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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Neural Regeneration Research 2025年第3期20卷 715-724页

作者： Xin Yang Yu-Wen Alvin Huang john Marshall Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRIUSA Department of Neurology Warren Alpert Medical School of Brown UniversityProvidenceRIUSA Center for Translational Neuroscience Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational ScienceBrown UniversityProvidenceRIUSA

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and *** activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term ***,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term *** this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and *** with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 *** TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific *** TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

关键词： Angelman syndrome autism brain-derived neurotrophic factor depression neurodegenerative disorder neurodevelopmental disorder postsynaptic density protein-95 synaptic plasticity TrkB

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A spotlight on dosage and subject selection for effective neuroprotection: exploring the central role of mitochondria

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Neural Regeneration Research 2025年第4期20卷 1081-1082页

作者： john Mitrofanis Jonathan Stone Michael R.Hamblin Pierre Magistretti Alim-Louis Benabid Glen Jeffery Fonds Clinatec UniversitéGrenoble AlpesGrenobleFrance School of Medical Science University of SydneySydneyAustralia Faculty of Health Sciences University of JohannesburgJohannesburgSouth Africa King Abdullah University of Science and Technology ThuwalSaudi Arabia Institute of Ophthalmology University College LondonLondonUK

Neurons are notoriously vulnerable cell *** the slightest change in their internal and/or external environments will cause much distress and dysfunction,leading often to their death.A range of pathological conditions,including stroke,head trauma,and neurodegenerative disease,can generate stress in neurons,affecting their survival and proper *** most neural pathologies,mitochondria become dysfunctional and this plays a pivotal role in the process of cell *** challenge over the last few decades has been to develop effective interventions that improve neuronal homeostasis under pathological *** interventions,often referred to as disease-modifying or neuroprotective,have,however,proved frustratingly elusive,at both preclinical and,in particular,clinical *** this perspective,we highlight two factors that we feel are key to the development of effective neuroprotective *** are:firstly,the choice of dose of intervention and method of application,and secondly,the selection of subjects,whether they be patients or the animal model.

关键词： protective dosage distress

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Tissue engineering for neuromuscular disorders of the gastrointestinal tract

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World Journal of Gastroenterology 2012年第47期18卷 6918-6925页

作者： Kenneth L Koch Khalil N Bitar john e.fortunato Khalil N Bitar Section on Gastroenterol-ogy Department of Medicine Wake Forest University School ofMedicine Winston-Salem NC 27101 United States Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine Winston-Salem NC 27101United States

The digestive tract is designed for the optimal processing of food that nourishes all organ *** esophagus,stomach,small bowel,and colon are sophisticated neuromuscular tubes with specialized sphincters that transport ingested food-stuffs from one region to *** contractions move ingested solids and liquids from the esophagus into the stomach;the stomach mixes the ingested nutrients into chyme and empties chyme from the stomach into the *** to-and-fro movement of the small bowel maximizes absorption of fat,protein,and *** contractions are necessary for colon function and defecation.

关键词： Neuromuscular disorders Gastrointestinal tract Dysfunction esophagus Stomach Small bowel Colon

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Search for a natural scientific measure of economy

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Frontiers of environmental Science & engineering 2011年第1期5卷 111-118页

作者： john e COULTeR Xiwangzhuang Shuangqing RdHaidianBeijing 100084China

Through human history,wealth has been measured in grain,gold,and,now,*** counterfeiting of coins and notes goes back a long way,it is only with electronic financial accounting in a global economy tainted by toxic loans and imaginary funds that there is an urgency to search for a realistic objective way to monitor and regulate what we are doing to our earth and *** schemes using analysis of utility functions,oil equivalents,entropy,energy,and other units have been tried and,while helping to understand some basic processes and flows,have always been swamped by the machinations of financiers and the attention big sums of money ***,the concept of exergy,pioneered in eastern europe in the 1950s,is being researched,developed,and applied,especially in China,driven by the desperation to measure the reality beyond the twin specters of global financial and environmental crises.A rough inventory of the matter in the biosphere at the coordinate details of an angstrom and an appreciation of how humans harness and manipulate electromagnetic forces can be enlightening as to what is and is not *** that understanding,any financial estimate and proposed stimulus packages or IMF reform will be wildly wrong and may even be headed in the wrong direction.

