow-up. Happiness as a sense of self and who you “should be” was challenged during the pandemic and changes in happiness over time were not systematic across classes. Stress was caused not only by the pandemic which was experienced by all, but by a tripartite state of individual circumstances, academic workload requirements, and the world at large. Primary themes from the interviews were clustered around the individual, learner, and future professional levels and focused on the primacy of relationships, emotional wellness, stress management, professional identity, and impacts of educational disruptions. These themes created risk factors for developing imposter syndrome. Students demonstrated resiliency across cohorts and were able to utilize a variety of strategies to achieve and maintain both physical and mental health, but the primacy of relationships both personally and professionally was noted. Conclusion Medical students’ identities as individual persons, a learner, and future medical professionals were all impacted by the pandemic. The results from this study suggest that the COVID-19 pandemic and changes in the learning format and environment may create a new risk factor in the development of imposter syndrome. There is also an opportunity to re-consider resources to achieve and maintain wellness during a disrupted academic environment.
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