Sending Your Grandparents to University Increases Cognitive Reserve: The Tasmanian Healthy Brain Project.

Increasing an individual’s level of cognitive reserve (CR) has been suggested as a nonpharmacological approach to reducing the risk for Alzheimer’s disease. We examined changes in CR in older adults participating over 4 years in the Tasmanian Healthy Brain Project. Method: A sample of 459 healthy older adults between 50 and 79 years of age underwent a comprehensive annual assessment of current CR, neuropsychological function, and psychosocial factors over a 4-year period. The intervention group of 359 older adults (M � 59.61 years, SD � 6.67) having completed a minimum of 12 months part-time university study were compared against a control reference group of 100 adults (M � 62.49 years, SD � 6.24) who did not engage in further education. Results: Growth mixture modeling demonstrated that 44.3% of the control sample showed no change in CR, whereas 92.5% of the further education participants displayed a significant linear increase in CR over the 4 years of the study. These results indicate that older adults engaging in high-level mental stimulation display an increase in CR over a 4-year period. Conclusion: Increasing mental activity in older adulthood may be a viable strategy to improve cognitive function and offset cognitive decline associated with normal aging

Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase

Background: Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO), is emerging as a novel entity with distinct pharmacology and therapeutic advantages over NO• [1]. Importantly, HNO has vasoprotective actions with the potential to serve as an antioxidant. Here we explored the ability of HNO to modulate cerebrovascular NADPH oxidase activity, a major source of superoxide (.O2-) in the vasculature. Materials and methods: Intracranial (pooled middle cerebral and basilar) and extracranial (carotid) cerebral arteries from male C57BL/6J mice were treated with angiotensin II (10 nM) acutely (30 min) and chronically (24 h), respectively, in the absence and presence of the HNO donor, Angeli's salt (AS). NADPH (100 μM)-stimulated .O2- production was then measured using lucigenin (5 μM)-enhanced chemiluminescence. Results: AS (1 μM) did not scavenge .O2- generated in a cell free xanthine (100 μM)/xanthine oxidase (0.05 U/ml) activity assay (control: 447.9 ± 90.8; AS 507.1 ± 113.3 counts, n = 4). In contrast, acute and chronic treatment with AS (0.01–1 μM) caused a concentration-dependent decrease in NADPH oxidase-derived .O2- production by intracranial and extracranial cerebral arteries, respectively (carotid 0.59 ± 0.05; AS 0.1 μM 0.33 ± 0.08; AS 1 μM 0.16 ± 0.03 103 counts/s/mg, P < 0.05, n = 8). The effects of AS were reversed by the HNO scavenger, L-cysteine (3 mM) but unchanged in the presence of the NO• scavenger carboxy-PTIO (200 μM) and sGC inhibitor, ODQ (10 μM). Conclusion: HNO suppresses vascular NADPH-oxidase activity both acutely and chronically, possibly via a cGMP-independent mechanism. Such antioxidant actions of HNO may confer therapeutic advantages in the treatment of cerebrovascular disorders

Synthesis-View: visualization and interpretation of SNP association results for multi-cohort, multi-phenotype data and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Initial genome-wide association study (GWAS) discoveries are being further explored through the use of large cohorts across multiple and diverse populations involving meta-analyses within large consortia and networks. Many of the additional studies characterize less than 100 single nucleotide polymorphisms (SNPs), often include multiple and correlated phenotypic measurements, and can include data from multiple-sites, multiple-studies, as well as multiple race/ethnicities. New approaches for visualizing resultant data are necessary in order to fully interpret results and obtain a broad view of the trends between DNA variation and phenotypes, as well as provide information on specific SNP and phenotype relationships.</p> <p>Results</p> <p>The Synthesis-View software tool was designed to visually synthesize the results of the aforementioned types of studies. Presented herein are multiple examples of the ways Synthesis-View can be used to report results from association studies of DNA variation and phenotypes, including the visual integration of p-values or other metrics of significance, allele frequencies, sample sizes, effect size, and direction of effect.</p> <p>Conclusions</p> <p>To truly allow a user to visually integrate multiple pieces of information typical of a genetic association study, innovative views are needed to integrate multiple pieces of information. As a result, we have created "Synthesis-View" software for the visualization of genotype-phenotype association data in multiple cohorts. Synthesis-View is freely available for non-commercial research institutions, for full details see <url>https://chgr.mc.vanderbilt.edu/synthesisview</url>.</p

Beyond clustering: mean-field dynamics on networks with arbitrary subgraph composition

Clustering is the propensity of nodes that share a common neighbour to be connected. It is ubiquitous in many networks but poses many modelling challenges. Clustering typically manifests itself by a higher than expected frequency of triangles, and this has led to the principle of constructing networks from such building blocks. This approach has been generalised to networks being constructed from a set of more exotic subgraphs. As long as these are fully connected, it is then possible to derive mean-field models that approximate epidemic dynamics well. However, there are virtually no results for non-fully connected subgraphs. In this paper, we provide a general and automated approach to deriving a set of ordinary differential equations, or mean-field model, that describes, to a high degree of accuracy, the expected values of system-level quantities, such as the prevalence of infection. Our approach offers a previously unattainable degree of control over the arrangement of subgraphs and network characteristics such as classical node degree, variance and clustering. The combination of these features makes it possible to generate families of networks with different subgraph compositions while keeping classical network metrics constant. Using our approach, we show that higher-order structure realised either through the introduction of loops of different sizes or by generating networks based on different subgraphs but with identical degree distribution and clustering, leads to non-negligible differences in epidemic dynamics

