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Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： jiang-Hui Wang Dominic j.Gessler Wei Zhan Thomas L.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

Influence of the zigzag fins and inlet arrangements on the cooling proficiency of the mini-channel heat sink

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Propulsion and Power Research 2024年第2期13卷 194-206页

作者： A.Torbatinezhad Y.Pahamli M.j.Hosseini R.Bahrampoury School of Mechanical Engineering Babol University of TechnologyBabolIran Department of Mechanical Engineering Semnan UniversitySemnanIran Department of Mechanical Engineering Faculty of EngineeringGolestan UniversityGorganIran Department of Mechanical Engineering K.N.Toosi University of TechnologyTehranIran

Mini-channel heatsinks are one of the most effective thermal management methods for high heatﬂux devices due to the high performance of convective heat *** recent years,various techniques have been innovated to improve the thermal proﬁciency of the mini-channel *** of these are taking advantage ofﬁns’structural designs and ar-rangements of inlets and *** zigzagﬁns and channels were considered in the previous works in heatsinks,and researchers analyzed their cooling enhancement ***,in the present work,a combined cooling technique,considering new-type zigzagﬁns’geometrical parameters(arrangement,length,and height)causes turbulenceﬂow and higher convective heat transfer along with different positionings ofﬂow inlet and outlets resulting in superior temper-ature uniformity,is proposed to evaluate their impacts on the cooling proﬁciency of the heat sink versus different Reynolds *** assess the thermal and hydraulic performance of the proposed heatsink,different parameters,including temperature contours,Nusselt numbers,thermal resistance,and entropy generation are *** a result,it is observed that in the case demonstrating the best thermal performance,the Nusselt number,pressure drop,thermal resistance,and entropy generation are respectively 37.13,4586.46 Pa,0.000078 m^(2)·K/W,and 0.1078 W/K in the best *** well,it is found that by changing the arrangements of inlets and outlets,the Nusselt number,and thermal resistance are improved by 12%and 13%,***,the proposed mini-channel heat sink could be used as a high-performance thermal management system for electronic devices in different industries,including energy,solar,and medical sectors.

关键词： Thermal management Heat transfer enhancement Mini-channel heatsink Zigzagﬁn Entropy generation Electronic cooling

Relative Impacts of Sea Ice Loss and Atmospheric Internal Variability on the Winter Arctic to East Asian Surface Air Temperature Based on Large-Ensemble Simulations with NorESM2

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Advances in Atmospheric Sciences 2024年第8期41卷 1511-1526页

作者： Shengping HE Helge DRANGE Tore FUREVIK Huijun WANG Ke FAN Lise Seland GRAFF Yvan j.ORSOLINI Geophysical Institute University of Bergen and Bjerknes Centre for Climate ResearchBergen 5020Norway Nansen Environmental and Remote Sensing Center Bergen 5007Norway Key Laboratory of Meteorological Disaster Ministry of Education/Joint International Research Laboratory of Climate and Environment Change(ILCEC)/Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters(CIC-FEMD)Nanjing University of Information Science&TechnologyNanjing 211544China Nansen-Zhu International Research Center Institute of Atmospheric PhysicsChinese Academy of SciencesBeijing 100029China Southern Marine Science and Engineering Guangdong Laboratory(Zhuhai) Zhuhai 511458China School of Atmospheric Science Sun Yat-Sen Universityand Southern Marine Science and Engineering Guangdong Laboratory(Zhuhai)Zhuhai 519082China Norwegian Meteorological Institute Oslo 0313Norway Norwegian Institute for Air Research Kjeller 2007Norway

