Widening the Road to Health Professions Education: Expanding Access for Diverse and Underserved Populations.

The Spring 2023 Webinar Audio Seminar (WAS) of the International Association of Medical Science Educators (IAMSE), titled "Widening the Road to Health Professions Education: Expanding Access for Diverse and Underserved Populations," was designed to help health science educators explore innovative practices in recruiting and enrolling students from underserved populations into health sciences programs. From March 2, 2023, to March 30, 2023, this five-part webinar series was broadcast live to institutions and educators worldwide. This series helped participants learn about creating pathways for students to meet the unique needs of their communities.

TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis.

Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart.

Back to the Future: Maximizing Student Learning and Wellbeing in the Virtual Age.

The virtual age of learning is no longer a concern of the future. It is here. The Fall 2021 Webinar Audio Series (WAS) of the International Association of Medical Science Educators (IAMSE), titled "Back to the Future: Maximizing Student Learning and Wellbeing in the Virtual Age," was designed to help health science educators equip themselves with tools to teach the next generation of health care professionals successfully. From September 2, 2021 to September 30, 2021, the Fall 2021 Series was broadcast live to audiences at academic institutions worldwide in five weekly webinars. This five-part webinar series explored theories and best practices in delivering content over virtual and online media while simultaneously promoting a positive learning environment and enhanced student wellbeing.

To Infinity and Beyond: Expanding the Scope of Basic Sciences in Meeting Accreditation Standards.

Interprofessional training, social sciences curricula, service-learning, pre-clerkship integration, and self-directed learning are all cornerstones of medical education and closely align with accreditation elements for most accreditation bodies within health professions education. As a sequel to the Winter 2022 series, the Spring 2022 Webcast Audio Seminar (WAS) of the International Association of Medical Science Educators (IAMSE) continued to examine the evolving roles of basic science educators. From March 3 to March 31, 2022, the five-part webinar series was broadcast live to audiences at academic institutions worldwide; recordings are available on the IAMSE website. This series built a framework through which basic scientists can leverage their content to meet various accreditation standards.

Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells.

We previously described a critical role for a fibroblast precursor population in the development of a murine fibrotic cardiomyopathy model (I/RC). These precursors arose from circulating bone marrow-derived cells of monocytic origin. Administration of serum amyloid P (SAP) prevented the presence of this cell population in the heart and the cardiomyopathy. Because SAP binds to Fc receptors (FcRs) expressed on monocytes, we investigated the involvement of FcR signaling. We chose mice lacking the FcRgamma chain protein (FcRgamma(-/-)), a common membrane-signaling component of activating FcRs. Like wild-type mice, FcRgamma(-/-) mice developed fibrosis and cardiac dysfunction when subjected to I/RC. However, unlike wild-type mice, SAP in FcRgamma(-/-) mice failed to inhibit the development of fibrosis and cardiac dysfunction and did not diminish the numbers of alpha-smooth muscle actin(+) and CD34(+), CD45(+) fibroblasts that were typical for I/RC. To further examine the role of SAP in monocyte-to-fibroblast transition, we performed in vitro assays in which human peripheral blood mononuclear cells (PBMCs) migrated through human umbilical vein endothelial cells (HUVECs). We found that MCP-1-dependent transendothelial migration of monocytes markedly accelerated their differentiation into fibroblasts. This monocyte differentiation to fibroblasts was eliminated when SAP was added to the PBMC suspension before endothelial transmigration. Adding SAP to cells after successful migration did not inhibit fibroblast maturation. These data indicate that SAP inhibits the differentiation of a blood-borne, myeloid cell population into fibroblasts by signaling through activating FcRs before transendothelial migration has occurred. We suggest that FcR activation of circulating precursor cells may represent a new treatment target for adverse remodeling and cardiac fibrosis.

USMLE Step-1 is Going to Pass/Fail, Now What Do We Do?

The Winter 2021 Webinar Audio Series (WAS) of the International Association of Medical Science Educators (IAMSE), titled, "USMLE Step-1 is Going to Pass/Fail, Now what do we do?" was broadcast live to audiences at academic institutions worldwide in five weekly webinars from January 7, 2021, to February 4, 2021. Recognized experts from various stakeholder groups discussed the impact of the decision to score the United States Medical Licensing Examination (USMLE) Step 1 exam Pass/Fail (P/F). The speakers identified challenges to their respective programs and explored creative ways to address potential consequences. Sessions included the perspectives of allopathic and osteopathic residency program directors, basic science faculty, undergraduate medical education curriculum designers, clinical educators, and programs for international medical students matriculating to the United States. On February 25, 2021, a bonus session provided cutting-edge updates from a co-chair of the Coalition for Physician Accountability Undergraduate Medical Education (UME) to Graduate Medical Education (GME) Review Committee (UGRC).

Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.

