The Church Bridge Project Focus Group Results: African American Perspectives of Weight Management Programs to Improve Nutrition and Physical Activity Behaviors

Background: The prevalence of obesity is disproportionately high among African Americans in the Southern US. More information is needed about factors that influence participation in nutrition and physical activity programs to promote healthy weight. Objective: The purpose of this study is to explore the weight management perceptions of young to middle aged adult African Americans. Methods: The Church Bridge Project intervention participants were recruited for two focus groups. Qualitative data were recorded, transcribed and a thematic content analysis was conducted to identify major themes. Results: Barriers included technology learning curve/burden and competing priorities. Facilitators included support, limited cost, convenience, and health. Participants perceived the term “weight management” program as overwhelming and defeating. Conclusion: The Church Bridge Project model confirmed social support and disease prevention as key factors for weight management. Further work should substantiate social support as a key factor to guide minority health efforts

Dynamic Proteomic Analysis of Pancreatic Mesenchyme Reveals Novel Factors That Enhance Human Embryonic Stem Cell to Pancreatic Cell Differentiation

Current approaches in human embryonic stem cell (hESC) to pancreatic beta cell differentiation have largely been based on knowledge gained from developmental studies of the epithelial pancreas, while the potential roles of other supporting tissue compartments have not been fully explored. One such tissue is the pancreatic mesenchyme that supports epithelial organogenesis throughout embryogenesis. We hypothesized that detailed characterization of the pancreatic mesenchyme might result in the identification of novel factors not used in current differentiation protocols. Supplementing existing hESC differentiation conditions with such factors might create a more comprehensive simulation of normal development in cell culture. To validate our hypothesis, we took advantage of a novel transgenic mouse model to isolate the pancreatic mesenchyme at distinct embryonic and postnatal stages for subsequent proteomic analysis. Refined sample preparation and analysis conditions across four embryonic and prenatal time points resulted in the identification of 21,498 peptides with high-confidence mapping to 1,502 proteins. Expression analysis of pancreata confirmed the presence of three potentially important factors in cell differentiation: Galectin-1 (LGALS1), Neuroplastin (NPTN), and the Laminin α-2 subunit (LAMA2). Two of the three factors (LGALS1 and LAMA2) increased expression of pancreatic progenitor transcript levels in a published hESC to beta cell differentiation protocol. In addition, LAMA2 partially blocks cell culture induced beta cell dedifferentiation. Summarily, we provide evidence that proteomic analysis of supporting tissues such as the pancreatic mesenchyme allows for the identification of potentially important factors guiding hESC to pancreas differentiation

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont.

Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Regulation of the development of pancreatic diseases by cell intrinsic and stromal influences

Diseases of the pancreas affect a large portion of the world's population; pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer deaths and type 2 diabetes is now reaching epidemic levels. Mouse models of pancreatic diseases have been instrumental in defining our understanding of the initiation and progression of these diseases. My studies examined various aspects of proper function of pancreatic cells and the development of disease, including the role of Numb in regulation of acinar cell dedifferentiation and metaplasia, and the role of stromal changes in the development of both PDA and regulation of glucose homeostasis.Studies of mouse models of PDA have indicated that the most common cell type in the pancreas, the acinar cell is capable of giving rise to precursor lesions and PDA under the direction of activated Kras. However, even when Kras is activated in a majority of acinar cells, only a small percentage of cells go on to result in precursor lesions and disease in the absence of additional stresses such as additional mutations and/or inflammation. Here I demonstrate that Numb, a protein with a multitude of functions in regulation of signaling pathways, cell junction formation, endocytosis and asymmetric division, restrains acinar cell dedifferentiation and acinar to ductal metaplasia and promotes cell viability. In addition to cell intrinsic changes, alterations in the stromal microenvironment are well documented in pancreatic disease. Specifically, changes in inflammatory cells have been well documented in PDA development, but how these different cell types influence PDA development is unclear. My work reveals that neutrophils are important for propagating pancreatic damage and acinar dedifferentiation, but are not instrumental in the formation of initiating lesions that lead to PDA development. Finally, the pancreatic mesenchyme is critical for pancreatic development, but how these cells contribute to tissue homeostasis is unknown. My studies demonstrate that pancreatic mesenchymal cells are found throughout the adult pancreas and that they are essential for maintenance of acinar cell organization and glucose homeostasis, partially through regulation of the extracellular matrix

Numb Regulates Acinar Cell Dedifferentiation and Survival During Pancreatic Damage and Acinar-to-Ductal Metaplasia

Background & aimsPancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death. Through the process of acinar-to-ductal metaplasia (ADM), pancreatic acinar cells give rise to pancreatic intraepithelial neoplasia (PanIN), the most common precursor of PDA. However, even when Kras is activated in a majority of acinar cells, ADM and subsequent development of PanINs is inefficient in the absence of additional stresses. Numb regulates cell junctions, integrins, and the activity of embryonic signaling pathways; therefore, we investigated its effects on acinar cell dedifferentiation, regeneration, and metaplasia.MethodsWe used mouse models of pancreatic regeneration and PDA as well as mice with loss-of-function alleles of Numb (p48Cre/p48Cre(ER);Numb(f/f) and p48Cre/p48Cre(ER);Kras(G12D);Numb(f/f) mice) to study the roles of Numb in pancreatic regeneration and ADM.ResultsLoss of Numb resulted in premature dedifferentiation of acinar cells in response to injury due to administration of the cholecystokinin analogue cerulein and interfered with acinar cell regeneration. Numb was found to regulate multiple signaling pathways in acinar cells during cerulein-induced pancreatitis. Disruption of Numb accelerated and destabilized ADM in the context of oncogenic Kras (in p48Cre;Kras(G12D);Numb(f/f) and p48Cre(ER);Kras(G12D);Numb(f/f) mice).ConclusionsNumb is an important regulator of acinar cell differentiation and viability during metaplasia. In mice with pancreatitis or pancreatic injury, elimination of Numb causes dedifferentiated acinar cells to undergo apoptosis, and this is not mitigated by oncogenic Kras

