Ž . Vasopressin in the forebrain of common marmosets Callithrix jacchus : studies with in situ hybridization, immunocytochemistry and receptor autoradiography

Abstract Ž . The distribution of vasopressin AVP producing cells, their projections and AVP receptors was examined in the brain of common Ž . marmosets Callithrix jacchus using in situ hybridization, immunocytochemistry and receptor autoradiography. Clusters of cells labeled Ž . Ž . Ž . for AVP mRNA or stained for AVP immunoreactivity AVP-ir were found in the paraventricular PVN , supraoptic SON and Ž . suprachiasmatic nuclei SCN of the hypothalamus. Scattered AVP producing cells were also found in the lateral hypothalamus and the Ž . bed nucleus of the stria terminalis BST . Neither AVP mRNA-labeled nor AVP-ir cells were detected in the amygdala. Although AVP-ir fibers were evident outside of the hypothalamic-neurohypophyseal tract, a plexus of fibers in the lateral septum, as observed in the rat brain, was not detected. Receptor autoradiography using 125 I-linear-AVP revealed specific binding for AVP receptors in the nucleus accumbens, diagonal band, lateral septum, the BST, SCN, PVN, amygdala, anterodorsal and ventromedial nucleus of the hypothalamus, indicating sites for central AVP action in the marmoset brain. Together, these data provide a comprehensive picture of AVP pathways in the marmoset brain, demonstrating differences from rodents in the distribution of cell bodies, fibers and receptors. q 1997 Elsevier Science B.V

Long-term retention of semantic knowledge.

Two hierarchical regressions were posed to examine the relative contribution of several predictor variables on retention test performance. The retention test encompassed content from a beginning graduate level statistics class. Cross-sectional methodology was employed to include students who had taken the course sometime during a twenty-two year interval. This study had a unique opportunity to examine long term remembering in an ecological setting where the content area and the teaching had been stable. Grade, from the original course, was the strongest predictor in both hierarchical models. Other independent variables which had significant impact on retention test performance were number of continuing classes in statistics and number of classes in research design and methodology. Rehearsal frequency as well as rehearsal recency were significant predictors. The level of original learning and what one does during the retention interval are more important than the length of the interval itself. The effect of spaced vs. mass practice, as defined by the length of the acquisition interval, was examined. Subjects who took the course over a 15 week semester session outperformed subjects who had the 5 week summer session. In this study, the rate of decline was affected by the subject's age at the time of the retention test. This indicates increasingly rapid forgetting during adult development and has implications for the maintenance of marginal knowledge

Cognitive Aging and Self-Management: Opportunities for Technology

Presented on January 16, 2019 at 3:00 p.m. in the J. S. Coon Building, Room 250.Kathleen C. Insel is the Interim Chair and Professor of Nursing in the College of Nursing at the University of Arizona. The focus of her research is on cognitive function over the lifespan and implications of cognitive function (specifically executive function and working memory) on self-management of chronic disease, or in the case of children, on school achievement.Runtime: 68:13 minutesSelf-management of chronic conditions increases among older adults at the same time capacity for self-management may diminish. Addressing limitations in prospective memory through strategies developed to improve medication adherence, provides an exemplar for applying what is known about cognitive aging to support older adults leading to optimal aging and improved quality of life. Leveraging technology, the use of which is ever more ubiquitous in this population, can provide a means for general dissemination of these strategies

Identification and validation of modulators of exchange protein activated by cAMP (Epac) activity: structure-function implications for Epac activation and inhibition.

The signaling molecule cAMP primarily mediates its effects by activating PKA and/or exchange protein activated by cAMP (Epac). Epac has been implicated in many responses in cells, but its precise roles have been difficult to define in the absence of Epac inhibitors. Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is directly activated by cAMP. Using a bioluminescence resonance energy transfer-based assay (CAMYEL) to examine modulators of Epac activity, we took advantage of its intramolecular movement that occurs upon cAMP binding to assess Epac activation. We found that the use of CAMYEL can detect the binding of cAMP analogs to Epac and their modulation of its activity and can distinguish between agonists (cAMP), partial agonists (8-chlorophenylthio-cAMP), and super agonists (8-chlorophenylthio-2'-O-Me-cAMP). The CAMYEL assay can also identify competitive and uncompetitive Epac inhibitors, e.g. (Rp)-cAMPS and CE3F4, respectively. To confirm the results with the CAMYEL assay, we used Swiss 3T3 cells and assessed the ability of cyclic nucleotide analogs to modulate the activity of Epac or PKA, determined by Rap1 activity or VASP phosphorylation, respectively. We used computational molecular modeling to analyze the interaction of analogs with Epac1. The results reveal a rapid means to identify modulators (potentially including allosteric inhibitors) of Epac activity that also provides insight into the mechanisms of Epac activation and inhibition

Diet quality and disease activity in rheumatoid arthritis

Objective:This study examined associations between diet quality and disease activity in adults with rheumatoid arthritis (RA). Perceived stress was also compared to diet and disease activity. Methods: In a cross-sectional design, 50 adults with RA were recruited. The Arizona Food Frequency Questionnaire was used to measure dietary intake (four weeks) and diet quality scores were calculated with the Healthy Eating Index – 2015. Perceived stress was measured with the Perceived Stress Scale. Disease activity was measured with the Health Assessment Questionnaire-Disability Index and Pain Scale, erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein, and Disease Activity Score Including 28 Joints-ESR. Results: Diet quality (56; SD ± 12) in participants was lower than the national mean (59). Age ( p = 0.015) and gender ( p = 0.003) were associated with higher diet quality. The belief that diet affects RA disease activity was reported by 44% of the participants, and these participants were significantly more likely to report dietary changes ( p < 0.0001). Higher educational level (at least some college) was associated with this belief ( B = −1.535, p = 0.023). Participants with lower diet quality also had significantly higher pain ( B = −0.396, p = 0.022) and ESR scores ( p = 0.019). Women were more likely to have higher HAQ-DI scores ( B = 0.570, p = 0.001). Perceived stress was significantly associated with HAQ-DI and pain scores ( B = 0.445, p = 0.001 and B = 0.289, p = 0.042, respectively). Medical cannabis was reportedly used by 8% of participants. Conclusion: In RA patients, lower diet quality may be associated with more pain and inflammation, and perceived stress may be associated with higher disability and disease activity

Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.

Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP