Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer's disease.

Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells in vitro. To test feasibility of this approach for Alzheimer's disease, we developed a cell morphology-based drug screen centred on the risk gene, SORL1 (which encodes the protein SORLA). Increased Alzheimer's disease risk has been repeatedly linked to variants in SORL1, particularly those conferring loss or decreased expression of SORLA, and lower SORL1 levels are observed in post-mortem brain samples from individuals with Alzheimer's disease. Consistent with its role in the endolysosomal pathway, SORL1 deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of SORL1-/- neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1-/- neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three SORL1-/- induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer's disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived SORL1-/- neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer's disease.

Comparative analysis of gender disparity in academic positions based on U.S. region and STEM discipline.

Despite a move toward gender parity in the United States (U.S.) workforce, a large gender gap persists in the fields of science, technology, engineering, and mathematics (STEM); this is particularly true for academic (i.e., instructor and tenure track) STEM positions. This gap increases as women advance through the traditional steps of academia, with the highest degree of gender disparity in tenured positions. As policies, politics, and culture, which all contribute to gender equity across the world, vary across regions in the United States, we expect that the gender gap in STEM might also vary across geographic regions. Here, we evaluated over 20,000 instructor and tenure track positions in university STEM departments across the U.S. to evaluate whether and how the geographic region of a university might determine its proportion of women in STEM academic positions. Similar to previous research, regardless of geographic region, more men were employed in both tenure track and instructor positions across STEM fields. However, variation existed regionally within the U.S., with the Mountain region employing the lowest proportion of women in tenure track positions and the East North Central and Pacific regions employing the greatest proportion. We expect this regional variation could be caused by differences in state and local policies, regional representation, and mentorship, resulting in inconsistent support for women, leading to differences in work environments, hiring, and job retention rates across the country. A better understanding of which geographic areas within the U.S. have more equal distributions of women in the STEM field will help us to identify the specific mechanisms that facilitate more equal and inclusive opportunities for women and other underrepresented groups across all levels of STEM academia.

An international collaborative approach to learning histology using a virtual microscope.

Histology is often taught in higher education settings using online virtual microscopes (VM). This study aimed to develop and evaluate the use of VM in teaching on a BSc degree at the University of Nottingham by surveying students and staff. A key development was the use of an e-workbook so that students were actively engaged in creating their own bespoke revision material. Subsequently, this approach was used in a second study evaluating the use of VM in teaching the histology and pathology of the gastrointestinal (GI) tract via group work with students from two BSc courses at the University of Nottingham; one based at Derby (RDHC) and the other in Malaysia (UNMC). Students worked together in groups to complete an e-workbook, develop a presentation, and decide how to collaborate and communicate. An evaluation of these activities revealed advantages in developing transferrable skills, and good engagement with both the histology topic and group work. Analysis of assessment of the module at UNMC showed that student performance improved in the histology-based module after the intervention (p < 0.01) and that this improvement was not evident in other modules taken by the cohort. Furthermore, when interrogating the questions from the examination paper that asked students to identify features from histological images, fewer questions were seen as 'difficult' (p < 0.001) and more were seen as 'average' (p < 0.01). This study demonstrates that the use of VM in histology combined with active learning in creating a revision resource enhances engagement and depth of learning. When further combined with collaborative active group work, students developed a range of histology knowledge and transferrable skills, with notable improvement in examination performance relative to other contemporaneous modules.

Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks.

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIß-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.

The Impact of Kindness in Medical Student Education in Rural South Dakota.

All medical students at the University of South Dakota Sanford School of Medicine (SSOM) have rural healthcare rotations. Because SSOM has adopted kindness as a focal point in its new five year strategic plan, we designed a qualitative study to assess students' perception of kindness in the rural setting.

Heart Transplantation in Children With Down Syndrome.

Background Children with Down syndrome (DS) have a high risk of cardiac disease that may prompt consideration for heart transplantation (HTx). However, transplantation in patients with DS is rarely reported. This project aimed to collect and describe waitlist and post- HTx outcomes in children with DS. Methods and Results This is a retrospective case series of children with DS listed for HTx. Pediatric HTx centers were identified by their participation in 2 international registries with centers reporting HTx in a patient with DS providing detailed demographic, medical, surgical, and posttransplant outcome data for analysis. A total of 26 patients with DS were listed for HTx from 1992 to 2020 (median age, 8.5 years; 46% male). High-risk or failed repair of congenital heart disease was the most common indication for transplant (N=18, 69%). A total of 23 (88%) patients survived to transplant. All transplanted patients survived to hospital discharge with a median posttransplant length of stay of 22 days. At a median posttransplant follow-up of 2.8 years, 20 (87%) patients were alive, 2 (9%) developed posttransplant lymphoproliferative disorder, and 8 (35%) were hospitalized for infection within the first year. Waitlist and posttransplant outcomes were similar in patients with and without DS (P=non-significant for all). Conclusions Waitlist and post-HTx outcomes in children with DS selected for transplant listing are comparable to pediatric HTx recipients overall. Given acceptable outcomes, the presence of DS alone should not be considered an absolute contraindication to HTx.

