Glycolysis Upregulation Is Neuroprotective As A Compensatory Mechanism In Als

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective

Measurements of knee rotation-reliability of an external device in vivo

<p>Abstract</p> <p>Background</p> <p>Knee rotation plays an important part in knee kinematics during weight-bearing activities. An external device for measuring knee rotation (the Rottometer) has previously been evaluated for validity by simultaneous measurements of skeletal movements with Roentgen Stereometric Analysis (RSA). The aim of this study was to investigate the reliability of the device.</p> <p>Method</p> <p>The within-day and test-retest reliability as well as intertester reliability of the device in vivo was calculated. Torques of 3, 6 and 9 Nm and the examiner's apprehension of end-feel were used at 90°, 60° and 30° of knee flexion. Intraclass Correlation Coefficient _2,1(ICC _2,1), 95% confidence interval (CI) of ICC and 95% CI between test trials and examiners were used as statistical tests.</p> <p>Result</p> <p>ICC_2,1ranged from 0.50 to 0.94 at all three flexion angles at 6 and 9 Nm as well as end-feel, and from 0.22 to 0.75 at 3 Nm applied torque.</p> <p>Conclusion</p> <p>The Rottometer was a reliable measurement instrument concerning knee rotation at the three different flexion angles (90°, 60° and 30°) with 6 and 9 Nm applied torques as well as the examiner's apprehension of end-feel. Three Nm was not a reliable torque. The most reliable measurements were made at 9 Nm applied torque.</p

Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.National Institutes of Health [T32GM008659, NS091299]; Howard Hughes Medical Institute; University of Arizona; Arnold and Mabel Beckman Foundation; Association pour la Recherche sur la Sclerose Laterale Amyotrophique et autres Maladies du Motoneurone; Target ALS; Barrow Neurological Foundation; Muscular Dystrophy Association [418515]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Changing the rules of the game: an analysis of EU influence on electricity and gas liberalization: with a focus on the Baltic Sea Region, and future challenges to EU energy market regulation

This study analyses the expansion of the EU into energy market regulation. It shows that the limits to EU influence and, thereby, EU energy market regulation for the internal energy market, begin where EU influence affects national interests with regard to ensuring energy security. This scientifically established insight bears an important practical implication. The further development of EU energy market regulation as a cornerstone of the internal energy market faces a particular policy challenge: It is necessary to establish a regulatory framework for the internal electricity and gas market, which acknowledges the primacy of national energy security interests. This finding is important in the light of the new and increasing energy policy challenges that some Member States face today, not least as a result of a liberalized energy market. Moreover, in the context of new systemic risks arising from ongoing energy market integration, a politically unstable (in the worst case - collapsing) EU regulatory framework can cause significant social and economic costs for individual Member States. With regard to that, the study points to the increasingly complex policy areas that are made subject to EU integration and calls for more attention to the related regulatory and political risks - also with a view to the current euro crisis. Diese Studie analysiert die Expansion der EU in die Energiemarktregulierung. Sie zeigt, dass die Grenzen des EU Einflusses und damit des EU Regulierungsrahmens für den Energiebinnenmarkt dort beginnen, wo nationale Interessen mit Blick auf die Gewährleistung der Energieversorgungssicherheit tangiert werden. Diese Erkenntnis hat eine wichtige praktische Implikation. Die weitere Ausgestaltung der EU Energiemarktregulierung und damit des Fundaments des Energiebinnenmarktes steht vor einer besonderen politischen Herausforderung: Es gilt einen stabilen gemeinschaftlichen Regulierungsrahmens für den europäischen Strom- und Gasmarkt unter dem Primat nationaler Energiesicherheitsinteressen bereitzustellen. Dies ist von Bedeutung im Lichte wachsender und neuer energiepolitischer Herausforderungen für die einzelnen Mitgliedstaaten, nicht zuletzt als Folge eines liberalisierten Energiemarktes. In Anbetracht neuer systemischer Risiken, die sich aus einem integrierten europäischen Energiemarkt ergeben, kann ein politisch instabiler (im schlimmsten Fall kollabierender) gemeinschaftlicher Regulierungsrahmen für die Mitgliedstaaten hohe soziale und ökonomische Kosten nach sich ziehen. An dieser Stelle verweist die Studie auf die immer komplexeren Integrationsgegenstände der EU und fordert, dass den damit einhergehenden Risiken, regulatorischer und politischer Art, grössere Aufmerksamkeit zu schenken ist - gerade auch mit Blick auf die aktuelle Krise der Gemeinschaftswährung

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits