The role of RasGRP3 in the embryonic response to phorbol esters and diabetes

RasGRP3 is a novel endothelial diacylglycerol (DAG) receptor expressed in developing blood vessels. Because DAG levels are elevated in diabetes, I hypothesized a role for RasGRP3 in the embryonic response to disrupted DAG signaling. Using whole embryo culture, I ascertained differences between wildtype embryos and embryos genetically deleted for RasGRP3 exposed to excess glucose or phorbol 12-myristate 13-acetate (PMA), a compound that mimics the effects of diacylglycerol. Wildtype embryos exhibited numerous vascular and nonvascular defects when cultured with excess glucose and increased severity of defects when cultured with PMA, most notably in the yolk sac vasculature. Deletion of RasGRP3 partially protected embryos from defects experienced by wildtype embryos cultured with PMA or glucose. I also analyzed embryos developing in a maternal diabetic environment induced by streptozotocin injection. In this system, wildtype embryos had defects similar to those seen in embryo culture studies, while embryos deleted for RasGRP3 were partially protected

Greater cognitive reserve is related to lower cortical excitability in healthy cognitive aging, but not in early clinical Alzheimer’s disease

ObjectiveTo investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD).MethodsData were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50–90 years. A cognitive reserve questionnaire score (CRQ) assessed education, occupation, leisure activities, physical activities, and social engagement. Cortical excitability was quantified as the average amplitude of motor evoked potentials (MEP amplitude) elicited with single-pulse transcranial magnetic stimulation delivered to primary motor cortex. A linear model compared MEP amplitudes between groups. A linear model tested for an effect of CRQ on MEP amplitude across all participants. Finally, separate linear models tested for an effect of CRQ on MEP amplitude within each group. Exploratory analyses tested for effect modification of demographics, cognitive scores, atrophy measures, and CSF measures within each group using nested regression analysis.ResultsThere was no between-group difference in MEP amplitude after accounting for covariates. The primary model showed a significant interaction term of group*CRQ (R2adj = 0.18, p = 0.013), but no main effect of CRQ. Within the CU group, higher CRQ was significantly associated with lower MEP amplitude (R2adj = 0.45, p = 0.004). There was no association in the AD group.ConclusionLower cortico-motor excitability is related to greater CRQ in CU, but not in AD. Lower MEP amplitudes may reflect greater neural efficiency in cognitively unimpaired older adults. The lack of association seen in AD participants may reflect disruption of the protective effects of CR. Future work is needed to better understand the neurophysiologic mechanisms leading to the protective effects of CR in older adults with and without neurodegenerative disorders

The Ras Activator RasGRP3 Mediates Diabetes-Induced Embryonic Defects and Affects Endothelial Cell Migration

Fetuses that develop in diabetic mothers have a higher incidence of birth defects that include cardiovascular defects, but the signaling pathways that mediate these developmental effects are poorly understood. It is reasonable to hypothesize that diabetic maternal effects are mediated by one or more pathways activated downstream of aberrant glucose metabolism, since poorly controlled maternal glucose levels correlate with the frequency and severity of the defects

A study exploring learners' informal learning space behaviors, attitudes, and preferences

What makes a successful informal learning space is a topic in need of further research. The body of discourse on informal space design is drawn from learning theory, placemaking and architecture, with a need for understanding of the synergy between the three. Findings from a longitudinal, quantitative and qualitative study at Sheffield Hallam University, explore learners' behaviours, attitudes and preferences towards informal learning spaces in higher education, within and outside of the context of the academic library. The learning spaces study contributes to the discourse on informal learning spaces design by producing a typology of nine learning space preference attributes which address aspects of learning theory, placemaking and architecture. The typology can be used to evaluate existing spaces and inform redevelopment of informal learning spaces in higher education institutions. Implementing the typology will be subject to localised conditions, but at Sheffield Hallam University the key conclusions have included developing a portfolio of discrete, interrelated learning environments, offering spaces with a clear identity and encouraging students to translate their learning preferences into space selection

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Seropositivity for CMV and IL-6 levels are associated with grip strength and muscle size in the elderly

