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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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Human development across the lifespan john S. Dacey, john f. Travers.

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2002年

作者： john S. Dacey john f. Travers.

来源：畅想之星图书光盘版（南... 评论

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Synchronous formation of the‘forearc’Bay of Islands ophiolite and its basal high-temperature metamorphic sole constrained by U-Pb zircon ages

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Geoscience frontiers 2023年第6期14卷 234-272页

作者： Weiyao Yan john f.Casey Department of Earth and Atmospheric Sciences University of HoustonHoustonTXUSA

The welded metamorphic sole at the base of the Bay of Islands Ophiolite Complex(BOIC)in the Northern Appalachians of Newfoundland shows a typical inverted pressure-temperature(P-T)metamorphic gradient from HT-MP granulite to LT-LP greenschist *** incorporates mafic volcanic/plutonic protoliths mixed with pelagic,hemi-pelagic and coarser epiclastic sedimentary *** LA-ICP-MS U–Pb concordia ages,trace elements,and Ti-in-zircon geothermometry for -250 zircon analyses from three metabasites of the upper HT sole amphibolites with N-MORB-like protoliths are *** samples collected within meters of the ophiolite peridotite-sole contact of the Blow Me Down Mountain and North Arm Mountain massifs yielded the oldest comparable concordia ages of 487.7±2.6 Ma and 489.1±3.1 Ma,respectively,that are both within error of the igneous age of 488.3±1.5 Ma of the directly overlying BOIC ophiolite,which formed at a supra-subduction zone(SSZ)forearc spreading center.A third slightly younger age of 484.2±2.4 Ma was obtained for an upper HT amphibolite sample with similar phase assemblages but collected30 m below the peridotite contact of the Table Mountain *** crystals analyzed have similar size and morphologies,subparallel rare earth element(REE)variation patterns,and steep heavy REE-enrichments((Lu/Gd)_(cn)>20),significant positive Ce anomalies(dominantly>5)and slight positive to dominantly negative Eu anomalies(1.2–0.4).Zircon shows Th/U mean values of 0.37–0.48 with little to no rim to core *** Ti-in-zircon mean crystallization temperatures range from764–787℃.These neocrystallized zircon crystals appear to be derived from thin leucosomes within the three *** other samples also from the upper HT sole show evidence of inherited detrital zircon with core dates spanning the Cambrian Notre Dame Arc through older Laurentian-like basement and rift age *** of the sole took place below a hot forearc asthenospheric wed

关键词： Ophiolite metamorphic sole U-Pb zircon ages Hot subduction interface Supra-subduction forearc spreading center Arc-continent collision Taconic Orogeny

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Xylose: absorption, fermentation, and post-absorptive metabolism in the pig

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Journal of Animal Science and Biotechnology 2018年第1期9卷 1-9页

作者： Nichole f.Huntley john f.Patience Department of Animal Science 213 Kildee HallIowa State University Department of Animal Science 201B Kildee HallIowa State University

Xylose, as β-1,4-linked xylan, makes up much of the hemicel ulose in cel wal s of cereal carbohydrates fed to pigs. As inclusion of fibrous ingredients in swine diets continues to increase, supplementation of carbohydrases, such as xylanase,is of interest. However, much progress is warranted to achieve consistent enzyme efficacy, including an improved understanding of the utilization and energetic contribution of xylanase hydrolysis product（i.e. xylooligosaccharides or monomeric xylose）. This review examines reports on xylose absorption and metabolism in the pig and identifies gaps in this knowledge that are essential to understanding the value of carbohydrase hydrolysis products in the nutrition of the pig. Xylose research in pigs was first reported in 1954, with only sporadic contributions since. Therefore, this review also discusses relevant xylose research in other monogastric species, including humans. In both pigs and poultry, increasing purified D-xylose inclusion general y results in linear decreases in performance, efficiency, and diet digestibility. However,supplementation levels studied thus far have ranged from 5% to 40%, while theoretical xylose release due to xylanase supplementation would be less than 4%. More than 95% of ingested D-xylose disappears before the terminal ileum but mechanisms of absorption have yet to be ful y elucidated. Some data support the hypothesis that mechanisms exist to handle low xylose concentrations but become overwhelmed as luminal concentrations increase. Very little is known about xylose metabolic utilization in vertebrates but it is wel recognized that a large proportion of dietary xylose appears in the urine and significantly decreases the metabolizable energy available from the diet. Nevertheless, evidence of labeled D-xylose-1-^（14）C appearing as expired^（14）CO_2 in both humans and guinea pigs suggests that there is potential,although small, for xylose oxidation. It is yet to be determined if pigs develop increased xy