Paradoxes of professional autonomy: a qualitative study of U.S. neonatologists from 1978‐2017

The professional autonomy of physicians often requires they take responsibility for life and death decisions, but they must also find ways to avoid bearing the full weight of such decisions. We conducted in‐person, semi‐structured interviews with neonatologists (n = 20) in four waves between 1978 and 2017 in a single Midwestern U.S. city. Using open coding analysis, we found over time that neonatologists described changes in their sense of professional autonomy and responsibility for decisions with life and death consequences. Through the early 1990s, as neonatology consolidated as a profession, physicians simultaneously enjoyed high levels of professional discretion and responsibility and were often constrained by bioethics and the law. By 2010s, high involvement of parents and collaboration with multiple subspecialties diffused the burden felt by individual practitioners, but neonatology’s professional autonomy was correlatively diminished. Decision‐making in the NICU over four decades reveal a complex relationship between the professional autonomy of neonatologist and the burden they bear, with some instances of ceding autonomy as a protective measure and other situations of unwelcomed erosion of professional autonomy that neonatologists see as complicating provision of care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163653/2/shil13169.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163653/1/shil13169_am.pd

Polyploidy influences plant-environment interactions in quaking aspen (Populus tremuloides Michx.)

Quaking aspen (Populus tremuloides Michx.), a widespread and keystone tree species in North America, experienced heat and drought stress in the years 2002 and 2003 in the southwestern United States. This led to widespread aspen mortality that has altered the composition of forests, and is expected to occur again if climate change continues. Understanding interactions between aspen and its environments is essential to understanding future mortality risk in forests. Polyploidy, which is common in aspen, can modify plant structure and function and therefore plant-environment interactions, but the influence of polyploidy on aspen physiology is still not well understood. Furthermore, the ploidy types of aspen have different biogeographies, with triploids being most frequent at lower latitudes in generally warmer and drier climates, while the northerly populations are virtually 100% diploid. This suggests that ploidy-environment interactions differ, and could mean that the ploidy types have different vulnerabilities to environmental stress. In this study, to understand aspen ploidy-environment interactions, we measured 38 different traits important to carbon uptake, water loss and water-use efficiency in diploid and triploid aspen in Colorado. We found that triploid aspen had lower stand density, and greater leaf area, leaf mass, leaf mass per area, percent nitrogen content, chlorophyll content and stomatal size. These differences corresponded to greater potential net carbon assimilation (A, measured using A/C-i curves, and chlorophyll fluorescence) and stomatal conductance (g(s)) in triploids than diploids. While triploid aspen had higher intrinsic water-use efficiency (iWUE, calculated from measurements of delta C-13 in leaf tissue), they also had greater potential water loss from higher measured g s and lower stomatal sensitivity to increasing vapor pressure deficit. Therefore, despite greater iWUE, triploids may have lower resilience to climate-induced stress. We conclude that ploidy type strongly influences physiological traits and function, and mediates drought stress responses in quaking aspen

Antibiotic-Induced Alterations in Gut Microbiota Are Associated with Changes in Glucose Metabolism in Healthy Mice

The gut microbiome plays an important role in health and disease. Antibiotics are known to alter gut microbiota, yet their effects on glucose tolerance in lean, normoglycemic mice have not been widely investigated. In this study, we aimed to explore mechanisms by which treatment of lean mice with antibiotics (ampicillin, metronidazole, neomycin, vancomycin, or their cocktail) influences the microbiome and glucose metabolism. Specifically, we sought to: (i) study the effects on body weight, fasting glucose, glucose tolerance, and fasting insulin, (ii) examine the changes in expression of key genes of the bile acid and glucose metabolic pathways in the liver and ileum, (iii) identify the shifts in the cecal microbiota, and (iv) infer interactions between gene expression, microbiome, and the metabolic parameters. Treatment with individual or a cocktail of antibiotics reduced fasting glucose but did not affect body weight. Glucose tolerance changed upon treatment with cocktail, ampicillin, or vancomycin as indicated by reduced area under the curve of the glucose tolerance test. Antibiotic treatment changed gene expression in the ileum and liver, and shifted the alpha and beta diversities of gut microbiota. Network analyses revealed associations between Akkermansia muciniphila with fasting glucose and liver farsenoid X receptor (Fxr) in the top ranked host-microbial interactions, suggesting possible mechanisms by which this bacterium can mediate systemic changes in glucose metabolism. We observed Bacteroides uniformis to be positively and negatively correlated with hepatic Fxr and Glucose 6-phosphatase, respectively. Overall, our transkingdom network approach is a useful hypothesis generating strategy that offers insights into mechanisms by which antibiotics can regulate glucose tolerance in non-obese healthy animals. Experimental validation of our predicted microbe-phenotype interactions can help identify mechanisms by which antibiotics affect host phenotypes and gut microbiota