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The concept of gene therapy for glaucoma:the dream that has not come true yet

Neural Regeneration Research 2024年第1期19卷 92-99页

作者： robert Sulak Xiaonan Liu Adrian Smedowski Department of Physiology Faculty of Medical Sciences in KatowiceMedical University of Silesia in KatowiceKatowicePoland Institute of Biotechnology HiLIFEUniversity of HelsinkiHelsinkiFinland GlaucoTech Co. KatowicePoland

Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in *** glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent *** most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic *** gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2j mice model of high-tension glaucoma and the optic nerve *** gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

关键词： adeno-associated virus gene editing gene therapy glaucoma IOP lowering IOP-independent mechanisms neuroprotection optic nerve optic neuropathy retinal ganglion cells

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Deterministic epidemic models overestimate the basic reproduction number of observed outbreaks

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Infectious Disease Modelling 2024年第3期9卷 680-688页

作者： Wajid Ali Christopher E.Overton robert R.Wilkinson Kieran j.Sharkey Department of Mathematical Sciences University of LiverpoolPeach StreetLiverpoolL697ZXEnglandUnited Kingdom Department of Applied Mathematics Liverpool John Moores UniversityByrom StreetLiverpoolL35UXEnglandUnited Kingdom

The basic reproduction number,R_(0),is a well-known quantifier of epidemic ***,a class of existing methods for estimating R_(0)from incidence data early in the epidemic can lead to an over-estimation of this *** particular,when fitting deterministic models to estimate the rate of spread,we do not account for the stochastic nature of epidemics and that,given the same system,some outbreaks may lead to epidemics and some may ***,an observed epidemic that we wish to control is a major *** amounts to implicit selection for major outbreaks which leads to the over-estimation *** formally characterised the split between major and minor outbreaks by using Otsu's method which provides us with a working *** show that by conditioning a‘deterministic’model on major outbreaks,we can more reliably estimate the basic reproduction number from an observed epidemic trajectory.

关键词： Estimating R_(0) Simple birth-death process Major outbreak Conditioned epidemic Stochastic fade-out

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Mechanocatalysis of CO to CO_(2)on TiO_(2)surface controlled at atomic scale

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Nano Research 2024年第7期17卷 5826-5834页

作者： Yuuki Adachi robert Turanský ján Brndiar Kamil Tokár Qiang Zhu Huan Fei Wen Yasuhiro Sugawara IvanŠtich Yan jun Li Department of Applied Physics Osaka University2-1 YamadaokaSuitaOsaka 565-0871Japan Institute of Physics Slovak Academy of SciencesBratislava 84511Slovakia Institute of Informatics Slovak Academy of SciencesBratislava 84507Slovakia Faculty of Natural Sciences University of Ss.Cyril and MethodiusTrnava 91701Slovakia Key Laboratory of Instrumentation Science and Dynamic Measurement School of Instrument and ElectronicsNorth University of ChinaTaiyuan 030051China

The common ways to activate a chemical reaction are by heat,electric current,or ***,mechanochemistry,where the chemical reaction is activated by applied mechanical force,is less common and only poorly understood at the atomic *** we report a tip-induced activation of chemical reaction of carbon monoxide to dioxide on oxidized rutile TiO_(2)(110)*** activation is studied by atomic force microscopy,Kelvin probe force microscopy under ultrahigh-vacuum and liquid nitrogen temperature conditions,and density functional theory(DFT)*** reaction is inferred from hysteretic behavior of frequency shift signal further supported by vector force mapping of vertical and lateral forces needed to trigger the chemical reaction with torque motion of carbon monoxide towards an oxygen *** reaction is found to proceed stochastically at very small tip-sample ***,the local contact potential difference reveals the atomic-scale charge redistribution in the reactants required to unlock the *** results open up new insights into the mechanochemistry on metal oxide surfaces at the atomic scale.