BACKGROUND: Sarcopenia is an important cause of morbidity and mortality in older adults, with immunosenescence and inflammation being possible underlying mechanisms. We investigated the relationship between latent cytomegalovirus (CMV) infection, Interleukin 6 (IL-6) levels, muscle size and strength in a group of healthy older community-dwelling people. METHODS: Participants were healthy volunteers from the Lothian Birth Cohort 1936 study. Participants had IL-6 level and CMV antibody titre measured at age 70 years and grip strength and a volumetric T1-weighted MRI brain scan (allowing measurement of neck muscle cross-sectional area (CSA)) at age 73. Markers of childhood deprivation were adjusted for in the analysis due to correlations between childhood deprivation and latent CMV infection. RESULTS: 866 participants were studied; 448 men (mean age 72.48 years, sd 0.70) and 418 women (mean age 72.51 years, sd 0.72). In men, CMV seropositivity was associated with smaller neck muscle CSA (p = 0.03, partial eta squared = 0.01), even after adjustment for IL-6 levels. Neck muscle CSA was not associated with CMV seropositivity in women, or CMV antibody titre or IL-6 level in either sex. Grip strength associated negatively with IL-6 level (right grip strength p<0.00001, partial eta squared 0.032 and left grip strength p<0.00001, partial eta squared 0.027) with or without adjustment for CMV serostatus or antibody titre. CMV status and antibody titre were not significantly associated with grip strength in either hand. CONCLUSION: These findings support the hypothesis that there is a relationship between markers of immunosenescence (i.e. CMV serostatus and IL6 level) and low muscle mass and strength and longitudinal studies in older cohorts are now required to investigate these relationships further

Life and living in advanced age: a cohort study in New Zealand - Te Puāwaitanga o Nga Tapuwae Kia Ora Tonu, LiLACS NZ: Study protocol

The number of people of advanced age (85&thinsp;years and older) is increasing and health systems may be challenged by increasing health-related needs. Recent overseas evidence suggests relatively high levels of wellbeing in this group, however little is known about people of advanced age, particularly the indigenous Māori, in Aotearoa, New Zealand. This paper outlines the methods of the study Life and Living in Advanced Age: A Cohort Study in New Zealand. The study aimed to establish predictors of successful advanced ageing and understand the relative importance of health, frailty, cultural, social &amp; economic factors to successful ageing for Māori and non-Māori in New Zealand

Habitat corridors function as both drift fences and movement conduits for dispersing flies

Corridors connect otherwise isolated habitat patches and can direct movement of animals among such patches. In eight experimental landscapes, we tested two hypotheses of how corridors might affect dispersal behavior. The Traditional Corridor hypothesis posits that animals preferentially leave patches via corridors, following them into adjacent patches. The Drift Fence hypothesis posits that animals dispersing through matrix habitat are diverted into patches with corridors because they follow corridors when encountered. House flies (Musca domestica L.), a species that prefers the habitat of our patches and corridors, were released in a central patch (100x100 m) and recaptured in peripheral patches that were or were not connected by a corridor. Flies were captured more frequently in connected than unconnected patches, thereby supporting the Traditional Corridor hypothesis. The Drift Fence hypothesis was also supported, as flies were captured more frequently in unconnected patches with blind (dead end) corridors than in unconnected patches of equal area without blind corridors. A second experiment tested whether these results might be dependent on the type of patch-matrix boundary encountered by dispersing flies and whether edge-following behavior might be the mechanism underlying the observed corridor effect in the first experiment. We recorded dispersal patterns of flies released along forest edges with dense undergrowth in the forest (‘‘closed’’ edges) and along edges with little forest understory (‘‘open’’ edges). Flies were less likely to cross and more likely to follow closed edges than open edges, indicating that when patch and corridor edges are pronounced, edge-following behavior of flies may direct them along corridors into connected patches. Because edges in the first experiment were open, these results also suggest that corridor effects for flies in that experiment would have been even stronger if the edges around the source patches and corridors had been more closed. Taken together, our results suggest that corridors can affect dispersal of organisms in unappreciated ways (i.e., as drift fences) and that edge type can alter dispersal behavior