Computational ethics.

Technological advances are enabling roles for machines that present novel ethical challenges. The study of 'AI ethics' has emerged to confront these challenges, and connects perspectives from philosophy, computer science, law, and economics. Less represented in these interdisciplinary efforts is the perspective of cognitive science. We propose a framework - computational ethics - that specifies how the ethical challenges of AI can be partially addressed by incorporating the study of human moral decision-making. The driver of this framework is a computational version of reflective equilibrium (RE), an approach that seeks coherence between considered judgments and governing principles. The framework has two goals: (i) to inform the engineering of ethical AI systems, and (ii) to characterize human moral judgment and decision-making in computational terms. Working jointly towards these two goals will create the opportunity to integrate diverse research questions, bring together multiple academic communities, uncover new interdisciplinary research topics, and shed light on centuries-old philosophical questions.

Hemp and buckwheat are valuable sources of dietary amino acids, beneficially modulating gastrointestinal hormones and promoting satiety in healthy volunteers.

PURPOSE: This study evaluated the postprandial effects following consumption of buckwheat, fava bean, pea, hemp and lupin compared to meat (beef); focussing on biomarkers of satiety, gut hormones, aminoacids and plant metabolites bioavailability and metabolism. METHODS: Ten subjects (n = 3 men; n = 7 women; 42 ± 11.8 years of age; BMI 26 ± 5.8 kg/m2) participated in six 1-day independent acute interventions, each meal containing 30 g of protein from buckwheat, fava bean, pea, hemp, lupin and meat (beef). Blood samples were collected during 24-h and VAS questionnaires over 5-h. RESULTS: Volunteers consumed significantly higher amounts of most amino acids from the meat meal, and with few exceptions, postprandial composition of plasma amino acids was not significantly different after consuming the plant-based meals. Buckwheat meal was the most satious (300 min hunger scores, p < 0.05).Significant increase in GLP-1 plasma (AUC, iAUC p = 0.01) found after hemp compared with the other plant-based meals. Decreased plasma ghrelin concentrations (iAUC p < 0.05) found on plant (hemp) vs. meat meal. Several plasma metabolites after hemp meal consumption were associated with hormone trends (partial least squares-discriminant analysis (PLS-DA): 4-hydroxyphenylpyruvic acid, indole 3-pyruvic acid, 5-hydoxytryptophan, genistein and biochanin A with GLP-1, PYY and insulin; 3-hydroxymandelic acid and luteolidin with GLP-1 and ghrelin and 4-hydroxymandelic acid, benzoic acid and secoisolariciresinol with insulin and ghrelin. Plasma branched-chain amino acids (BCAAs), (iAUC, p < 0.001); and phenylalanine and tyrosine (iAUC, p < 0.05) were lower after buckwheat comparison with meat meal. CONCLUSION: Plants are valuable sources of amino acids which are promoting satiety. The impact of hemp and buckwheat on GLP-1 and, respectively, BCAAs should be explored further as could be relevant for aid and prevention of chronic diseases such as type 2 diabetes. Study registered with clinicaltrial.gov on 12th July 2013, study ID number: NCT01898351.

Large Solitary Fibrous Tumor of the Kidney.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that can affect any soft tissue in the body. Given their infrequency, no definitive risk factors have been identified. Typically, surgical extrication en bloc is the only known curative treatment option for SFTs; however, systemic therapy can be used for metastatic or unresectable disease. Only 10 perent to 15 perent of SFTs are aggressive in behavior and termed malignant, leading to a high survival rate for affected patients. Surveillance is required post-operatively to detect recurrence.

Comparison of Physical Activity, Healthy Eating Habits, and Knowledge of Diabetes and Pre-diabetes in Rural Reservation and Off-reservation Communities.

