Extracellular matrix components isolated from diabetic mice alter cardiac fibroblast function through the AGE/RAGE signaling cascade

© 2020 The Authors Individuals suffering from diabetes have an increased risk of developing cardiovascular complications such as heart failure. Heart failure can be a result of the stiffening of the left ventricle, which occurs when cardiac fibroblasts become “active” and begin to remodel the extracellular matrix (ECM). Fibroblast “activation” can be triggered by the AGE/RAGE signaling cascade. Advanced Glycation End products (AGEs) are produced and accumulate in the ECM over time in a healthy individual, but under hyperglycemic conditions, this process is accelerated. In this study, we investigated how the presence of AGEs in either non-diabetic or diabetic ECM affected fibroblast-mediated matrix remodeling. In order to address this question, diabetic and non-diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either non-diabetic or diabetic mice. Fibroblast function was assessed using gel contraction, migration, and protein expression. Non-diabetic fibroblasts displayed similar gel contraction to diabetic cells when embedded in diabetic collagen. Thus, suggesting the diabetic ECM can alter fibroblast function from an “inactive” to “active” state. Addition of AGEs increase the AGE/RAGE cascade leading to increased gel contraction, whereas inhibiting the cascade resulted in little or no gel contraction. These results indicated 1) the ECM from diabetic and non-diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them toward an “active” state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggested the importance of understanding the impact diabetes has on the ECM and fibroblast function

Improving Access to Books for Young School-age Children One Library at a Time

Johnson and Donham (2012) found that Iowa elementary school library check out policies for young children did not always support early literacy development because of their being overly restrictive concerning the number of books children could borrow each week. A state-wide survey of Idaho elementary school library staff revealed similar challenges. Preschoolers, kindergarteners, and 1st graders were not being given adequate access to books. A state-wide grant program was developed and implemented that provided funds for collection development while stipulating the implementation of less restrictive check out policies for young children. Results from the grant program are reported along with future plans and recommendations for others wanting to implement similar programs

Librarians: Key Partners in a State-Wide Book Distribution Outreach Program

Book distribution programs targeted at young children and their families that include the children own-ing the books have been in existence for a long time. Results are provided from a multi-year program evaluation of a unique, state-wide book distribution program developed in 1997 by the Idaho Commis-sion for Libraries called My First Books. The program is unique among book distribution programs because it relies on local librarians to deliver and showcase the books each month during the academic year in a variety of public and private early childhood care and education settings. My First Books thus becomes a powerful mechanism for library outreach to local childcare and education facilities, parents and caregivers of young children, and the children themselves. Program evaluation results reveal a highly popular and effective program for all of these constituencies that fits well within the resources available in public libraries of all sizes throughout Idaho

R05. The Impact of Diabetic Conditions and AGE/RAGE Signaling on Cardiac Fibroblast Migration

Corresponding author (BioMolecular Sciences): Stephanie Burr, [email protected]://egrove.olemiss.edu/pharm_annual_posters/1004/thumbnail.jp

The Impact of Diabetic Conditions and AGE/RAGE Signaling on Cardiac Fibroblast Migration

© Copyright © 2020 Burr, Harmon and Stewart. Diabetic individuals have an increased risk for developing cardiovascular disease due to stiffening of the left ventricle (LV), which is thought to occur, in part, by increased AGE/RAGE signaling inducing fibroblast differentiation. Advanced glycated end-products (AGEs) accumulate within the body over time, and under hyperglycemic conditions, the formation and accumulation of AGEs is accelerated. AGEs exert their effect by binding to their receptor (RAGE) and can induce myofibroblast differentiation, leading to increased cell migration. Previous studies have focused on fibroblast migration during wound healing, in which diabetics have impaired fibroblast migration compared to healthy individuals. However, the impact of diabetic conditions as well as AGE/RAGE signaling has not been extensively studied in cardiac fibroblasts. Therefore, the goal of this study was to determine how the AGE/RAGE signaling pathway impacts cell migration in non-diabetic and diabetic cardiac fibroblasts. Cardiac fibroblasts were isolated from non-diabetic and diabetic mice with and without functional RAGE and used to perform a migration assay. Cardiac fibroblasts were plated on plastic, non-diabetic, or diabetic collagen, and when confluency was reached, a line of migration was generated by scratching the plate and followed by treatment with pharmacological agents that modify AGE/RAGE signaling. Modification of the AGE/RAGE signaling cascade was done with ERK1/2 and PKC-ζ inhibitors as well as treatment with exogenous AGEs. Diabetic fibroblasts displayed an increase in migration compared to non-diabetic fibroblasts whereas inhibiting the AGE/RAGE signaling pathway resulted in a significant increase in migration. The results indicate that the AGE/RAGE signaling cascade causes a decrease in cardiac fibroblast migration and altering the pathway will produce alterations in cardiac fibroblast migration

