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Background: The MedZou Community Health Clinic at the University of Missouri School of Medicine is a student-run free clinic (SRFC) providing primary care and specialty services to uninsured patients of Missouri. Little is published about the relationship of volunteerism in SRFCs and residency match results. This study evaluated the association of SRFC volunteering on residency placement. We hy-pothesized that there would be an increased likelihood of medical students matching into specialties correlating with specialty clinics they volunteered with as students. Methods: We analyzed data on volunteers who graduated from the University of Missouri School of Medicine between 2010-2019 in this retrospective study. Selection criteria included students who per-mitted publishing their residency match results publicly and actively volunteered for MedZou (at least five volunteer shifts). Odds ratios (OR) were calculated with Fisher exact tests using a confidence in-terval (CI) of 95% to assess whether volunteering in a specialty clinic was associated with matching in that specialty. Clinics with at least five volunteers during the study period were analyzed (Dermatol-ogy, Musculoskeletal [MSK], and Neurology). Results: Twenty-nine percent of the MedZou volunteers that fit the inclusion criteria volunteered for the Dermatology, MSK, or Neurology Clinic. We found significant associations between those who volunteered in a specialty clinic and those who matched in a related specialty for Dermatology (OR = 4.25, 95% CI = 1.37, 12.13), Musculoskeletal (OR = 3.49, 95% CI = 1.45, 7.98), and Neurology Clinics (OR = 10.89, CI = 1.71, 50.39). Additionally, 51% of MedZou volunteers that fit inclusion criteria volunteered for Primary Care Clinic. These students were also found to have a significant association with matching into a related primary care specialty (OR= 2.01, CI= 1.14, 3.62). Conclusions: The results of this study indicated that clinical exposure at a SRFC specialty clinic was associated with residency match into related specialties.

Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy., CLN3 disease is characterised by childhood-onset vision loss and premature death. Using patient-derived retinal cells, the authors show that CLN3 is required for retinal pigment epithelium (RPE) cell structure, microvilli and phagocytosis of photoreceptor outer segments that are essential for vision. They further suggest that gene-therapy targeting RPE cells can be effective for CLN3 disease.

Retinal pigment epithelium (RPE) cell dysfunction is central to the pathogenesis of age-related macular degeneration (AMD), a leading cause of adult blindness. Aging, the single biggest risk factor for AMD development, favors increase in RPE autofluorescent material due to accumulation of POS-digestion by-products through lysosomal dysfunction and impaired POS degradation. Apart from aging, environmental agents affect lysosomal function in multiple model systems and are implicated in AMD. Iron (Fe) overload and cigarette smoke exposure are the two environmental factors that are known to affect the lysosomal pathway and impact RPE cell health. However, the impact of Fe and cigarette smoke, on POS processing and its consequence for autofluorescent material accumulation in human RPE cells are yet to be established. Human induced pluripotent stem cell (hiPSC)-derived RPE, which phagocytoses and degrades POS in culture and can be derived from control individuals (no history/susceptibility for retinal disease), provides a model system to investigate the singular effect of excess Fe and/or cigarette smoke on POS processing by RPE cells. Using at least three distinct control hiPSC lines, we show that, compared to untreated hiPSC-RPE cells, POS uptake is reduced in both Fe (ferric ammonium citrate or FAC) and FAC + CSE (cigarette smoke extract)-treated hiPSC-RPE cells. Furthermore, exposure of hiPSC-RPE cultures to FAC + CSE leads to reduced levels of active cathepsin-D (CTSD), a lysosomal enzyme involved in POS processing, and causes delayed degradation of POS. Notably, delayed degradation of POS over time (2 weeks) in hiPSC-RPE cells exposed to Fe and CSE was sufficient to increase autofluorescent material build-up in these cells. Given that inefficient POS processing-mediated autofluorescent material accumulation in RPE cells has already been linked to AMD development, our results implicate a causative role of environmental agents, like Fe and cigarette smoke, in AMD.

Investigations into stem cell-fueled renewal of an organ benefit from an inventory of cell type-specific markers and a deep understanding of the cellular diversity within stem cell niches. Using the adult mouse incisor as a model for a continuously renewing organ, we performed an unbiased analysis of gene co-expression relationships to identify modules of co-expressed genes that represent differentiated cells, transit-amplifying cells, and residents of stem cell niches. Through in vivo lineage tracing, we demonstrated the power of this approach by showing that co-expression module members Lrig1 and Igfbp5 define populations of incisor epithelial and mesenchymal stem cells. We further discovered that two adjacent mesenchymal tissues, the periodontium and dental pulp, are maintained by distinct pools of stem cells. These findings reveal novel mechanisms of incisor renewal and illustrate how gene co-expression analysis of intact biological systems can provide insights into the transcriptional basis of cellular identity. DOI: http://dx.doi.org/10.7554/eLife.24712.001, eLife digest To maintain healthy tissues and organs in adult animals, the cells that die or become damaged need to be replaced. This process is made possible by adult stem cells, which can divide to produce more stem cells (via a process called self-renewal) or specialize into other types of cells. This means that stem cells can maintain their own population by self-renewal while continually being able to generate specialized cells that replenish tissues and organs. Mouse incisor teeth are useful models to understand how adult organs are regenerated because, unlike human teeth, the incisor teeth of mice and other rodents grow continuously throughout the life of the animal. The tip of the mouse incisor is eroded as the animal eats, resulting in the loss of cells. A group of adult stem cells at the base of the tooth produce new cells that then move to the tip to replace the lost cells. Although virtually all cells in the body have the same set of genes, only small subsets are active in each cell type. It is possible to distinguish cells of different types by their patterns of gene activity. However, little is known about the gene expression patterns that distinguish stem cells and specialized cells in mouse incisors. Using a technique called gene co-expression analysis, Seidel et al. set out to identify all the genes that are active in stem cells and their descendants at the base of the mouse incisor. The experiments reveal the patterns of activity of thousands of genes, providing a clearer picture of the different cell types present and the biological processes at play. Seidel et al. then used other techniques to identify two genes that can be used as markers to identify distinct types of stem cells in the incisor. The next steps following on from this work will be to understand in more detail how stem cells behave in renewing the incisor. In the future, these findings may help guide the use of stem cells in regenerating human teeth and other organs. DOI: http://dx.doi.org/10.7554/eLife.24712.002