INTRODUCTION: Residents in two small rural communities on the Northern Great Plains completed surveys to determine their community's needs for physical activity, healthy eating habits, and knowledge of diabetes/pre-diabetes. METHODS: One rural American Indian reservation (Community A) and one off-reservation (Community B) were selected for the study. Both communities had similar population size, medical clinic, pharmacy, grocery store and fitness center. Surveys were collected in-person during local community events. RESULTS: More respondents in Community A (41 percent) compared to Community B (18 percent) used the Fitness Center and had more vigorous physical activity (44 percent vs. 5 percent respectively). Compared to Community A, Community B respondents bought more fruits and vegetables (85 percent vs. 96 percent respectively). While a higher rate of diabetes (15.1 percent) in the American Indian population has been reported, this study did not find a significant difference when comparing these two rural communities. Fewer respondents with diabetes in Community A (25 percent), compared to Community B (85 percent) had attended diabetes education. More respondents in Community A (31 percent) than B (13 percent) had pre-diabetes. CONCLUSIONS: Community A's fitness center had personal trainers that provided education, motivation and encouraged individuals to exercise. The majority of respondents in Communities A (85 percent) and B (96 percent) purchased fruits and vegetables. Fruits and vegetables were readily available in the local grocery stores for both small rural communities. More individuals with diabetes (83 percent) in Community B had attended diabetes education classes. More Community A respondents had pre-diabetes; however, diabetes prevention education could reduce their risk of developing type 2 diabetes by 58 percent.

Does the UKCAT predict performance in medical and dental school? A systematic review.

OBJECTIVES: For the first time, this systematic review provides a summary of the literature exploring the relationship between performance in the UK Clinical Aptitude Test (UKCAT) and assessments in undergraduate medical and dental training. DESIGN: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, relevant studies were identified through systematic literature searches. Electronic searches were carried out on EBSCO, EMBASE, Educational Resources Information Centre, SCOPUS, Web of Knowledge. Studies which included the predictive validity of selection criteria including some element of the UKCAT were considered. RESULTS: 22 papers were identified for inclusion in the study. Four studies describe outcomes from dental programmes with limited results reported. 18 studies reported on relationships between the UKCAT and performance in undergraduate medical training. Of these, 15 studies reported relationships between the UKCAT cognitive tests and undergraduate medical assessments. Weak relationships (r=0.00-0.29) were observed in 14 of these studies; four studies reported some moderate relationships (r=0.30-0.49). The strongest relationships with performance in medical school were observed for the UKCAT total score and the verbal reasoning subtest. Relationships with knowledge-based assessments scores were higher than those for assessments of skills as the outcome. Relationships observed in small (single and double centre studies) were larger than those observed in multicentre studies. CONCLUSION: The results indicate that UKCAT scores predict performance in medical school assessments. The relationship is generally weak, although noticeably stronger for both the UKCAT total score and the verbal reasoning subtest. There is some evidence that UKCAT continues to predict performance throughout medical school. We recommend more optimal approaches to future studies. This assessment of existing evidence should assist medical/dental schools in their evaluation of selection processes.

Undercarboxylated osteocalcin has no adverse effect on endothelial function in rabbit aorta or human vascular cells.

Undercarboxylated osteocalcin (ucOC) improves glucose metabolism; however, its effects on endothelial cell function are unclear. We examined the biological effect of ucOC on endothelial function in animal models ex vivo and human cells in vitro. Isometric tension and immunohistochemistry techniques were used on the aorta of male New Zealand white rabbits and cell culture techniques were used on human aortic endothelial cells (HAECs) to assess the effect of ucOC in normal and high-glucose environments. Overall, ucOC, both 10 and 30 ng/ml, did not significantly alter acetylcholine-induced blood vessel relaxation in rabbits (p > .05). UcOC treatment did not cause any significant changes in the immunoreactivity of cellular signalling markers (p > .05). In HAEC, ucOC did not change any of the assessed outcomes (p > .05). UcOC has no negative effects on endothelial function which is important to reduce the risks of off target adverse effects if it will be used as a therapeutic option for metabolic disease in the future.

Skin Cancer Prevention and Screening Behaviors among Agricultural Workers: A Survey of the Attendees of the Sioux Falls Farm Show.

INTRODUCTION: Agricultural workers are at a higher risk for skin cancer due to excessive amounts of sun exposure, poor sun safety practices, and limited access to healthcare. This study aimed to assess skin cancer history, sun protection practices, and skin cancer surveillance measures among Midwestern agricultural workers. METHODS: Individuals that attended the 2020 Sioux Falls Farm Show were asked to complete a 12-question survey on sun exposure, sun protective practices, and skin cancer surveillance. Survey responses were aggregated and analyzed using Microsoft Excel. RESULTS: A total of 99 individuals participated in the study, of which 70 identified as agricultural workers. Most individuals reported working outdoors eight to 10 hours daily for 10-12 months of the year. Most participants reported poor sun protection habits, such as limited sunscreen and limited wide-brimmed hat use. A large number of participants reported they had previously received a professional skin check, although 33 percent reported never examining their own skin for suspicious lesions. CONCLUSIONS: Midwestern agricultural workers present a unique population that could benefit from improved skin cancer prevention. Opportunities for improvement include education of skin cancer preventative measures using platforms that are likely to reach rural agricultural workers and education regarding skin self-examinations. This study identified high risk factors of this population including substantial sun exposure, poor sun protection, and minimal self-skin examinations. Our findings may help guide future methods to increase skin cancer education, prevention, and surveillance in agricultural workers.