Angiotensin-II (Ang-II) is an autacoid generated as part of the pathophysiology of cardiac hypertrophy and failure. In addition to its role in cardiac and smooth muscle contraction and salt retention, it was shown to play a major role in the cardiac interstitial inflammatory response and fibrosis accompanying cardiac failure. In this study, we examined a model of Ang-II infusion to clarify the early cellular mechanisms linking interstitial fibrosis with the onset of the tissue inflammatory response. Continuous infusion of Ang-II resulted in increased deposition of collagen in the heart. Ang-II infusion also resulted in the appearance of distinctive small, spindle-shaped, bone marrow-derived CD34(+)/CD45(+) fibroblasts that expressed collagen type I and the cardiac fibroblast marker DDR2 while structural fibroblasts were CD34(-)/CD45(-). Genetic deletion of monocyte chemoattractant protein (MCP)-1 (MCP-1-KO mice) prevented the Ang-II-induced cardiac fibrosis and the appearance of CD34(+)/CD45(+) fibroblasts. Real-time PCR in Ang-II-treated hearts revealed a striking induction of types I and III collagen, TGF-beta1, and TNF mRNA expression; this was obviated in Ang-II-infused MCP-1-KO hearts. In both wild-type and MCP-1-KO mice, Ang-II infusion resulted in cardiac hypertrophy, increased systolic function and hypertension which were not significantly different between the WT and MCP-1-KO mice over the 6-week course of infusion. In conclusion, the development of Ang-II-induced non-adaptive fibrosis in the heart required induction of MCP-1, which modulated the uptake and differentiation of a CD34(+)/CD45(+) fibroblast precursor population. In contrast to the inflammatory and fibrotic response, the hemodynamic response to Ang-II was not affected by MCP-1 in the first 6weeks.

TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways.

Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.

TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function.

Angiotensin-II (Ang-II) infusion is associated with the development of interstitial fibrosis in both heart and kidney as a result of chemokine-dependent uptake of monocytes and subsequent development of myeloid fibroblasts. This study emphasizes on the synergistic role of tumor necrosis factor (TNF) on the time course of Ang-II-induced fibrosis and inflammation in heart and kidney. In wild-type (WT) hearts, Ang-II-induced fibrosis peaked within 1 week of infusion and remained stable over a 6-week period, while the myeloid fibroblasts disappeared; TNF receptor-1-knockout (TNFR1-KO) hearts did not develop a myeloid response or cardiac fibrosis during this time. WT hearts developed more accelerated cardiac hypertrophy and remodeling than TNFR1-KO In the kidney, 1-week Ang-II infusion did not evoke a fibrotic response; however, after 6 weeks, WT kidneys displayed modest but significant tubulointerstitial collagen deposition associated with the appearance of myeloid cells and profibrotic gene activation. Renal fibrosis was not seen in Ang-II-infused TNFR1-KO By contrast, while hypertension increased and cardiac function decreased more slowly in TNFR1-KO than WT, they were equivalently abnormal at 6 weeks. Similarly, serum markers for renal dysfunction were not different after 6 weeks. In conclusion, Ang-II infusion initiated fibroinflammatory responses with different time courses in heart and kidney, both requiring TNFR1 signaling, and both associated with monocyte-derived myeloid fibroblasts. TNFR1 deletion obviated the fibroinflammatory effects of Ang-II, but did not alter changes in blood pressure and cardiorenal function after 6 weeks. Thus, the synergy of TNF with Ang-II targets the fibroinflammatory component of Ang-II signaling.

Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction.

BACKGROUND: Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor kappaB (NF-kappaB) and given that NF-kappaB mediates cytoprotective responses, we asked whether NF-kappaB activation conferred cytoprotective responses in acute myocardial ischemia/infarction. METHODS AND RESULTS: We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IkappaBalpha protein (IkappaBalphaDeltaN) that prevents nuclear translocation of NF-kappaB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was approximately 50% greater (P<0.02) in the IkappaBalphaDeltaN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IkappaBalphaDeltaN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IkappaBalphaDeltaN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. CONCLUSIONS: Transgenic mice with a defect in activation of NF-kappaB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-kappaB are mediated, at least in part, by Bcl-2 or c-IAP1.

Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis.

BACKGROUND: Continuous angiotensin-II infusion induced the uptake of monocytic fibroblast precursors that initiated the development of cardiac fibrosis; these cells and concurrent fibrosis were absent in mice lacking tumor necrosis factor receptor 1 (TNFR1). We now investigated their cellular origin and temporal uptake and the involvement of TNFR1 in monocyte-to-fibroblast differentiation. METHODS AND RESULTS: Within a day, angiotensin-II induced a proinflammatory environment characterized by production of inflammatory chemokines, cytokines, and TH1-interleukins and uptake of bone marrow-derived M1 cells. After a week, the cardiac environment changed to profibrotic with growth factor and TH2-interleukin synthesis, uptake of bone marrow-derived M2 cells, and the presence of M2-related fibroblasts. TNFR1 signaling was not necessary for early M1 uptake, but its absence diminished the amount of M2 cells. TNFR1-knockout hearts also showed reduced levels of cytokine expression, but not of TH-related lymphokines. Reconstitution of wild-type bone marrow into TNFR1-knockout mice was sufficient to restore M2 uptake, upregulation of proinflammatory and profibrotic genes, and development of fibrosis in response to angiotensin-II. We also developed an in vitro mouse monocyte-to-fibroblast maturation assay that confirmed the essential role of TNFR1 in the sequential progression of monocyte activation and fibroblast formation. CONCLUSIONS: Development of cardiac fibrosis in response to angiotensin-II was mediated by myeloid precursors and consisted of 2 stages. A primary M1 inflammatory response was followed by a subsequent M2 fibrotic response. Although the first phase seemed to be independent of TNFR1 signaling, the later phase (and development of fibrosis) was abrogated by deletion of TNFR1.