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Amyloidβ-based therapy for Alzheimer’s disease:challenges,successes and future

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3374-3399页

作者： Yun Zhang Huaqiu Chen Ran Li keenan Sterling Weihong Song National Clinical Research Center for Geriatric Disorders Xuanwu HospitalCapital Medical UniversityBeijingChina The Second Affiliated Hospital and Yuying Children’s Hospital Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceWenzhou Medical UniversityWenzhouZhejiangChina Townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouverBC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiangChina

Amyloidβprotein(Aβ)is the main component of neuritic plaques in Alzheimer’s disease(AD),and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression.Aβhas been the prime target for the development of AD ***,the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course.

关键词： Alzheimer Aβ clinical

Microbial community coalescence and nitrogen cycling in simulated mortality decomposition hotspots

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Ecological Processes 2023年第1期12卷 608-624页

作者： Sarah W.keenan Alexandra L.Emmons jennifer M.DeBruyn Department of Geology and Geological Engineering South Dakota School of Mines and Technology501 East St.Joseph StreetRapidSD 57701USA Department of Anthropology University of TennesseeKnoxvilleTNUSA Department of Biosystems Engineering and Soil Science University of Tennessee2506 E.J.Chapman DriveKnoxvilleTN 37996USA

Background The pulsed introduction of dead plant and animal material into soils represents one of the primary mechanisms for returning organic carbon(C)and nitrogen(N)compounds to biogeochemical *** of animal carcasses provides a high C and N resource that stimulates indigenous environmental microbial communities and introduces non-indigenous,carcass-derived microbes to the ***,the dynamics of the coalesced microbial communities,and the relative contributions of environment-and carcass-derived microbes to C and N cycling are *** test whether environment-derived,carcass-derived,or the combined microbial communities exhibited a greater influence on C and N cycling,we conducted controlled laboratory experiments that combined carcass decomposition fluids and soils to simulate carcass decomposition *** selectively sterilized the decomposition fluid and/or soil to remove microbial communities and create different combinations of environment-and carcass-derived communities and incubated the treatments under three temperatures(10,20,and 30℃).Results Carcass-derived bacteria persisted in soils in our simulated decomposition scenarios,albeit at low *** communities had higher respiration rates at 10 and 30℃ compared to soil or carcass communities ***,at higher temperatures,mixed communities had reduced diversity,but higher respiration,suggesting functional *** communities treatments also provided evidence that carcass-associated microbes may be contributing to ammonification and denitrification,but that nitrification is still primarily carried out by native soil *** Our work yields insight into the dynamics of microbial communities that are coalescing during carcass decomposition,and how they contribute to recycling carcasses in terrestrial ecosystems.

关键词： Carcass decomposition Microcosm Nitrogen Carbon Biogeochemical cycling Coalescence

Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease:A paradigm shift from acid to bacteria?

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World journal of Gastroenterology 2021年第18期27卷 2054-2072页

作者： Steve M D'Souza Kevin Houston Lauren keenan Byung Soo Yoo Parth j Parekh David A johnson Department of Internal Medicine Division of GastroenterologyEastern Virginia Medical SchoolNorfolkVA 23502United States

Genomic sequencing,bioinformatics,and initial speciation(e.g.,relative abundance)of the commensal microbiome have revolutionized the way we think about the“human”body in health and *** interactions between the gut bacteria and the immune system of the host play a key role in the pathogenesis of gastrointestinal diseases,including those impacting the *** relatively stable,there are a number of factors that may disrupt the delicate balance between the luminal esophageal microbiome(EM)and the *** changes are thought to be a product of age,diet,antibiotic and other medication use,oral hygiene,smoking,and/or expression of antibiotic products(bacteriocins)by other *** effects may lead to persistent dysbiosis which in turn increases the risk of local inflammation,systemic inflammation,and ultimately disease *** has suggested that the etiology of gastroesophageal reflux disease-related esophagitis includes a cytokine-mediated inflammatory component and is,therefore,not merely the result of esophageal mucosal exposure to corrosives(i.e.,acid).Emerging evidence also suggests that the EM plays a major role in the pathogenesis of disease by inciting an immunogenic response which ultimately propagates the inflammatory ***,we discuss the potential role for manipulating the EM as a therapeutic option for treating the root cause of various esophageal disease rather than just providing symptomatic relief(i.e.,acid suppression).

