Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p

A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

[Background] One of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations. [Results] We present a hierarchical and modular approach to the analysis of genome wide genotype data that incorporates quality control, linkage disequilibrium, physical distance and gene ontology to identify authentic associations among those found by statistical association tests. The method is developed for the allelic association analysis of pooled DNA samples, but it can be easily generalized to the analysis of individually genotyped samples. We evaluate the approach using data sets from diverse genome wide association studies including fetal hemoglobin levels in sickle cell anemia and a sample of centenarians and show that the approach is highly reproducible and allows for discovery at different levels of synthesis. [Conclusion] Results from the integration of Bayesian tests and other machine learning techniques with linkage disequilibrium data suggest that we do not need to use too stringent thresholds to reduce the number of false positive associations. This method yields increased power even with relatively small samples. In fact, our evaluation shows that the method can reach almost 70% sensitivity with samples of only 100 subjects.Supported by NHLBI grants R21 HL080463 (PS); R01 HL68970 (MHS); K-24, AG025727 (TP); K23 AG026754 (D.T.)

Sit still and pay attention: Using the Wii Balance-Board to detect lapses in concentration in children during psychophysical testing.

During psychophysical testing, a loss of concentration can cause observers to answer incorrectly, even when the stimulus is clearly perceptible. Such lapses limit the accuracy and speed of many psychophysical measurements. This study evaluates an automated technique for detecting lapses based on body movement (postural instability). Thirty-five children (8-11 years of age) and 34 adults performed a typical psychophysical task (orientation discrimination) while seated on a Wii Fit Balance Board: a gaming device that measures center of pressure (CoP). Incorrect responses on suprathreshold catch trials provided the "reference standard" measure of when lapses in concentration occurred. Children exhibited significantly greater variability in CoP on lapse trials, indicating that postural instability provides a feasible, real-time index of concentration. Limitations and potential applications of this method are discussed

Productivity trends and collaboration patterns: A diachronic study in the eating disorders field

[EN] Objective The present study seeks to extend previous bibliometric studies on eating disorders (EDs) by including a time-dependent analysis of the growth and evolution of multi-author collaborations and their correlation with ED publication trends from 1980 to 2014 (35 years). Methods Using standardized practices, we searched Web of Science (WoS) Core Collection (WoSCC) (indexes: Science Citation Index-Expanded [SCIE], & Social Science Citation Index [SSCI]) and Scopus (areas: Health Sciences, Life Sciences, & Social Sciences and Humanities) to identify a large sample of articles related to EDs. We then submitted our sample of articles to bibliometric and graph theory analyses to identify co-authorship and social network patterns. Results We present a large number of detailed findings, including a clear pattern of scientific growth measured as number of publications per five-year period or quinquennium (Q), a tremendous increase in the number of authors attracted by the ED subject, and a very high and steady growth in collaborative work. Conclusions We inferred that the noted publication growth was likely driven by the noted increase in the number of new authors per Q. Social network analyses suggested that collaborations within ED follow patters of interaction that are similar to well established and recognized disciplines, as indicated by the presence of a ¿giant cluster¿, high cluster density, and the replication of the ¿small world¿ phenomenon¿the principle that we are all linked by short chains of acquaintances.This work was performed with a subsidy from Universidad Catolica de Valencia "San Vicente Martir" to resarch group INDOTEI: Evaluacion de la Ciencia, for the years 2016-2017. This work is benefited from Spanish Government assistance through Government Delegation for the National Drugs Plan of the Ministry of Health, Social Services and Equality (project 2016/028); and National R+D+I (projects: CS02012-39632-C02-01 and CS02015-65594-C2-2-R) and 2015-Networks of Excellence Call (project CS02015-71867-REDT) of the Ministry of Economy and Competitiveness.Valderrama Zurian, JC.; Aguilar-Moya, R.; Cepeda-Benito, A.; Melero-Fuentes, D.; Navarro-Moreno, MÁ.; Gandía-Balaguer, A.; Aleixandre-Benavent, R. (2017). Productivity trends and collaboration patterns: A diachronic study in the eating disorders field. PLoS ONE. 12(8):1-17. https://doi.org/10.1371/journal.pone.0182760S117128McClelland, J., Bozhilova, N., Campbell, I., & Schmidt, U. (2013). A Systematic Review of the Effects of Neuromodulation on Eating and Body Weight: Evidence from Human and Animal Studies. 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Asking the right questions: Scoping studies in the commissioning of research on the organisation and delivery of health services

Scoping studies have been used across a range of disciplines for a wide variety of purposes. However, their value is increasingly limited by a lack of definition and clarity of purpose. The UK's Service Delivery and Organisation Research Programme (SDO) has extensive experience of commissioning and using such studies; twenty four have now been completed

Teaching the science of learning

The science of learning has made a considerable contribution to our understanding of effective teaching and learning strategies. However, few instructors outside of the field are privy to this research. In this Tutorial Review, we focus on six specific cognitive strategies that have received robust support from decades of research: spaced practice, interleaving, retrieval practice, elaboration, concrete examples, and dual coding. We describe the basic research behind each strategy and relevant applied research, present examples of existing and suggested implementation, and make recommendations for further research that would broaden the reach of these strategies

Three pillars of sustainability: in search of conceptual origins

The three-pillar conception of (social, economic and environmental) sustainability, commonly represented by three intersecting circles with overall sustainability at the centre, has become ubiquitous. With a view of identifying the genesis and theoretical foundations of this conception, this paper reviews and discusses relevant historical sustainability literature. From this we find that there is no single point of origin of this three-pillar conception, but rather a gradual emergence from various critiques in the early academic literature of the economic status quo from both social and ecological perspectives on the one hand, and the quest to reconcile economic growth as a solution to social and ecological problems on the part of the United Nations on the other. The popular three circles diagram appears to have been first presented by Barbier (Environ Conserv 14:101, doi: 10.1017/s0376892900011449, 1987), albeit purposed towards developing nations with foci which differ from modern interpretations. The conceptualisation of three pillars seems to predate this, however. Nowhere have we found a theoretically rigorous description of the three pillars. This is thought to be in part due to the nature of the sustainability discourse arising from broadly different schools of thought historically. The absence of such a theoretically solid conception frustrates approaches towards a theoretically rigorous operationalisation of ‘sustainability’