To quantify the relative contributions of Arctic sea ice and unforced atmospheric internal variability to the “warm Arctic, cold East Asia”(WACE) teleconnection, this study analyses three sets of large-ensemble simulations carried out by the Norwegian Earth System Model with a coupled atmosphere–land surface model, forced by seasonal sea ice conditions from preindustrial, present-day, and future periods. Each ensemble member within the same set uses the same forcing but with small perturbations to the atmospheric initial state. Hence, the difference between the present-day(or future) ensemble mean and the preindustrial ensemble mean provides the ice-loss-induced response, while the difference of the individual members within the present-day(or future) set is the effect of atmospheric internal variability. Results indicate that both present-day and future sea ice loss can force a negative phase of the Arctic Oscillation with a WACE pattern in winter. The magnitude of ice-induced Arctic warming is over four(ten) times larger than the ice-induced East Asian cooling in the present-day(future) experiment;the latter having a magnitude that is about 30% of the observed cooling. Sea ice loss contributes about 60%(80%) to the Arctic winter warming in the present-day(future) experiment. Atmospheric internal variability can also induce a WACE pattern with comparable magnitudes between the Arctic and East Asia. Ice-lossinduced East Asian cooling can easily be masked by atmospheric internal variability effects because random atmospheric internal variability may induce a larger magnitude warming. The observed WACE pattern occurs as a result of both Arctic sea ice loss and atmospheric internal variability, with the former dominating Arctic warming and the latter dominating East Asian cooling.

关键词： Arctic sea ice loss warm Arctic–cold East Asia atmospheric internal variability large-ensemble simulation NorESM2 PAMIP

Generation of brain vascular heterogeneity:recent advances from the perspective of angiogenesis

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Neural Regeneration Research 2025年第7期20卷 2013-2014页

作者： Nathanael j.Lee Ryota L.Matsuoka Department of Neurosciences Lerner Research InstituteCleveland ClinicClevelandOHUSA Department of Molecular Medicine Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandOHUSA

Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular *** vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the *** elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing *** capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.

关键词： angiogenesis homeostasis network

The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

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Neural Regeneration Research 2024年第6期19卷 1308-1317页

作者： Daniel j.Hellenbrand Charles M.Quinn Zachariah j.Piper Ryan T.Elder Raveena R.Mishra Taylor L.Marti Phoebe M.Omuro Rylie M.Roddick jae Sung Lee William L.Murphy Amgad S.Hanna Department of Neurosurgery University of Wisconsin-Madison School of Medicine and Public HealthMadisonWIUSA Department of Biomedical Engineering University of Wisconsin-MadisonMadisonWIUSA Department of Orthopedics and Rehabilitation University of Wisconsin-MadisonMadisonWIUSA Department of Materials Science and Engineering University of Wisconsin-MadisonMadisonWIUSA Forward BIO Institute University of Wisconsin-MadisonMadisonWIUSA

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural ***,a major aim of current research involves targeting the immune response as a treatment for spinal cord *** much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine *** objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord *** were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex *** demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days *** contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days *** spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured *** a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male *** conclusion,pro-inflammatory cytokines in

关键词： astrocytes chemokines cytokines inflammation macrophages microglia secondary damage spinal cord injury

Influence of gastric inhibitory polypeptide on pentagastrinstimulated gastric acid secretion in patients with type 2 diabetes and healthy controls

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World journal of Gastroenterology 2006年第12期12卷 1874-1880页

作者： juris j Meier Michael A Nauck Bartholomaeus Kask j.ns j.hoist Carolyn F Deacon Wolfgang E Schmidt Baptist Gallwitz Department of Medicine I St. Josef-HospitalRuhr-University Bochum Germany Diabeteszentrum Bad Lauterberg Germany Department of Medical Physiology The Panum Institute University of Copenhagen Denmark Department of Medicine IV Eberhard-Karls- University Ttibingen Germany