关键词： atomic resolution mechanochemistry atomic force microscopy Kelvin probe force microscopy density functional theory(DFT)simulation CO oxidation catalysis rutile TiO_(2)surface

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Increases in the incremental exercise mean response time across the steady state domain:Implications for exercise testing&prescription

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Sports Medicine and Health Science 2024年第4期6卷 315-323页

作者： Bridgette G.j.O'Malley robert A.Robergs Todd A.Astorino Queensland University of Technology Faculty of Health:School of Exercise and Nutrition SciencesBrisbaneAustralia Department of Kinesiology CSU-San MarcosSan MarcosCAUSA

We hypothesized that slowed oxygen uptake(VO_(2))kinetics for exercise transitions to higher power outputs(PO)within the steady state(SS)domain would increase the mean response time(MRT)with increasing exercise intensity during incremental *** highly trained cyclists(mean±standard deviation[SD]);age(39±6)years[yr];and VO_(2) peak=(61±9)mL/kg/min performed a maximal,ramp incremental cycling test and on separate days,four 6-min bouts of cycling at 30%,45%,65%&75% of their incremental peak PO(Wpeak).SS trial data were used to calculate the MRT and verified by mono-exponential and linear curve *** the ramp protocol attained the value from SS,the PO,in Watts(W),was converted to time(min)based on the ramp function W to quantify the incremental MRT(iMRT).Slope analyses for the VO_(2) responses of the SS versus incremental exercise data below the gas exchange threshold(GET)revealed a significant difference(p=0.003;[0.437±0.08]vs.[0.382±0.05]L·min^(-1)).There was a significant difference between the 45%Wpeak steady state VO_(2)(ss VO_(2))([3.08±0.30]L·min^(-1),respectively),and 30% Wpeak ss VO_(2)(2.26±0.24)(p<0.0001;[3.61±0.80]vs.[2.20±0.39]L·min^(-1))and between the iMRT for 45% and 30% Wpeak ss VO_(2) values([50.58±36.85]s vs.[32.20±43.28]s).These data indicate there is no single iMRT,which is consistent with slowed VO_(2) kinetics and an increasing VO_(2) deficit for higher exercise intensities within the SS domain.

关键词： Mean responsetime(MRT) Incremental exercise Steady state(SS) Exercise testing Exercise prescription

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Surgeon preferences in the treatment of thumb carpometacarpal osteoarthritis

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World journal of Orthopedics 2024年第5期15卷 435-443页

作者： Edward j Wu Bradley W Fossum Wyatt Vander Voort Christopher O Bayne robert M Szabo Department of Orthopedic Surgery University of Minnesota Medical SchoolMinneapolisMN 55455United States Department of Orthopaedic Surgery UC Davis School of MedicineSacramentoCA 95817United States

BACKGROUND Primary thumb carpometacarpal(CMC)osteoarthritis is one of the most common conditions encountered by hand *** the vast number of operations that have been proposed,none have demonstrated results significantly superior to trapeziectomy *** The purpose of our study was to determine why surgeons opt for their technique in treating CMC *** A cross-sectional survey of active members of the American Society for Surgery of the Hand was conducted to evaluate the reasons behind their preferred technique in the treatment of isolated thumb CMC *** were contacted by email once and provided with a link to a de-identified survey consisting of 5 treatment questions and 5 demographic *** Of 950 responses were received.40.5%of surgeons preferred trapeziectomy+ligament reconstruction tendon interposition(LRTI),followed by trapeziectomy+suspensionplasty(28.2%),suture button suspension(5.9%),trapeziectomy alone(4.6%),prosthetic arthroplasty(3.2%),arthrodesis(1.1%),and other(6.6%).Proponents of trapeziectomy+LRTI cited familiarity(73.2%),exposure during fellowship(48.8%)and less proximal migration(60%)to be the main reasons affecting their *** who preferred trapeziectomy+suspensionplasty most reported simplicity(74.9%),fewer complications(45.3%),less proximal migration(43.8%),and avoidance of autogenous tissue harvest(42.7%).Advocates of suture button suspension cited avoidance of autogenous tissue harvest(80.4%),shorter immobilization(76.8%),and quicker recovery(73.2%)with their *** of trapeziectomy alone cited simplicity(97.7%),fewer complications(86.4%),and avoidance of autogenous tissue harvest(59.1%).In their comments,45%of surgeons choosing trapeziectomy alone cited evidence as an additional *** of prosthetic arthroplasty cited improved pinch strength(83.3%)and improved range of motion(63.3%),while those preferring arthrodesis cited better pinch strength(90%)and freque