关键词： Pentose utilization Swine Threitol Xylose absorption Xylose metabolism

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The Use of VGPM to Estimate Oceanic Primary Production:A“Tango”Difficult to Dance

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Journal of Remote Sensing 2022年第1期2022卷 139-145页

作者： Zhongping Lee john f.Marra State Key Lab of Marine Environmental Science College of Earth and Ocean SciencesXiamen UniversityXiamenChina School for the Environment University of Massachusetts BostonBostonMA 02125USA Brooklyn College of the City University of New York BrooklynNY 11210USA

One of the primary goals of launching an ocean color satellite is to obtain over the global ocean synoptic measurements of primary production(PP),a measure of phytoplankton *** reach this ultimate goal,in addition to precise measurements of radiance at the satellite altitude and robust data processing systems,a key requirement is to link primary production with satellitederived products,where a model must be developed and *** many models have been developed in the past decades,the vertically generalized production model(VGPM)developed by Behrenfeld and falkowski,due to its simplicity and ease of use with satellite products,has been a de facto“standard”for the estimation of PP from ocean color measurements over the past 20+***,it has significantly influenced the ocean color remote sensing and the biological oceanographic *** this article,we discuss the limitations of VGPM(and PP models based on chlorophyll concentration)in estimating primary production.

关键词： Dance simplicity precise

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Lipopolysaccharide immune stimulation but not β-mannanase supplementation affects maintenance energy requirements in young weaned pigs

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Journal of Animal Science and Biotechnology 2018年第4期9卷 901-916页

作者： Nichole f.Huntley C.Martin Nyachoti john f.Patience Department of Animal Science Iowa State University Department of Animal Science University of Manitoba

Background: Pathogen or diet-induced immune activation can partition energy and nutrients away from growth,but clear relationships between immune responses and the direction and magnitude of energy partitioning responses have yet to be elucidated. The objectives were to determine how β-mannanase supplementation and lipopolysaccharide(LPS) immune stimulation affect maintenance energy requirements(MEm) and to characterize immune parameters, digestibility, growth performance, and energy ***: In a randomized complete block design, 30 young weaned pigs were assigned to either the control treatment(CON; basal corn, soybean meal and soybean hul s diet), the enzyme treatment(ENZ; basal diet + 0.056% β-mannanase),or the immune system stimulation treatment(ISS; basal diet + 0.056% β-mannanase, chal enged with repeated increasing doses of Escherichia coli LPS). The experiment consisted of a 10-d adaptation period, 5-d digestibility and nitrogen balance measurement, 22 h of heat production(HP) measurements, and 12 h of fasting HP measurements in indirect calorimetry chambers. The immune chal enge consisted of 4 injections of either LPS(ISS) or sterile saline(CON and ENZ), one every48 h beginning on d 10. Blood was collected pre-and post-challenge for complete blood counts with differential,haptoglobin and mannan binding lectin, 12 cytokines, and glucose and insulin ***: Beta-mannanase supplementation did not affect immune status, nutrient digestibility, growth performance,energy balance, or MEm. The ISS treatment induced fever, elevated proinflammatory cytokines and decreased leukocyte concentrations(P 0.10),but increased total HP(21%) and MEm(23%), resulting in decreased lipid deposition(-30%) and average daily gain(-18%)(P ffects on immune parameters and energy balance i

关键词： Acute phase proteins β-Mannan Cytokines Digestibility feed induced immune response Heat production Inflammation Lipopolysaccharide Nitrogen balance Swine