Enhanced Storytimes: Effects on Parent/Caregiver Knowledge, Motivation, and Behaviors

The article offers information regarding the released of the Every Child Ready @ your library initiative\u27s second edition of the Public Library Association and the Association for Library Service to Children in 2011. It states that the initiative features five practices based in high-quality oral language development in children such as reading, writing, and talking. It mentions that the initiative will help children in early literacy development and will educate caregivers and parents

DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network

During DNA replication, stalled replication forks and DSBs arise when the replication fork encounters ICLs (interstrand crosslinks), covalent protein/DNA intermediates or other discontinuities in the template. Recently, homologous recombination proteins have been shown to function in replication-coupled repair of ICLs in conjunction with the Fanconi anemia (FA) regulatory factors FANCD2-FANCI, and, conversely, the FA gene products have been shown to play roles in stalled replication fork rescue even in the absence of ICLs, suggesting a broader role for the FA network than previously appreciated. Here we show that DNA2 helicase/nuclease participates in resection during replication-coupled repair of ICLs and other replication fork stresses. DNA2 knockdowns are deficient in HDR (homology-directed repair) and the S phase checkpoint and exhibit genome instability and sensitivity to agents that cause replication stress. DNA2 is partially redundant with EXO1 in these roles. DNA2 interacts with FANCD2, and cisplatin induces FANCD2 ubiquitylation even in the absence of DNA2. DNA2 and EXO1 deficiency leads to ICL sensitivity but does not increase ICL sensitivity in the absence of FANCD2. This is the first demonstration of the redundancy of human resection nucleases in the HDR step in replication-coupled repair, and suggests that DNA2 may represent a new mediator of the interplay between HDR and the FA/BRCA pathway

Magnesium intake, plasma C-peptide, and colorectal cancer incidence in US women: a 28-year follow-up study

Background: Laboratory studies suggest a possible role of magnesium intake in colorectal carcinogenesis but epidemiological evidence is inconclusive. Method: We tested magnesium–colorectal cancer hypothesis in the Nurses' Health Study, in which 85 924 women free of cancer in 1980 were followed until June 2008. Cox proportional hazards regression models were used to estimate multivariable relative risks (MV RRs, 95% confidence intervals). Results: In the age-adjusted model, magnesium intake was significantly inversely associated with colorectal cancer risk; the RRs from lowest to highest decile of total magnesium intake were 1.0 (ref), 0.93, 0.81, 0.72, 0.74, 0.77, 0.72, 0.75, 0.80, and 0.67 (Ptrend<0.001). However, in the MV model adjusted for known dietary and non-dietary risk factors for colorectal cancer, the association was significantly attenuated; the MV RRs were 1.0 (ref), 0.96, 0.85, 0.78, 0.82, 0.86, 0.84, 0.91, 1.02, and 0.93 (Ptrend=0.77). Similarly, magnesium intakes were significantly inversely associated with concentrations of plasma C-peptide in age-adjusted model (Ptrend=0.002) but not in multivariate-adjusted model (Ptrend=0.61). Results did not differ by subsite or modified by calcium intakes or body mass index. Conclusion: These prospective results do not support an independent association of magnesium intake with either colorectal cancer risk or plasma C-peptide levels in women

Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Background: Antimicrobial resistance (AMR) is a global threat and the antimicrobial stewardship program (ASP) is a globally used tool to combat AMR. There is little information on the views among Pakistani physicians regarding AMR and the benefits of hospital antimicrobial stewardship implementation. This study was designed to explore the physicians’ views about ASP. Methods: Qualitative face-to-face and telephonic interviews were conducted by using purposive sampling method with 22 physicians working in seven tertiary care public hospitals of Punjab, Pakistan. All interviews were audio recorded and transcribed verbatim. Qualitative software was used, and a thematic analysis was conducted. Results: Three broad themes were identified: (1) the growing concern of antimicrobial resistance in Pakistan, (2) the role(s) of healthcare professionals in antibiotic prescribing, and (3) managing antibiotic resistance in hospitals. Inadequate resources, poor healthcare facilities, and insufficiently trained medical staff were the major hurdles in ASP implementation in Pakistan. Conclusions: Our study found a poor familiarity of hospital ASP among physicians working in public sector tertiary care teaching hospitals, and a number of distinct themes emerged during this study that could be helpful in establishing the concept of hospital ASP in Pakistan. Overall, physicians showed a positive attitude towards the enforcement of ASP in all healthcare settings, including teaching hospitals