关键词： climate change financial crisis energy exergy environment

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Development of Light Weight Structures to Provide Blast-Resistant Designs

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Transactions of Tianjin University 2006年第B09期12卷 16-21页

作者： CRAWFORD john e Karagozian & Case 2550 N.Hollywood Way #500BurbankCA 91505USA

In the past, blast-resistant designs for structures were often constructed with massive type structural systems, which relied more on brute strength than on finesse to achieve the required blast resistance. However, structures composed of COLD-FORMeD steel components, such as sheet metal and metal studs, have shown great promise in providing blast resistance with the added benefits of low cost and ease of construction. Some examples of using such structures to provide containment for package handling facilities (PHF) are described in the paper for situations where blast containment is needed, such as a potential package bomb being discovered during the package vetting process. Results from tests and analytic data are used to illustrate aspects of design peculiar to such types of applications. Designs for specific capacities of PHF are described.

关键词： blast containment package handling facility hardened design light weight structures COLD-FORMeD steel structures

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Simulation of Fragment Impact on Multi-Layer Targets Using Contact Method

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Transactions of Tianjin University 2006年第B09期12卷 152-157页

作者： CRAWFORD john e Karagozian & Case 2550 N.Hollywood WaySuite 500BurbankCA 91505USA

Cased explosives generate highly energetic fragments as their casing breaks up. Due to the complexity of casing fragment related behavior such as embedment, perforation and ricochet, it may be insufficient to use equivalent triangular pressure loading in fragment impact simulations. This simplified method may over- or under-predict the target response. Recently, a procedure using contact techniques has been proposed to overcome such difficulties. It has been shown that the new method has the inherent capability in modeling the multi-piece and multi-hit fragment impact problems in a more realistic way. To investigate the applicability of the proposed method to simulations involving multi-layer penetration, the selected problems of fragment impact on multi-layer targets are described in this paper. It is demonstrated that this method is capable of predicting the complicated multi-layer structural response caused by fragment impact and penetration. Modeling procedures and some technical issues are also discussed.

关键词： contact finite element fragment impact multi-layer penetration simulation

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SWITCHING AND SeQUeNCING AVAILABLe THeRAPIeS SO AS TO MAXIMIZe A PATIeNT＇S eXPeCTeD TOTAL LIFeTIMe

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International Journal of Biomathematics 2012年第4期5卷 113-125页

作者： john e. GOULIONIS Department of Statistics and Insurance Science University of Piraeus 80 Karaoli a Dimitriou Street 18534 Piraeus Greece

This paper has focused on applying mathematical techniques to address fundamental question in therapy planning when to switch, and how to sequence therapies. We consider switching and sequencing available therapies so as to maximize a patient＇s expected total lifetime. We assume knowledge only about the lifetime distributions induced by the therapies. We discuss a specialization of this model that is tailored to a frequently reoccurring type of management problem, where our goal is to determine the best timing for testing and treatment decisions for patients with ischemic heart disease. Typically, decisions are made with an overall, goal of maximizing the patient＇s expected lifetime or quality-adjusted lifetime.

关键词： expected total lifetime maintenance ischemic heart disease stochasticordering relationships statistical distributions.