AIM： Gastric inhibitory polypeptide is secreted from intestinal K-cells in response to nutrient ingestion and acts as an incretin hormone in human physiology. While animal experiments suggested a role for GIP as an inhibitor of gastric secretion, the GIP effects on gastric acid output in humans are still controversial. METHODS： Pentagastrin was administered at an infusion rate of 1 μg . kg^-1 . h^-1 over 300 min in 8 patients with type 2 diabetes （2 female, 6 male, 54± 10 years, BMI 30.5 ± 2.2 kg/m^2; no history of autonomic neuropathy） and 8 healthy subjects （2/6, 46 ± 6 years., 28.9 ± 5.3 kg/ m^2）. A hyperglycaemic clamp （140 mg/dl） was performed over 240 min. Placebo, GIP at a physiological dose （1 pmol . kg^-1 . min^-1）, and GIP at a pharmacological dose （4 mol . kg^-1 . min^-1） were administered over 60 min each. Boluses of placebo, 20 pmol GIP/kg, and 80 pmol GIP/kg were injected intravenously at the beginning of each infusion period, respectively. Gastric volume, acid and chloride output were analysed in 15-min intervals. Capillary and venous blood samples were drawn for the determination of glucose and total GIP. Statistics were carried out by repeated-measures ANOVA and one-way ANOVA. RESULTS： Plasma glucose concentrations during the hyperglycaemic clamp experiments were not different between patients with type 2 diabetes and controls. Steady-state GIP plasma levels were 61 ±8 and 79 ± 12 pmol/I during the low-dose and 327±35 and 327± 17 pmol/I during the high-dose infusion of GIP, in healthy control subjects and in patients with type 2 diabetes, respectively （P= 0.23 and p 0.99）. Pentagastrin markedly increased gastric acid and chloride secretion （P〈 0.001）. There were no significant differences in the rates of gastric acid or chloride output between the experimental periods with placebo or any dose of GIP. The temporal patterns of gastric acid and chloride secretion were similar in patients with type 2 diabetes and healthy controls （P= 0.86 and P= 0.6

关键词： Gastric inhibitory polypeptide Gastric acid secretion Type 2 diabetes Hyperglycemic clamp Pentagastrin-stimulated acid secretion

Neuroprotection by resveratrol-glucuronide and quercetin-glucuronide via binding to polyphenol-and glycosaminoglycan-binding sites in the laminin receptor

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Neural Regeneration Research 2025年第3期20卷 819-820页

作者： Rayudu Gopalakrishna jennifer Aguilar Emily Lee William j.Mack Department of Integrative Anatomical Sciences Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA Department of Neurological Surgery Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA

The dietary polyphenolic compounds resveratrol and quercetin prevent neurodegenerative diseases in experimental models;however, they reach the brain only in nanomolar concentrations in the glucuronidated and sulfated ... 详细信息

关键词： resveratrol molar dated

An Approximate Riemann Solver for Advection-Diffusion Based on the Generalized Riemann Problem

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Communications on Applied Mathematics and Computation 2020年第3期2卷 515-539页

作者： Steven j.ns Claus-Dieter Munz Institute of Aerodynamics and Gas Dynamics University of StuttgartPfafenwaldring 2170569 StuttgartGermany

We construct an approximate Riemann solver for scalar advection-diffusion equations with piecewise polynomial initial *** objective is to handle advection and diffusion simultaneously to reduce the inherent numerical diffusion produced by the usual advection flux *** approximate solution is based on the weak formulation of the Riemann problem and is solved within a space-time discontinuous Galerkin approach with two *** novel generalized Riemann solver produces piecewise polynomial solutions of the Riemann *** conjunction with a recovery polynomial,the Riemann solver is then applied to define the numerical flux within a finite volume *** results for a piecewise linear and a piecewise parabolic approximation are *** results indicate a reduction in numerical dissipation compared with the conventional separated flux calculation of advection and ***,it is shown that using the proposed solver only in the vicinity of discontinuities gives way to an accurate and efficient finite volume scheme.

关键词： Generalized Riemann problem Advection-diffusion Discontinuous Galerkin Numerical flux ADER Diffusive generalized Riemann problem Space-time solution Recovery method

Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

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Neural Regeneration Research 2025年第6期20卷 1711-1712页

作者： Haoqi Sun Shiqian Shen Robert j.Thomas M.Brandon Westover Can Zhang Department of Neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Center for Translational Pain Research Department of AnesthesiaCritical Care and Pain MedicineMassachusetis General HospitalHarvard Medical SchoolBostonMAUSA Division of Pulmonary Critical Care and Sleep MedicineDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Genetics and Aging Research Unit McCance Center for Brain HealthMass General Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

关键词： Alzheimer inflammation hypothesis