Novel role for thioredoxin reductase-2 in mitochondrial redox adaptations to obesogenic diet and exercise in heart and skeletal muscle

Increased fatty acid availability and oxidative stress are physiological consequences of exercise (Ex) and a high-fat, high-sugar (HFHS) diet. Despite these similarities, the global effects of Ex are beneficial, whereas HFHS diets are largely deleterious to the cardiovascular system. The reasons for this disparity are multifactorial and incompletely understood. We hypothesized that differences in redox adaptations following HFHS diet in comparison to exercise may underlie this disparity, particularly in mitochondria. Our objective in this study was to determine mechanisms by which heart and skeletal muscle (red gastrocnemius, RG) mitochondria experience differential redox adaptations to 12 weeks of HFHS diet and/or exercise training (Ex) in rats. Surprisingly, both HFHS feeding and Ex led to contrasting effects in heart and RG, in that mitochondrial H2O2 decreased in heart but increased in RG following both HFHS diet and Ex, in comparison to sedentary animals fed a control diet. These differences were determined to be due largely to increased antioxidant/anti-inflammatory enzymes in the heart following the HFHS diet, which did not occur in RG. Specifically, upregulation of mitochondrial thioredoxin reductase-2 occurred with both HFHS and Ex in the heart, but only with Ex in RG, and systematic evaluation of this enzyme revealed that it is critical for suppressing mitochondrial H2O2 during fatty acid oxidation. These findings are novel and important in that they illustrate the unique ability of the heart to adapt to oxidative stress imposed by HFHS diet, in part through upregulation of thioredoxin reductase-2. Furthermore, upregulation of thioredoxin reductase-2 plays a critical role in preserving the mitochondrial redox status in the heart and skeletal muscle with exercise.Funding from the National Institutes of Health, United State

Untangling knowledge creation and knowledge integration in enterprise wikis

A central challenge organizations face is how to build, store, and maintain knowledge over time. Enterprise wikis are community-based knowledge systems situated in an organizational context. These systems have the potential to play an important role in managing knowledge within organizations, but the motivating factors that drive individuals to contribute their knowledge to these systems is not very well understood. We theorize that enterprise wiki initiatives require two separate and distinct types of knowledge-sharing behaviors to succeed: knowledge creation (KC) and knowledge integration (KI). We examine a Wiki initiative at a major German bank to untangle the motivating factors behind KC and KI. Our results suggest KC and KI are indeed two distinct behaviors, reconcile inconsistent findings from past studies on the role of motivational factors for knowledge sharing to establish shared electronic knowledge resources in organizations, and identify factors that can be leveraged to tilt behaviors in favor of KC or KI

Research in progress: report on the ICAIL 2017 doctoral consortium

This paper arose out of the 2017 international conference on AI and law doctoral consortium. There were five students who presented their Ph.D. work, and each of them has contributed a section to this paper. The paper offers a view of what topics are currently engaging students, and shows the diversity of their interests and influences

Architectures and Design Methodologies for Scalable and Sustainable Remote Laboratory Infrastructures

With the increasing demand for distance learning opportunities in the higher education sector, there isan ever-growing need for the design and deployment of remote laboratories, especially for engineering,science, and technology curricula. In order to accommodate the offering of entire degrees for distancelearning students whose curricula require remote laboratories, scalable information technology infrastructuresthat support the large scale use and deployment of these remote laboratories must exist. Thischapter provides a discussion of architectures and design methodologies using technology such as commandand control communications, Web 2.0, and cloud computing, which provide a scalable, manageable,and sustainable technological infrastructure-basis for large scale remote laboratory deployment

Balancing, Proportionality, and Constitutional Rights

In the theory and practice of constitutional adjudication, proportionality review plays a crucial role. At a theoretical level, it lies at core of the debate on rights adjudication; in judicial practice, it is a widespread decision-making model characterizing the action of constitutional, supra-national and international courts. Despite its circulation and centrality in contemporary legal discourse, proportionality in rights-adjudication is still extremely controversial. It raises normative questions—concerning its justification and limits—and descriptive questions—regarding its nature and distinctive features. The chapter addresses both orders of questions. Part I centres on the justification of proportionality review, the connection between proportionality, balancing and theories of rights and the critical aspects of this connection. Part II identifies and analyses the different forms of proportionality both in review, as a template for rights-adjudication, and of review, as a way of defining the scope and limits of adjudication

Comparison of yoga versus stretching for chronic low back pain: protocol for the Yoga Exercise Self-care (YES) trial

