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From single to combinatorial therapies in spinal cord injuries for structural and functional restoration

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Neural Regeneration Research 2025年第3期20卷 660-670页

作者： Ernesto Doncel-pérez Gabriel Guízar-Sahagún Israel Grijalva-Otero hospital Nacional de parapléjicos de Toledo Servicio de Salud de Castilla La Mancha(SESCAM)ToledoSpain Medical Research Unit for Neurological Diseases UMAE Hospital de EspecialidadesCentro Médico Nacional Siglo XXIIMSSCiudad de MéxicoMéxico

Spinal cord injury results in paralysis, sensory disturbances, sphincter dysfunction, and multiple systemic secondary conditions, most arising from autonomic dysregulation. All this produces profound negative psychosocial implications for affected people, their families, and their communities;the financial costs can be challenging for their families and health institutions. Treatments aimed at restoring the spinal cord after spinal cord injury, which have been tested in animal models or clinical trials, generally seek to counteract one or more of the secondary mechanisms of injury to limit the extent of the initial damage. Most published works on structural/functional restoration in acute and chronic spinal cord injury stages use a single type of treatment: a drug or trophic factor, transplant of a cell type, and implantation of a biomaterial. Despite the significant benefits reported in animal models, when translating these successful therapeutic strategies to humans, the result in clinical trials has been considered of little relevance because the improvement, when present, is usually insufficient. Until now, most studies designed to promote neuroprotection or regeneration at different stages after spinal cord injury have used single treatments. Considering the occurrence of various secondary mechanisms of injury in the acute and sub-acute phases of spinal cord injury, it is reasonable to speculate that more than one therapeutic agent could be required to promote structural and functional restoration of the damaged spinal cord. Treatments that combine several therapeutic agents, targeting different mechanisms of injury, which, when used as a single therapy, have shown some benefits, allow us to assume that they will have synergistic beneficial effects. Thus, this narrative review article aims to summarize current trends in the use of strategies that combine therapeutic agents administered simultaneously or sequentially, seeking structural and functional restoratio

关键词： neural regeneration neuroprotection spinal cord injury repair spinal cord injury treatments structural restoration of spinal cord injury

The Role of Toxicology in Evaluating Marketing Applications for prescription Drug products in the United States

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毒理学杂志 2005年第A3期19卷 169-170页

作者： Kenneth L hastings p.h. D.A.B.T. Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration Dr.Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration

In the United States, in order to market a prescription drug product studies need to be conducted to demonstrate safety and efficacy.

关键词：毒物学临床应用处方药代谢产物

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.helmold Angela Ahrens Zachary Fitzgerald p.h.nde Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SpAST spastin

The Role of Toxicology in Evaluating Marketing Applications for prescription Drug products in the United States

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毒理学杂志 2005年第S1期 169-170页

作者： Kenneth L hastings,p.h.,D.A.B.T. Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration Dr. Associate Director Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration

Dynamic stress concentration in an infinitely long cylindrical cavity due to a point spherical source embedded within a fluid-saturated poroelastic formation of infinite extent

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Applied Mathematics and Mechanics(English Edition) 2025年第1期46卷 139-156页

作者： h.hOSSEINI O.BALILAShAKI Department of Mechanical Engineering Faculty of EngineeringGolestan University

The effects of a harmonically exciting monopole source on an infinitely long cylindrical cavity embedded entirely within a fluid-saturated poroelastic formation of infinite extent are examined theoretically. It is assumed that the source is located outside the cavity at a specified distance from the borehole axis. The magnitudes of the hoop and radial stresses beside the pore pressures exerted on the interface and inside the porous medium surrounding the borehole are calculated and discussed. Biot's poroelastic modeling along with three types of boundary conditions for the cylindrical interface including the ideal fluid, empty borehole, and rigid inclusion with a hard boundary is employed for the analysis. Utilizing a proper translational addition theorem for expressing the incident spherical wave in terms of cylindrical wave expansions, the proposed boundary conditions at the interface are satisfied. Stresses are formulated by means of wave potential functions in a three-dimensional(3D) manner. The effects of the frequency and the radial distance between the source and borehole on the induced stresses are examined for the first cylindrical modes over frequency spectra. Two permeability conditions for the interface and three types of soils for the porous formation are considered throughout the analysis. To give an overall outline of the study, a numerical example is presented. The results clearly indicate that the distance is a key parameter and has considerable effects on the induced stress values. In addition, the interface permeability condition and soil characteristics play an important role in determining the dynamic response of the borehole. Finally,the obtained results are compared with the relevant analyses existing in the literature for some limit cases, and good agreement is achieved.

