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231.
Anji Song Gwang-Won Cho Karthikeyan A. Vijayakumar Changjong Moon Mary Jasmin Ang Jahae Kim Ilyong Park Chul Ho Jang 《International journal of molecular sciences》2022,23(1)
High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein—an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model. 相似文献
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234.
J.H. Argyris H. Balmer M. Kleiber U. Hindenlang 《Computer Methods in Applied Mechanics and Engineering》1980,22(3):361-389
The paper presents an extension of the range of application of the simple triangular shell element evolved in [1] to the domain of large inelastic deformations. The element is partly based on ideas of physical lumping which contain a simple mechanical interpretation. None of the virtual work or variational principles are applicable to the present model of a finite element thus implying its approximate character. Nevertheless it is hoped that the proposed element, denoted as in [1] by TRUMP, will prove useful for the study of geometrically complicated and materially nonlinear problems of shell systems in which transverse shear may have to be included. In such cases the application of the high order “formal” displacement elements may prove difficult and expensive. Some examples illustrate the technique. 相似文献
235.
Formulas are often monotonic in the sense that satisfiability for a given domain of discourse entails satisfiability for all
larger domains. Monotonicity is undecidable in general, but we devised three calculi that infer it in many cases for higher-order
logic. The third calculus has been implemented in Isabelle’s model finder Nitpick, where it is used both to prune the search
space and to soundly interpret infinite types with finite sets, leading to dramatic speed and precision improvements. 相似文献
236.
Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure. 相似文献
237.
Jasmin Christian Blanchette Sascha Böhme Lawrence C. Paulson 《Journal of Automated Reasoning》2013,51(1):109-128
Sledgehammer is a component of Isabelle/HOL that employs resolution-based first-order automatic theorem provers (ATPs) to discharge goals arising in interactive proofs. It heuristically selects relevant facts and, if an ATP is successful, produces a snippet that replays the proof in Isabelle. We extended Sledgehammer to invoke satisfiability modulo theories (SMT) solvers as well, exploiting its relevance filter and parallel architecture. The ATPs and SMT solvers nicely complement each other, and Isabelle users are now pleasantly surprised by SMT proofs for problems beyond the ATPs’ reach. 相似文献
238.
The singing of adult birds shows a clear hierarchical organization and, due to its development through vocal imitation of sound patterns, makes an excellent biological model to examine the variables that influence the imitation of patterns on different hierarchy levels, e.g., songs and elements composing the songs. We studied such variables in the nightingale (Luscinia megarhynchos), i.e., a species that in the wild uses a large repertoire of songs. Subjects were raised in the lab and tutored by presenting them with a serial learning task, here a sequence of differently patterned songs. Analyses of singing, which the trained subjects performed at the end of their vocal ontogeny, allowed us to uncover hierarchy-related accomplishments and also specific constraints in learning by imitation. Our results showed that an imitation of elements and element sequences reflected a kind of "gestalt" learning, which finally became visible in the form of specific song patterns. An imitation of song sequences, on the other hand, reflected a kind of "list" learning, which finally emerged into the formation of specific subrepertoires of song types. The structure of such subrepertoires mirrored the serial order of imitated songs but allowed, nevertheless, a serially flexible retrieval of single types of songs. These findings contribute to a better understanding of relationships between signal imitation and signal use during vocal interactions among songbirds. 相似文献
239.
Stabilization and Control of Delayed Recycling High Order Systems with one Unstable Pole at the Direct Path 下载免费PDF全文
Juan Francisco Marquez‐Rubio Rocio Jasmin Vazquez‐Guerra Basilio del Muro‐Cuéllar Olivier Sename 《Asian journal of control》2016,18(3):789-801
In this work the stabilization and control of delayed recycling systems is addressed. Recycling systems are characterized by possessing two main paths, named the direct (feedforward) and the recycling (feedback) paths. Such class of systems reuse the energy and/or the partially processed matter increasing the efficiency of the overall process. A control methodology is proposed for the stabilization and control of this kind of system. The particular class of systems addressed here contains one unstable pole, m stable poles, a delay term and possible p left half plane (LHP) zeros in the direct path and a delayed stable subsystem in the recycling path. The strategy is based on an asymptotic observer‐predictor to estimate the required internal signals. Necessary and sufficient conditions are stated in order to guarantee the stabilization of the proposed scheme, achieving step tracking and rejection. 相似文献
240.
Jordi C. J. Hintzen Laust Moesgaard Sebastian Kwiatkowski Prof. Jakub Drozak Prof. Jacob Kongsted Prof. Jasmin Mecinović 《ChemMedChem》2021,16(17):2695-2702
SETD3 was recently identified as the histidine methyltransferase responsible for N3-methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin peptide was found to be the most potent SETD3 inhibitor (IC50=161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for β-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3. 相似文献