775 research outputs found

    Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

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    Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development

    The Grizzly, September 24, 2015

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    CIE Professors Lend a Hand at Columbia U. • As Rush Week Ends, Greek Numbers Defy Expectations • Getting Back on Track • Healthy Addition: HEP Welcomes Rugby Coach to Faculty Lineup • Improving the Higher Education Experience • UC Student Trains Service Dog on Campus • Students Work with College Communications Office • Main Street Life: Upperclassmen Debate Housing\u27s Pros and Cons • Opinions: The Visit Rates 5 / 10; Extra-curricular Options for Students • Going Pro : Symposium on Sports Business and the Entrepreneurial Mindset Comes to Ursinus • Looking to Three-peathttps://digitalcommons.ursinus.edu/grizzlynews/1671/thumbnail.jp

    Effective action and density functional theory

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    The effective action for the charge density and the photon field is proposed as a generalization of the density functional. A simple definition is given for the density functional, as the functional Legendre transform of the generator functional of connected Green functions for the density and the photon field, offering systematic approximation schemes. The leading order of the perturbation expansion reproduces the Hartree-Fock equation. A renormalization group motivated method is introduced to turn on the Coulomb interaction gradually and to find corrections to the Hartree-Fock and the Kohn-Sham schemes.Comment: New references and a numerical algorithm added, to appear in Phys. Rev. B. 30 pages, no figure

    Accuracy and repeatability of wrist joint angles in boxing using an electromagnetic tracking system

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    © 2019, The Author(s). The hand-wrist region is reported as the most common injury site in boxing. Boxers are at risk due to the amount of wrist motions when impacting training equipment or their opponents, yet we know relatively little about these motions. This paper describes a new method for quantifying wrist motion in boxing using an electromagnetic tracking system. Surrogate testing procedure utilising a polyamide hand and forearm shape, and in vivo testing procedure utilising 29 elite boxers, were used to assess the accuracy and repeatability of the system. 2D kinematic analysis was used to calculate wrist angles using photogrammetry, whilst the data from the electromagnetic tracking system was processed with visual 3D software. The electromagnetic tracking system agreed with the video-based system (paired t tests) in both the surrogate ( 0.9). In the punch testing, for both repeated jab and hook shots, the electromagnetic tracking system showed good reliability (ICCs > 0.8) and substantial reliability (ICCs > 0.6) for flexion–extension and radial-ulnar deviation angles, respectively. The results indicate that wrist kinematics during punching activities can be measured using an electromagnetic tracking system

    Ordinary morality does not imply atheism

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    Many theist as well as many atheist philosophers have maintained that if God exists, then every instance of undeserved, unwanted suffering ultimately benefits the sufferer. Recently, several authors have argued that this implication of theism conflicts with ordinary morality. I show that these arguments all rest on a common mistake. Defenders of these arguments overlook the role of merely potential instances of suffering in determining our moral obligations toward suffering

    Lectures on the functional renormalization group method

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    These introductory notes are about functional renormalization group equations and some of their applications. It is emphasised that the applicability of this method extends well beyond critical systems, it actually provides us a general purpose algorithm to solve strongly coupled quantum field theories. The renormalization group equation of F. Wegner and A. Houghton is shown to resum the loop-expansion. Another version, due to J. Polchinski, is obtained by the method of collective coordinates and can be used for the resummation of the perturbation series. The genuinely non-perturbative evolution equation is obtained in a manner reminiscent of the Schwinger-Dyson equations. Two variants of this scheme are presented where the scale which determines the order of the successive elimination of the modes is extracted from external and internal spaces. The renormalization of composite operators is discussed briefly as an alternative way to arrive at the renormalization group equation. The scaling laws and fixed points are considered from local and global points of view. Instability induced renormalization and new scaling laws are shown to occur in the symmetry broken phase of the scalar theory. The flattening of the effective potential of a compact variable is demonstrated in case of the sine-Gordon model. Finally, a manifestly gauge invariant evolution equation is given for QED.Comment: 47 pages, 11 figures, final versio

    Clinical study of the factors affecting radioulnar deviation of the wrist joint

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    <p>Abstract</p> <p>Background</p> <p>The radioulnar carpal joint is critical for hand and wrist function. Radioulnar deviation indicates distal radioulnar joint flexibility and reflects the structure and function of the carpal bones, ulna, radius and ligaments. The present study examined whether radioulnar deviation is affected by gender, manual labor, playing a musical instrument, playing sport, handedness, previous fracture or prior inflammation. The study used clinical findings based on anatomical landmarks</p> <p>Methods</p> <p>The ulnar, radial and total deviations for both left and right hands were measured in 300 subjects (157 men and 143 women) of mean age 21.7 years. Measurements were made with the forearm in a fixed pronated position using a novel specially designed goniometer. The gender of each subject was recorded, and information on playing of sport, playing a musical instrument, manual labor, handedness, and history of fracture or inflammation was sought. Data were analyzed using a multifactor ANOVA test.</p> <p>Results</p> <p>No statistically significant difference (p-value > 0.05) was found between those comparing groups except the total deviation of athletes' left hand versus the total deviation of non athletes' left hand (p-value 0.041 < 0.05) and the radial deviation of manual workers' left hand and non manual workers' left hand (p-value 0.002 < 0.05).</p> <p>Conclusions</p> <p>This study was based on clinical findings using anatomical landmarks. We found that manual workers and athletes showed greater left hand flexibility. This suggests that activities that place chronic stress on the radiocarpal joint can independently affect radioulnar deviation.</p
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