<p>Abstract</p> <p>Background</p> <p>Back pain, one of the most prevalent conditions afflicting American adults, is the leading reason for using complementary and alternative medicine (CAM) therapies. Yoga is an increasingly popular "mind-body" CAM therapy often used for relieving back pain and several small studies have found yoga effective for this condition. This study will assess whether yoga is effective for treating chronic low back pain compared with self care and exercise and will explore the mechanisms responsible for any observed benefits.</p> <p>Methods/Design</p> <p>A total of 210 participants with low back pain lasting at least 3 months will be recruited from primary care clinics of a large healthcare system based in Seattle. They will be randomized in a 2:2:1 ratio to receive 12 weekly yoga classes, 12 weekly conventional therapeutic exercise classes of comparable physical exertion, or a self-care book. Interviewers masked to participants' treatment group will assess outcomes at baseline and 6, 12 and 26 weeks after randomization. Primary outcomes will be back-related dysfunction and symptom bothersomeness. In addition, data will be collected on physical measurements (e.g., flexion) at baseline and 12 weeks and saliva samples will be obtained at baseline, 6 and 12 weeks. Information will be collected on specific physical, psychological, and physiological factors to allow exploration of possible mechanisms of action through which yoga could relieve back pain and dysfunction. The effectiveness of yoga will be assessed using analysis of covariance (using general estimating equations - GEE) within an intention-to-treat context. If yoga is found effective, further analyses will explore whether yoga's benefits are attributable to physical, psychological and/or physiological factors.</p> <p>Conclusions</p> <p>This study will provide the clearest evidence to date about the value of yoga as a therapeutic option for treating chronic back pain, and if the results are positive, will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study.</p> <p>Trial registration</p> <p>This trial is registered in ClinicalTrials.gov, with the ID number of <it>NCT00447668</it>.</p

Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis

Purpose To explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis. Methods: Patients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics). Independent genotyping and two-phase data transfer mitigated bias. The primary analysis compared the effect of DrotAA in IRP+ and IRP− groups on in-hospital 28-day mortality. Secondary endpoints included time to death in hospital; intensive care unit (ICU)-, hospital-, and ventilator-free days; and overall DrotAA treatment effect on mortality. Results: Six hundred and ninety-two patients treated with DrotAA were successfully matched to 1935 patients not treated with DrotAA. Genotyping was successful for 639 (DrotAA) and 1684 (nonDrotAA) matched patients. The primary hypothesis of a genotype-by-treatment interaction (assessed by conditional logistic regression analysis) was not significant (P = 0.30 IRP A; P = 0.78 IRP B), and there was no significant genotype by treatment interaction for any secondary endpoint. Conclusions: Neither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality. ClinicalTrials.gov registration NCT01486524 Electronic supplementary material The online version of this article (10.1186/s13613-018-0353-2) contains supplementary material, which is available to authorized users.Version of Recor

A Maternal Influence on Reading the Mind in the Eyes Mediated by Executive Function: Differential Parental Influences on Full and Half-Siblings

BACKGROUND: Parent-of-origin effects have been found to influence the mammalian brain and cognition and have been specifically implicated in the development of human social cognition and theory of mind. The experimental design in this study was developed to detect parent-of-origin effects on theory of mind, as measured by the 'Reading the mind in the eyes' (Eyes) task. Eyes scores were also entered into a principal components analysis with measures of empathy, social skills and executive function, in order to determine what aspect of theory of mind Eyes is measuring. METHODOLOGY/PRINCIPAL FINDINGS: Maternal and paternal influences on Eyes scores were compared using correlations between pairs of full (70 pairs), maternal (25 pairs) and paternal siblings (15 pairs). Structural equation modelling supported a maternal influence on Eyes scores over the normal range but not low-scoring outliers, and also a sex-specific influence on males acting to decrease male Eyes scores. It was not possible to differentiate between genetic and environmental influences in this particular sample because maternal siblings tended to be raised together while paternal siblings were raised apart. The principal components analysis found Eyes was associated with measures of executive function, principally behavioural inhibition and attention, rather than empathy or social skills. CONCLUSIONS/SIGNIFICANCE: In conclusion, the results suggest a maternal influence on Eye scores in the normal range and a sex-specific influence acting to reduce scores in males. This influence may act via aspects of executive function such as behavioural inhibition and attention. There may be different influences acting to produce the lowest Eyes scores which implies that the heratibility and/or maternal influence on poor theory of mind skills may be qualitatively different to the influence on the normal range