关键词： Thumb carpometacarpal Osteoarthritis Trapeziectomy Ligament reconstruction tendon interposition Suspensionplasty Preferences Trends

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Characterization of squash polysaccharide and the anti-diabetic effect on type 2 diabetic rat revealed by urine metabolomics analysis

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Food Science and Human Wellness 2024年第5期13卷 2937-2946页

作者： Li Liang Fuming Zhang Quanhong Li Baoguo Sun Yuyu Zhang robert j.Linhardt Beijing Advanced Innovation Center for Food Nutrition and Human Health Beijing Key Laboratory of Flavor ChemistryBeijing Technology and Business University(BTBU)Beijing 100048China Departments of Chemical and Biological Engineering Chemistry and Chemical BiologyBiomedical Engineering and Biological ScienceCenter for Biotechnology and Interdisciplinary StudiesRensselaer Polytechnic InstituteTroy 12180USA College of Food Science and Nutritional Engineering China Agricultural UniversityBeijing 100083China China National Engineering Research Center for Fruit and Vegetable Processing Beijing 100083China

The present study reports the structural characteristics of 3 polysaccharide fractions(SPS-F1,SPS-F2 and SPS-F3)isolated and purified from ***-F1(molecular weight(Mw)=12.30 kDa)and SPS-F2(Mw=19.40 kDa)were likely to contain HG and RG-I domain of pectic polysaccharide,***-F2(Mw=270.4 kDa)was mainly composed of rhamnose,galactose and *** treatment with SPS decreased body weight gain,glucose and TG levels in type 2 diabetes ***,25 differential metabolites were identified based on urinary metabolomics analysis,which are crucial to the anti-diabetic effect of *** regulation of nicotinamide N-oxide,histamine,cis-aconitate,citrate,L-malic acid,3-(3-hydroxyphenyl)propanoic acid and N-acetyl-L-aspartic acid were mainly associated with energy metabolism,gut microbiota and *** of surface plasmon resonance revealed the binding kinetics with galectin-3(Gal-3)and fibroblast growth factor 2(FGF2).The K_(D)values of SPS-F2 and SPS-F3 to Gal-3 were 4.97×10^(-3)and 1.48×10^(-3)mol/L,indicating a weak binding *** 3 fractions showed moderate binding to FGF2 and the affinity was SPS-F3>SPS-F2>***,the metabolomics and SPR approach were proved to be a promising tool in exploring the anti-diabetes effects of SPS and provided a deep understanding of the mechanisms.

关键词： Polysaccharide Metabolomics Type 2 diabetes Surface plasmon resonance

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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

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Hepatic vein reconstruction during hepatectomy:A feasible and underused technique

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 421-427页

作者： Manish Ahuja Kunal joshi Chris Coldham Paulo Muiesan Bobby Dasari Manuel Abradelo Ravi Marudanayagam Darius Mirza john Isaac David Bartlett Nikolaos A Chatzizacharias robert P Sutcliffe Keith j roberts Department of HPB and Liver Transplant Surgery University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Immunology and Immunotherapy University of BirminghamBirminghamUK

Complete surgical resection(R0)of liver tumors,primary or metastatic,remains the main objective in management of primary and metastatic liver tumors[1].Tumors invading to the proximity of the hepatic venous outflow pose a peculiar challenge to achieve R0 resections,because this location may render a tumor *** median survival of patients with liver tumor without surgery is less than 12 months[2].Even with surgery,post-hepatectomy liver failure and subsequently increased mortality are the main problems associated with complex resection[3].Moreover,when the vein is affected,vein resection and subsequent reconstruction are *** resection is a standard practice in liver resection and transplantation[4],for example,hepatic vein reconstruction during a living-donor liver transplant,porto-mesenteric axis reconstruction during resection of advanced pancreatic cancer and caval reconstruction during resection of retroperitoneal ***,novel techniques like total hepatic vascular exclusion(HVE)[5],veno-venous bypass[6]and ex vivo hepatic resection[7,8]have facilitated curative resections of tumors close to one or more major hepatic veins.