关键词： Stress concentration

Evaluation of sampling strategies to estimate crown biomass

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Forest Ecosystems 2015年第1期2卷 20-30页

作者： Krishna p poudel hailemariam Temesgen Andrew N gray Department of Forest Engineering Resources and Management College of Forestry Oregon State University USDA Forest Service PNW Research Station3200 SW Jefferson WayCorvallis OR 97331 USA

Background：Depending on tree and site characteristics crown biomass accounts for a significant portion of the total aboveground biomass in the *** biomass estimation is useful for different purposes including evaluating the economic feasibility of crown utilization for energy production or forest products,fuel load assessments and fire management strategies,and wildfire ***,crown biomass is difficult to predict because of the variability within and among species and *** the allometric equations used for predicting crown biomass should be based on data collected with precise and unbiased sampling *** this study,we evaluate the performance different sampling strategies to estimate crown biomass and to evaluate the effect of sample size in estimating crown ***：Using data collected from 20 destructively sampled trees,we evaluated 11 different sampling strategies using six evaluation statistics：bias,relative bias,root mean square error（RMSE）,relative RMSE,amount of biomass sampled,and relative biomass *** also evaluated the performance of the selected sampling strategies when different numbers of branches（3,6,9,and 12）are selected from each *** specific log linear model with branch diameter and branch length as covariates was used to obtain individual branch ***：Compared to all other methods stratified sampling with probability proportional to size estimation technique produced better results when three or six branches per tree were ***,the systematic sampling with ratio estimation technique was the best when at least nine branches per tree were *** the stratified sampling strategy,selecting unequal number of branches per stratum produced approximately similar results to simple random sampling,but it further decreased RMSE when information on branch diameter is used in the design and estimation ***：Use of auxiliary information in design or estimation phase reduc

关键词： Aboveground biomass Crown Sampling strategies pacific Northwest

Ductile deformation within Upper himalaya Crystalline Sequence and geological implications,in Nyalam area,Southern Tibet

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Chinese Science Bulletin 2012年第26期57卷 3469-3481页

作者： LIU XiaoBing LIU Xiaohan LELOUp p.h. MAhEO G. pAQUETTE J.L. ZhANG XinGang ZhOU XueJun Key Laboratory of Continental Collision and Plateau UpliftInstitute of Tibetan Plateau ResearchChinese Academy of SciencesBeijing 100085China Laboratoire des sciences de la terre de Lyon TerrePlanktesEnvironementCNRS UMR 5276Universitd Lyonl-ENS LyonVilleurbanne69622France Graduate University of Chinese Academy of Scienees Beijing 100049China Laboratoire Magmas et Volcans CNRS UMR 6524Universite Blaise PascalClermont-Ferrand63038France

