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Loss of the Nutrient Sensor Tas1R3 Leads to Reduced Bone Resorption
Get PDFBackground: The Taste receptor, type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient needs. TAS1R member 3 (TAS1R3) either recognizes amino acids such as glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. Loss of TAS1R3 expression can cause impaired mTORC1 signaling and increased autophagy, indicating that signaling through this receptor is critical for assessing nutrient needs. Recently, it was reported that global deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass and trabecular remodeling but the underlying cellular mechanism leading to this phenotype remains unclear. Results: To address this open question, we quantified bone turnover markers in serum from 20-week-old wild type and Tas1R3 mutant mice and found that levels of the resorption marker Collagen Type I C-telopeptide (CTx) were reduced on average by \u3e60% in the absence of TAS1R3 expression. Levels of the bone formation marker Procollagen Type I N-terminal Propeptide (P1NP) tend to be higher in Tas1R3 mutant mice but this finding did not reach statistical significance (
Elucidating the Antagonistic Relationship Between Bone Morphogenetic Proteins and Activins in the Skeleton
No full textOsteoporosis is a disease that results from changes in bone mineral density (BMD). In the United States, over 10 million people have low BMD and have an increased risk for fractures, hospitalization and mortality. BMD is the sum of bone formation and bone reabsorption. A growing body of evidence indicates that the Bone Morphogenetic Protein (BMP) pathway promotes bone formation through action of the effectors SMAD1, 5, and 8 while the Activin pathway negatively influences bone mass through action of the effectors SMAD2 and 3. Recent studies from our lab suggest that BMP and Activin ligands regulate bone mass in a see-saw-like mechanism via competition for a shared pool of receptors. Design: In the present study we seek to test this hypothesis in vitro via signaling responsiveness assays using pathway-specific transcriptional reporters and western blot. Proof of principle experiments were carried out in the non-skeletal cell line HEK293 and current work utilizes the osteogenic cell line W-20-17. Results: We first used western blots to confirm that HEK293 cells specifically respond to BMP2 and Activin-A treatment by increasing levels of activated SMAD1, 5, and 8 or SMAD2 and 3, respectively. We then performed dose response assays utilizing increasing concentrations of each ligand to identify the ECmin and ECmax for each ligand. These data informed our reporter assays, which were confirmed to be specific to either BMP or Activin pathway activation with no cross-activation observed. Current studies are extending these preliminary findings to W-20-17 cells where we will perform competition assays between BMP and Activin ligands to examine the role of receptor-level competition in determining the ratio of these two pathways. We hope that elucidating the mechanisms that regulate the antagonism between these pathways will identify novel opportunities for safer and more effective therapies to treat low BMD in humans
Loss of BMPR2 Leads to High Bone Mass Due to Increased Osteoblast Activity
Get PDFImbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health
Sr. Norma Rocklage
Get PDFIn this oral history, Sr. Norma reflects on her sixty-four years (as of 2015) of being a Franciscan Sister. She discusses her upbringing in St. Louis, Missouri, during the Depression era, and how that led to her vocation of service to all people (the poor, as well as tending to fellow Sisters in particular) in various capacities, despite her own perceived shortcomings.https://mushare.marian.edu/wrp/1003/thumbnail.jp
Kidney Paired Donation: National Activity and Perspectives
No full textWhile utilization of Kidney Paired Donation (KPD) continues to increase, the potential is not fully realized. We surveyed kidney transplant (KTX) professionals to evaluate perceptions of barriers and solutions to increasing KPD and correlated the results with KPD utilization patterns and center volume. Methods: Transplant directors (medical, surgical, HLA), coordinators and administrators from all US KTX programs were invited to complete a 31 question survey in May 2014. Center specific data for 2013 was obtained from UNOS. Results: While only 100 of 225(44%) centers participated in KPD, 22 centers performed 20-50% of their living donor (LD) KTXs via KPD. Survey respondents(N=199) represented 129 centers(57%). 