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Dock-able linear and homodetic di, tri, tetra and pentapeptide library from canonical amino acids: SARS-CoV-2 Mpro as a case study

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Journal of Pharmaceutical Analysis 2023年第5期13卷 523-534页

作者： Sarfraz Ahmad Muhammad Usman Mirza john f.Trant Department of Chemistry and Biochemistry University of WindsorWindsor N9B 3P4OntarioCanada Binary Star Research Services LaSalle N9J 3X8OntarioCanada

Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low *** noncanonical residues can always be used,employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico *** this goal,the dataset comprising all possible di-,tri-,and tetra-peptide combinations of the canonical residues has been previously ***,with increasing computational power,the comprehensive set of pentapeptides is now also feasible for screening as the comprehensive set of cyclic peptides comprising four or five ***,we provide both the complete and prefiltered libraries of all di-,tri-,tetra-,and penta-peptide sequences from 20 canonical amino acids and their homodetic(N-to-C-terminal)cyclic *** fASTA,simplified molecular-input line-entry system(SMILES),and structure-data file(SDf)-three dimension(3D)libraries can be readily used for screening against protein *** also provide a simple method and tool for conducting identity-based *** to this dataset will accelerate small peptide screening workflows and encourage their use in drug discovery *** a case study,the developed library was screened against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main protease to identify potential small peptide inhibitors.

关键词： Dipeptides Tripeptides Tetrapeptides Pentapeptides N-to-C-terminal cyclic peptides Peptide library

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Design of Poiseuille flow Controllers Using the Method of Inequalities

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International Journal of Automation and computing 2009年第1期6卷 14-21页

作者： john McKernan James f. Whidborne George Papadakis Department of Mechanical Engineering King s College London Strand Department of Aerospace Sciences Cranfield University

This paper investigates the use of the method of inequalities （MoI） to design output-feedback compensators for the problem of the control of instabilities in a laminar plane Poiseuille flow. In common with many flows, the dynamics of streamwise vortices in plane Poiseuille flow are very non-normal. Consequently, small perturbations grow rapidly with a large transient that may trigger nonlinearities and lead to turbulence even though such perturbations would, in a linear flow model, eventually decay. Such a system can be described as a conditionally linear system. The sensitivity is measured using the maximum transient energy growth, which is widely used in the fluid dynamics community. The paper considers two approaches. In the first approach, the MoI is used to design low-order proportional and proportional-integral （PI） controllers. In the second one, the MoI is combined with Mcfarlane and Glover＇s H∞ loop-shaping design procedure in a mixed-optimization approach.

关键词： Transient energy growth transient behaviour flow control Poiseuille flow method of inequalities (MoI) mixed opti-mization H∞-optimization.

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Novel fast Operating Moving Coil Actuator with Compensation Coil for HVDC Circuit Breakers

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CSEE Journal of Power and Energy Systems 2021年第5期7卷 1041-1050页

作者： Boyuan Yin Xianwu Zeng john f.Eastham Damian Vilchis-Rodriguez Xiaoze Pei Department of Electronic&Electrical Engineering.University of Bath.Bath.United Kingdom Department of Mechanical Engineering University of Bath.Bath.United Kingdom. Power and Energy Division School of Electrical and Electronic EngineeringThe University of ManchesterManchester M139PLUnited Kingdom.

DC circuit breakers are major enabling components for multi-terminal HVDC *** key design targets are operating speed and *** paper proposes a novel moving coil actuator using a compensation coil topology to operate mechanical circuit *** topology aims to significantly improve the magnetic field saturation and reduce the system inductance,so that the operating speed is *** possible connection methods for the compensation coils are proposed and analyzed using finite element modeling,ensuing simulation results are compared and *** operating speed of the moving coil actuator with compensation coils is significantly improved compared with the original moving coil *** moving coil actuator with compensation coils can open a distance of 5 mm within 2.8 ms and the peak efficiency is 47%.

关键词： Compensation coil DC circuit breaker HVDC mechanical circuit breaker moving coil actuator

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