The South Tibet Detachment System(STDS) is a flat normal fault that separates the Upper himalaya Crystalline Sequence(UhCS) below from the Tethyan Sedimentary Sequence(TSS) *** of deformations related to the STDS is critical to understand the mechanism and evolution of the himalaya collision *** Nyalam detachment(ND)(～86°E) locates in the middle portion of STDS(81°-89°E).Dating of deformed leucocratic dykes that are most probably syntectonic at different dep.h.beneath the ND,allow us to constrain the timing of deformation.(1) Dyke T11N37 located ～3500 m structurally below the ND emplaced at 27.4± 0.2 Ma;(2) Dyke T11N32 located ～1400 m structurally below the ND emplaced at 22.0±0.3 Ma;(3) T11N25 located within the top to the north STD shear zone,～150 m structurally below the ND,emplaced at 17.1±0.2 *** ND footwall cooling history and T11N25 deformation temperature,we indicate a probable onset of top to the north deformation at ～16 Ma at this *** results show an upward younging of the probable timing of onset of the deformation at different structural distance below the *** then propose a new model for deformation migration below the ND with deformation starting by pure shear deformation at dep.h.prior to ～27.5 Ma that migrates upward at a rate of ～ 0.3 mm/a until ～18 Ma when deformation switches to top to the north shearing in the South Tibet Detachment shear zone(STDsz).As deformation on the ND stops at 14-13 Ma this would imply that significant top to the North motion would be limited to less than 5 Ma and would jeopardize the importance of lower channel flow.

关键词：喜马拉雅碰撞带塑性变形聂拉木地区西藏南部地质意义序列结晶藏南拆离系

Impacts of pI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

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Neural Regeneration Research 2025年第4期20卷 1031-1041页

作者： Ramón pérez-Núñez María Fernanda González Ana María Avalos Lisette Leyton Cellular Communication Laboratory Programa de Biología Celular y MolecularCenter for Studies on ExerciseMetabolism and Cancer(CEMC)Instituto de Ciencias Biomédicas(ICBM)Facultad de MedicinaUniversidad de ChileSantiagoChile Advanced Center for Chronic Diseases(ACCDiS) Faculty of Chemical and Pharmaceutical Sciences&Faculty of MedicineUniversidad de ChileSantiagoChile Instituto de Ciencias Biomédicas Facultad de Ciencias de la SaludUniversidad Autónoma de ChileSantiagoChile

Astrocytes are the most abundant type of glial cell in the central nervous *** injury and inflammation,astrocytes become reactive and undergo morphological and functional *** on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,***,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and *** analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their *** actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune *** phosphoinositide 3-kinase(pI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo *** astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory ***,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their *** highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the pI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/pI3K/AKT/connexin 43,and Notch/pI3K/AKT *** targeting the inactivation of the pI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial *** dual function of the pI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function *** review emphasizes the importance of employing astrocyte-exclusive models to underst

关键词： inflammation integrins neuroprotective neurotoxic phosphatidylinositol 3-kinase reactive astrocytes signal transduction Thy-1(CD90)

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基于多变量概率模型的钻井周期预测方法

石油勘探与开发 2021年第4期48卷 851-860页

作者： LUU Quang hung LAU Man Fai NG Sebastian p.h. TING Clement p.W. WEE Reuben ThEN patrick h.h. 斯威本科技大学科学、工程与技术系澳大利亚霍桑3122 斯威本科技大学工程、计算与科学系马来西亚砂拉越93350 IDS公司马来西亚砂拉越93100

鉴于现有的预测钻井周期的方法忽视了影响钻井周期的关键因素因而精确度有限,提出采用多变量概率法预测钻井周期,并采用实测数据进行了算例分析和验证。利用自适应核密度估计法建立了各主要钻井阶段与深度相关的钻井周期概率模型,结合... 详细信息

鉴于现有的预测钻井周期的方法忽视了影响钻井周期的关键因素因而精确度有限,提出采用多变量概率法预测钻井周期,并采用实测数据进行了算例分析和验证。利用自适应核密度估计法建立了各主要钻井阶段与深度相关的钻井周期概率模型,结合蒙特卡洛模拟得出了一次完整钻井施工作业的总周期的概率分布。采用该方法对澳大利亚及亚洲地区192口井的钻井周期进行了预测。尽管现有数据记录不全,但经过统计分析发现,模型模拟结果与实测数据的匹配度很高。研究表明,在10%~90%的置信区间内,总钻井周期比无事故钻井周期延长至少4 d,至多12 d。采用该方法可以得到钻至一定深度的可能的施工周期,有利于评价整个钻井施工过程的风险,模拟数据还可以用于机器学习模型的训练。图10表2参34。

关键词：钻井周期多变量概率模型概率法马尔科夫链蒙特卡洛方法

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