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A FAST LAGRANGIAN SIMULATION MeTHOD FOR FLOW ANALYSIS AND RUNNeR DeSIGN IN PeLTON TURBINeS

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Journal of Hydrodynamics 2012年第6期24卷 930-941页

作者： ANAGNOSTOPOULOS john S. PAPANTONIS Dimitris e. School of Mechanical engineering National Technical University of Athens

In the present work, an alternative numerical methodology is developed for a fast and effective simulation and analysis of the complex flow and energy conversion in Pelton impulse hydro turbines. The algorithm is based on the Lagrangian approach and the unsteady free-surface flow during the jet-bucket interaction is simulated by tracking the trajectories of representative fluid particles at very low computer cost. Modern regression tools are implemented in a new parameterization technique of the inner bucket surface. Key-feature of the model is the introduction of additional terms into the particle motion equations to account for various hydraulic losses and the flow spreading, which are regulated and evaluated with the aid of experimental data in a Laboratory Pelton turbine. The model is applied to study the jet-runner interaction in various operation conditions and then to perform numerical design optimization of the bucket shape, using a stochastic optimizer based on evolutionary algorithms. The obtained optimum runner attains remarkably higher hydraulic efficiency in the entire load range. Finally, a new small Pelton turbine （150 kW） is designed, manufactured and tested in the Laboratory, and its performance and efficiency verify the model predictions.

关键词： Pelton turbine hydraulic efficiency Lagrangian simulation bucket shape parameterization numerical design optimization

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25 Years of sensory drive： the evidence and its watery bias

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Current Zoology 2018年第4期64卷 471-484页

作者： Molly e. CUMMINGS john A. eNDLeR Department of Integrative Biology University of Texas Austin TX 78712 USA School of Life and environmental Sciences Deakin University Waurn Ponds VIC 3216 Australia

It has been 25years since the formalization of the Sensory Drive hypothesis was published in the American Naturalist （1992）. Since then, there has been an explosion of research identifying its utility in contributing to our understanding of inter- and intra-specific variation in sensory systems and signaling properties. The main tenet of Sensory Drive is that environmental characteristics will influence the evolutionary trajectory of both sensory （detecting capabilities） and signaling （detectable features and behaviors） traits in predictable directions. We review the accumulating evidence in 154 studies addressing these questions and categorized their approach in terms of testing for environmental influence on sensory tuning, signal characteristics, or both. For the subset of studies that examined sensory tuning, there was greater support for Sensory Drive processes shaping visual than auditory tuning, and it was more prevalent in aquatic than terrestrial habitats. Terrestrial habitats and visual traits were the prevalent habitat and sensory modality in the 104 studies showing support for environmental influence on signaling properties. An additional 19 studies that found no supporting evidence for environmental influence on signaling traits were all based in terrestrial ecosystems and almost exclusively involved auditory signals. Only 29 studies examined the complete coevolutionary process between sensory and signaling traits and were dominated by fish visual communication. We discuss biophysical factors that may contribute to the visual and aquatic bias for Sensory Drive evidence, as well as biotic factors that may contribute to the lack of Sensory Drive processes in terrestrial acoustic signaling systems.

关键词： animal communication sensory drive sensory ecology sexual selection

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Is Takotsubo syndrome in patients receiving chemotherapy drug-specific?

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World Journal of Clinical Cases 2015年第2期3卷 204-205页

作者： john e Madias Icahn School of Medicine at Mount Sinai Division of Cardiology Elmhurst Hospital Center

In commenting on a case report of a 55-year-old man who suffered Takotsubo syndrome(TTS), in the setting of receiving chemotherapy with cytarabine and daunorubicin for acute myeloid leukemia, the author expresses his views that TTS in the setting of chemotherapy for malignancies may not be chemotherapeutic drug-specific(like in the chemotherapeutic drug induced-cardiomyopathy), but may be due to the emotional and physical stresses resulting from the realization of having diagnosed with a malignancy, and the diagnostic testing, and therapeutic management which follows.

关键词： Daunorubicin Radiotherapy Cardiotoxicity Takotsubo syndrome Malignancies Chemotherapy Cytarabine Anthracyclines Cardiomyopathy Autonomic sympathetic Nervous system

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