Teaching Undergraduates to Communicate Science, Cultivate Mentoring Relationships, and Navigate Science Culture.

The historic underrepresentation of women, certain racial and ethnic minorities, and members of other marginalized groups in careers in science, technology, engineering, and mathematics (STEM) reflects a disproportionate exit of individuals from these academic and career paths due to both environmental and personal factors. To transition successfully from classroom-based learning to the research environment, students must acquire various forms of capital nested within a largely hidden curriculum that most scientists learn informally. We have developed a semester-long course for undergraduate researchers that makes explicit concepts and strategies that contribute to STEM persistence. The course teaches skills for: 1) scientific communication; 2) maximizing the effectiveness of research mentoring relationships; and 3) navigating scientific culture and its interactions with multiple social identities. We offered the course for three consecutive semesters at the University of Massachusetts Boston to 33 students from different backgrounds, academic majors, and educational experiences. Quantitative and qualitative assessments demonstrated student learning in all three areas of emphasis. By deliberately combining instruction and practice in skills, such as those needed to present and critique scientific research, with skills needed to optimize personal interactions and key research relationships, we have created a novel learning experience to promote persistence in STEM.

The Health Equity Scholars Program: Innovation in the Leaky Pipeline.

Despite attempts to increase enrollment of under-represented minorities (URMs: primarily Black/African American, Hispanic/Latino, and Native American students) in health professional programs, limited progress has been made. Compelling reasons to rectify this situation include equity for URMs, better prepared health professionals when programs are diverse, better quality and access to health care for UMR populations, and the need for diverse talent to tackle difficult questions in health science and health care delivery. However, many students who initiate traditional "pipeline" programs designed to link URMs to professional schools in health professions and the sciences, do not complete them. In addition, program requirements often restrict entry to highly qualified students while not expanding opportunities for promising, but potentially less well-prepared candidates. The current study describes innovations in an undergraduate pipeline program, the Health Equity Scholars Program (HESP) designed to address barriers URMs experience in more traditional programs, and provides evaluative outcomes and qualitative feedback from participants. A primary outcome was timely college graduation. Eighty percent (80%) of participants, both transfer students and first time students, so far achieved this outcome, with 91% on track, compared to the campus average of 42% for all first time students and 58-67% for transfers. Grade point averages also improved (p = 0.056) after program participation. Graduates (94%) were working in health care/human services positions and three were in health-related graduate programs. Creating a more flexible program that admits a broader range of URMs has potential to expand the numbers of URM students interested and prepared to make a contribution to health equity research and clinical care.

Iron homeostasis and erythropoiesis.

Erythrocytes require iron to perform their duty as oxygen carriers. Mammals have evolved a mechanism to maintain systemic iron within an optimal range that fosters erythroid development and function while satisfying other body iron needs. This chapter reviews erythroid iron uptake and utilization as well as systemic factors that influence iron availability. One of these factors is hepcidin, a circulating peptide hormone that maintains iron homeostasis. Elevated levels of hepcidin in the bloodstream effectively shut off iron absorption by disabling the iron exporter ferroportin. Conversely, low levels of circulating hepcidin allow ferroportin to export iron into the bloodstream. Aberrations in hepcidin expression or responsiveness to hepcidin result in disorders of iron deficiency and iron overload. It is clear that erythroid precursors communicate their iron needs to the liver to influence the production of hepcidin and thus the amount of iron available for use. However, the mechanism by which erythroid cells accomplish this remains unclear and is an area of active investigation.

Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin.

Progressive iron overload is the most salient and ultimately fatal complication of beta-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both beta-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by beta-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of beta-thalassemia.

Interleukin-6 induces hepcidin expression through STAT3.

Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation.

Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.