关键词： hepatectomy surgery mortality

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Integrins and their potential roles in mammalian pregnancy

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journal of Animal Science and Biotechnology 2024年第1期15卷 1-19页

作者： Gregory A.johnson robert C.Burghardt Fuller W.Bazer Heewon Seo joe W.Cain Department of Veterinary Integrative Biosciences School of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTX 77843‑4459USA Department of Animal Science College of Agriculture and Life SciencesTexas A&M UniversityCollege StationTX 77843‑2471USA

Integrins are a highly complex family of receptors that, when expressed on the surface of cells, can mediate reciprocal cell-to-cell and cell-to-extracellular matrix(ECM) interactions leading to assembly of integrin adhesion complexes(IACs) that initiate many signaling functions both at the membrane and deeper within the cytoplasm to coordinate processes including cell adhesion, migration, proliferation, survival, differentiation, and metabolism. All metazoan organisms possess integrins, and it is generally agreed that integrins were associated with the evolution of multicellularity, being essential for the association of cells with their neighbors and surroundings, during embryonic development and many aspects of cellular and molecular biology. Integrins have important roles in many aspects of embryonic development, normal physiology, and disease processes with a multitude of functions discovered and elucidated for integrins that directly influence many areas of biology and medicine, including mammalian pregnancy, in particular implantation of the blastocyst to the uterine wall, subsequent placentation and conceptus(embryo/fetus and associated placental membranes) development. This review provides a succinct overview of integrin structure, ligand binding, and signaling followed with a concise overview of embryonic development, implantation, and early placentation in pigs, sheep, humans, and mice as an example for rodents. A brief timeline of the initial localization of integrin subunits to the uterine luminal epithelium(LE) and conceptus trophoblast is then presented, followed by sequential summaries of integrin expression and function during gestation in pigs, sheep, humans, and rodents. As appropriate for this journal, summaries of integrin expression and function during gestation in pigs and sheep are in depth, whereas summaries for humans and rodents are brief. Because similar models to those illustrated in Fig. 1, 2, 3, 4, 5 and 6 are present throughout the sc

关键词： Humans Implantation Integrins Pigs Pregnancy Rodents Sheep

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Evaluating for unrecognized deficits in perimetry associated with functional upper eyelid malposition

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Advances in Ophthalmology Practice and Research 2024年第1期4卷 39-44页

作者： Linyan Wang Davin C.Ashraf Michael Deiner Oluwatobi O.Idowu Seanna R.Grob Bryan j.Winn M Reza Vagefi robert C.Kersten Department of Ophthalmology The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Ophthalmology University of CaliforniaSan FranciscoUSA Department of Ophthalmology Oregon Health and Science UniversityPortlandUSA Department of Ophthalmology Tufts Medical CenterBostonUSA Department of Ophthalmology University of UtahSalt Lake CityUtahUSA

Objective:To investigate whether functional upper eyelid malposition is associated with unrecognized deficits in automated perimetry among glaucoma patients by examining patients undergoing eyelid surgery who had not been identified as requiring eyelid taping during glaucoma field ***:In this retrospective pre-post study,an automated database search followed by manual chart review was used to identify eligible patients from january 2012 to March *** patients had reliable visual field testing within two years before and after functional upper blepharoplasty or ptosis repair and no comorbid ocular *** part of routine practice,glaucoma visual field technicians taped patients with pupil-obstructing eyelid malposition;taped examinations were excluded from *** and demographic characteristics,mean deviation,and pattern standard deviation were evaluated within a two year period before and after eyelid ***:The final analysis included 60 eyes of 38 *** in visual field parameters after eyelid surgery did not reach statistical significance in crude or adjusted *** patients with ptosis,the margin reflex distance-1 was not associated with change in mean deviation after surgery(Pearson R2=0.0061;P=0.700).Five of 17 eyes excluded from analysis due to unreliable pre-operative visual fields demonstrated substantial improvement after ***:Functional upper eyelid malposition does not appear to cause spurious visual field abnormalities among glaucoma patients with reliable visual fields who were determined not to require eyelid taping at the time of their visual *** visual fields could be a sign of eyelid interference in this population.

关键词： Visual field Ptosis Dermatochalasis Glaucoma Perimetry Visually significant

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