An Investigation Into the Role of Osteocalcin in Human Arterial Smooth Muscle Cell Calcification.

Osteocalcin (OCN) is a bone-derived protein that is detected within human calcified vascular tissue. Calcification is particularly prevalent in chronic kidney disease (CKD) patients but the role of OCN in calcification, whether active or passive, has not been elucidated. Part 1: The relationship between OCN, CKD and vascular calcification was assessed in CKD patients (n = 28) and age-matched controls (n = 19). Part 2: in vitro, we analyzed whether addition of uncarboxylated osteocalcin (ucOCN) influenced the rate or extent of vascular smooth muscle cell (VSMC) calcification. Human aortic VSMCs were cultured in control media or mineralisation inducing media (MM) containing increased phosphate with or without ucOCN (10 or 30 ng/mL) for up to 21 days. Markers of osteogenic differentiation and calcification were determined [alkaline phosphatase (ALP) activity, total intracellular OCN, Runx2 expression, α-SMA expression, alizarin red calcium staining, and calcium quantification]. Part 1 results: In our human population, calcification was present (mean age 76 years), but no differences were detected between CKD patients and controls. Plasma total OCN was increased in CKD patients compared to controls (14 vs. 9 ng/mL; p < 0.05) and correlated to estimated glomerular filtration rate (p < 0.05), however no relationship was detected between total OCN and calcification. Part 2 results: in vitro, ALP activity, α-SMA expression and calcium concentrations were significantly increased in MM treated VSMCs at day 21, but no effect of ucOCN was observed. Cells treated with control media+ucOCN for 21 days did not show increases in ALP activity nor calcification. In summary, although plasma total OCN was increased in CKD patients, this study did not find a relationship between OCN and calcification in CKD and non-CKD patients, and found no in vitro evidence of an active role of ucOCN in vascular calcification as assessed over 21 days. ucOCN appears not to be a mediator of vascular calcification, but further investigation is warranted.

Osteocalcin does not influence acute or chronic inflammation in human vascular cells.

Some human observational studies have suggested an anti-inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon-γ and tumor necrosis factor-α (10 ng/ml) was employed to examine the acute (24 hr) and chronic (144 hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1) and proinflammatory cytokines (interleukin-6 [IL-6], IL-8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro- or anti-inflammatory effects when administered acutely or chronically on its own in either cell type. Additionally, ucOCN did not affect lipopolysaccharide (LPS)-induced acute inflammation in HAECs or HASMCs. The findings of this study do not support a causal role for OCN within the models of vascular inflammation chosen. Further confirmatory studies are warranted.

Skin Cancer Education in the Rural Salon.

INTRODUCTION: Due to an increase in the incidence of skin cancer and a shortage of primary care and specialty physicians in rural areas, creative public health strategies must be employed to address disparities in skin cancer education, prevention, and detection. METHODS: Hair salons in eastern South Dakota communities with populations less than 15,000 were visited in-person by medical student facilitators. Hair professionals at these locations completed pre-survey assessments for baseline self-assessed comfort with detecting suspicious skin lesions and with educating patrons on skin cancer prevention strategies. Their likelihood to both alert patrons of suspicious skin lesions and encourage them to have their lesion evaluated by a physician was also assessed. A 20-minute educational PowerPoint presentation was given. Final assessment was evaluated with a post-presentation survey. RESULTS: Self-assessed hair professional comfort with identifying suspicious skin lesions was higher in post-survey results, in addition, the educational presentation increased comfort with sharing skin cancer prevention information with patrons. Hair professionals also reported increased likelihood that they would alert patrons to suspect skin lesions. Also, hair professionals reported increased likelihood that they would encourage patrons to seek medical care for their concerning lesions. CONCLUSIONS: Hair professionals may act as lay skin cancer educators in rural salons. Educational programs for hair professionals can increase their comfort with detecting lesions suspicious for skin cancer, increase their comfort with sharing skin protection information with patrons, and increase their likelihood of both alerting their patrons about suspicious skin lesions and encouraging their patrons to have their suspicious lesions evaluated.