161/199(81%) of respondents were from centers participating in KPD; representing 10/11(91%) of centers performing \u3e100/yr LD KTX, 23/31(74%) performing \u3e50/yr, and 36/87(41%) performing \u3c10/yr. Overall, 55% of respondents felt that their center ‘probably’ or ‘definitely’ underutilized KPD. 88/161(55%) indicated their program participated in more than 1 KPD program. Center KPD volume correlated with the practice of inviting all pairs to participate (p=0.04). Surgeons were most commonly cited as leading their center’s KPD program(34%), with just 16% led by committee. Only 33% said their program dedicated ≥1 FTE to KPD. Lack of patient interest was most often selected as the ‘#1 barrier’. The ‘#1 solution’ selected was the need to optimize one KPD program(27.4%), followed closely by decreasing financial risk(23.7%) and increasing patient education(21.5%). KPD activity was significantly less in non-major vs major metropolitan areas (population of more than 1 million), p=0.034. Conclusion: Utilization of KPD is still limited, with non-involvement of \u3e50% of centers. By increasing patient education, unifying KPD programs, and controlling financial risk, there is the potential to significantly increase LD KTX activity. Some centers routinely utilized KPD, even when located in a non-major metropolitan area. While transplant center location in a major metro area may facilitate KPD utilization, these data suggest other factors influence participation rates. Additional reasons for underutilization of KPD are unclear, and require further analysis
Boric Acid and EDTA Combination Inhibits Growth of Candida albicans and Gardnerella vaginalis
Get PDFCandida albicans and Gardnerella vaginalis are two common infectious organisms of the female urogenital tract. Single agent boric acid (BA) topical preparations have been a treatment for resistant gynecologic Candida and Gardnerella infections, but it is worth exploring combinations of inhibitors to determine if a more effective treatment may be developed. Our study aims to determine the efficacy of BA alone in comparison to the combination of BA and EDTA (BA + EDTA) by measuring organism growth, size, and morphology. Experiments used 12 clinical strains of Candida albicans and 7 strains of Gardnerella vaginalis. The organisms were grown in varying concentrations of BA and BA + EDTA media. Organisms were characterized by microscopy and flow cytometry. We report that the median effective dose of BA alone was greater than that of BA + EDTA in Candida strains. Microscopic evaluation revealed that exposure to BA and BA + EDTA decreased typical hyphal transformation of Candida, and cells appeared smaller in size. Flow cytometry forward scatter data of Candida grown in inhibitors revealed smaller cells than those grown in control conditions. Cell counts of organisms grown in inhibitors were also significantly decreased compared to control conditions. Incidental evaluation of autofluorescence revealed increased fluorescence of organisms exposed to inhibitors. Preliminary results of Candida strains grown in BA and BA + EDTA also revealed inhibition of virulence-associated protease activity. These data provide evidence supporting the potential use of a combination therapy in Candida and Gardnerella infections and prompt additional investigation into combination therapies with EDTA
“What Is There about Us Always”: The Archbishop and Willa Cather’s [Roman] Catholic Imagination
Get PDFThe article focuses on the influence of author Willa Cather\u27s Roman Catholic imagination on her works, in which topics discussed include Thomas Aquinas\u27 doctrine of analogy, the depiction of the Roman Catholic world in the novel Death Comes for the Archbishop and the difference between Cather and Father Latour\u27s perceptions of the world
Sr. Diane Jamison
Get PDFIn her oral history, Sr. Diane Jamison describes how her mother and seventh grade teacher shaped her character and guided her decision to become a Sister of Saint Francis. A math and religious teacher, a director of religious education, and a director of Christian formation, Sr. Jamison underscores her belief in the importance of “justice for all students regardless of economic ability.” She also reports on the many unique ways she taught the sacraments to her students, her “exodus experiences” living and thriving far away from home, and the numerous ways she worked to “deepen her relationship of God, with God’s people.” She recalls the time she gave the commencement address after obtaining a degree in Franciscan Studies from Saint Bonaventure University and her position as the Director of Ongoing Formation at Marian University. With honesty and sincerity, Sr. Jamison describes how she strove to embrace constancy and change in her life, including a diagnosis of cancer, and the ideal of a “living discernment with God as the constant.”https://mushare.marian.edu/wrp/1023/thumbnail.jp