Nitroxyl (HNO) Stimulates Soluble Guanylyl Cyclase to Suppress Cardiomyocyte Hypertrophy and Superoxide Generation

Background: New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NON attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated. Methods: Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli’s salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 mmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. Results: We now demonstrate that Angeli’s salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and b-myosin heavy chain expression. Angeli’s salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli’s salt were mimicked by BNP. We also demonstrate that the effects of Angeli’s salt are specifically mediated by HNO (with no role for NON or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependen

Tree migration-rates : narrowing the gap between inferred post-glacial rates and projected rates

Faster-than-expected post-glacial migration rates of trees have puzzled ecologists for a long time. In Europe, post-glacial migration is assumed to have started from the three southern European peninsulas (southern refugia), where large areas remained free of permafrost and ice at the peak of the last glaciation. However, increasing palaeobotanical evidence for the presence of isolated tree populations in more northerly microrefugia has started to change this perception. Here we use the Northern Eurasian Plant Macrofossil Database and palaeoecological literature to show that post-glacial migration rates for trees may have been substantially lower (60–260 m yr–1) than those estimated by assuming migration from southern refugia only (115–550 m yr–1), and that early-successional trees migrated faster than mid- and late-successional trees. Post-glacial migration rates are in good agreement with those recently projected for the future with a population dynamical forest succession and dispersal model, mainly for early-successional trees and under optimal conditions. Although migration estimates presented here may be conservative because of our assumption of uniform dispersal, tree migration-rates clearly need reconsideration. We suggest that small outlier populations may be a key factor in understanding past migration rates and in predicting potential future range-shifts. The importance of outlier populations in the past may have an analogy in the future, as many tree species have been planted beyond their natural ranges, with a more beneficial microclimate than their regional surroundings. Therefore, climate-change-induced range-shifts in the future might well be influenced by such microrefugia

e-Roster Policy: Insights and implications of codifying nurse scheduling

Following a decade of dissemination, particularly within the British National Health Service (NHS), electronic rostering systems were recently endorsed within the Carter Review. However, e-rostering necessitates the formal codification of the roster process. This research investigates that codification through the lens of the 'Roster Policy', a formal document specifying the rules and procedures used to prepare staff rosters. This study is based upon analysis of twenty-seven publicly available policies, each approved within a four-year period from January 2010 to July 2014. This research finds that, at an executive level, codified knowledge is used as a proxy for the common language and experience otherwise acquired on a ward through everyday interaction, while at ward level the nurse rostering problem continues to resist all efforts at simplification. Ultimately, it is imperative that executives recognise that e-rostering is not a silver-bullet and that information from such systems requires careful interpretation and circumspection

Fast variables determine the epidemic threshold in the pairwise model with an improved closure

Pairwise models are used widely to model epidemic spread on networks. These include the modelling of susceptible-infected-removed (SIR) epidemics on regular networks and extensions to SIS dynamics and contact tracing on more exotic networks exhibiting degree heterogeneity, directed and/or weighted links and clustering. However, extra features of the disease dynamics or of the network lead to an increase in system size and analytical tractability becomes problematic. Various `closures' can be used to keep the system tractable. Focusing on SIR epidemics on regular but clustered networks, we show that even for the most complex closure we can determine the epidemic threshold as an asymptotic expansion in terms of the clustering coefficient.We do this by exploiting the presence of a system of fast variables, specified by the correlation structure of the epidemic, whose steady state determines the epidemic threshold. While we do not find the steady state analytically, we create an elegant asymptotic expansion of it. We validate this new threshold by comparing it to the numerical solution of the full system and find excellent agreement over a wide range of values of the clustering coefficient, transmission rate and average degree of the network. The technique carries over to pairwise models with other closures [1] and we note that the epidemic threshold will be model dependent. This emphasises the importance of model choice when dealing with realistic outbreaks

Computed cardiopulmonography and the idealized lung clearance index, iLCI2.5, in early-stage cystic fibrosis.

This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early-stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early-stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified through CCP parameter σlnCl, was significantly greater (P < 0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (P < 0.002). Participant-specific parameters were used with the CCP model to calculate idealized values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardized. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r = 0.46, P < 0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F ratio = 2.2, P = 0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflects an amalgam of different underlying lung changes in early-stage CF that would require a multiparameter approach, such as potentially CCP, to resolve.NEW & NOTEWORTHY Computed cardiopulmonography is a new technique comprising a highly accurate sensor for measuring respiratory gas exchange coupled with a cardiopulmonary model that is used to identify a set of patient-specific characteristics of the lung. Here, we show that this technique can improve on a standard clinical approach for lung function testing in cystic fibrosis. Most particularly, an approach incorporating multiple model parameters can potentially separate different aspects of pathological change in this disease