关键词： Microbiome Gastroesophageal reflux disease Probiotics Prebiotics Bacteriocins Dysbiosis Barrett’s esophagus Esophageal cancer Esophagitis Eosinophilic esophagitis

Clinical classification of symptomatic heterotopic pancreas of the stomach and duodenum:A case series and systematic literature review

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World journal of Gastroenterology 2022年第14期28卷 1455-1478页

作者： Michael T Le Compte Brandon Mason keenan j Robbins Motoyo Yano Deyali Chatterjee Ryan C Fields Steven M Strasberg William G Hawkins Department of Surgical Oncology University of North CarolinaRaleighNC 27608United States Department of Radiology Stillwater Medical CenterStillwaterOK 74074United States Department of General Surgery Washington University St.LouisSt.LouisMO 63110-8109United States Department of Radiology Mayo ClinicPhoenixAZ 8505United States Department of Pathology and Immunology MD Anderson Cancer CenterHoustonTX 77030United States Department of Surgical Oncology Washington University School of MedicineSt.LouisMO 63110-8109United States Section of Hepatobiliary-Pancreatic and GI Surgery Washington University St.LouisSt.LouisMO 63110United States

BACKGROUND Heterotopic pancreas(HP)is an aberrant anatomic malformation that occurs most commonly in the upper gastrointestinal *** the majority of heterotopic pancreatic lesions are asymptomatic,many manifest severe clinical symptoms which require surgical or endoscopic *** of the clinical manifestations and symptoms of HP is limited due to the lack of large volume studies in the *** purpose of this study is to review symptomatic cases at a single center and compare these to a systematic review of the literature in order to characterize common clinical manifestations and treatment of this *** To classify the common clinical manifestations of heterotopic *** A retrospective review was conducted of pathologic samples containing heterotopic pancreas from *** was limited to HP of the upper gastrointestinal tract due to the frequency of presentation in this *** patients were identified from review of the medical records and clinical symptoms were *** were compared to a systematic review of the literature utilizing Pub Med and Embase searches for papers pertaining to heterotopic *** describing symptomatic presentation of HP were selected for *** including demographics,symptoms,presentation and treatment were compiled and *** Twenty-nine patient were identified with HP at a single center,with six of these identified has having clinical *** manifestations included,gastrointestinal bleeding,gastric ulceration with/without perforation,pancreatitis,and gastric outlet *** review of the literature yielded 232 publications detailing symptomatic cases with only 20 studies describing ten or more *** and multi-patient studies were combined to form a cohort of 934 symptomatic *** majority of patients presented with abdominal pain(67%)combined with one of the following clinical catego

关键词： Heterotopic pancreas Ectopic pancreas Aberrant pancreas Pancreatic rest Groove pancreatitis

Mining Rehabilitation in New South Wales （Australia） and Germany

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journal of Earth Science and Engineering 2015年第8期5卷 499-511页

作者： Lisa j. K. Zillig Naomi keenan Tim Roberts University of Duisburg-Essen Essen 45141 Germany Tom Farrell Institute for the Environment the University of Newcastle Callaghan NSW 2308 Australia

The rehabilitation of coal mines is an up-to-date issue, heavily discussed not only by the industry but also by scientists and the adjacent communities since open cut coal mining has extensive impacts affecting all parties. Whereas, before and during the mining process not only nature but sometimes also the population of a whole region has to give way to a mine, the consequences of the operations remain long after mining closure. Typically a once intact and functioning ecosystem is replaced with a destroyed wideness evocative of a moon landscape. Fortunately, the awareness of the need to rehabilitate the destroyed nature is increasing steadily and all involved parties are making efforts to improve the situation, even if it is a major challenge to bring all parties to a consensus. Therefore, a legislative basis is required and the know-how of optimal rehabilitation solutions must be developed. In this article the rehabilitation of mined land in Australia and Germany are compared. More precisely the article will present an overview of the legislative regulations, certain applied methods of rehabilitation work and the problems that are likely to occur in respect to the influence of mining on nature.

关键词： Mining rehabilitation mining Australia mining Germany mine closure legislation mining rehabilitation.

Reduced striatal volumes in Parkinson’s disease:a magnetic resonance imaging study

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Translational Neurodegeneration 2012年第1期1卷 132-139页

作者： Toni L Pitcher Tracy R Melzer Michael R MacAskill Charlotte F Graham Leslie Livingston Ross j.keenan Richard Watts john C Dalrymple-Alford Tim j Anderson Department of Medicine University of OtagoChristchurchNew Zealand New Zealand Brain Research Institute 66 Stewart StChristchurch 8011New Zealand Department of Psychology University of CanterburyChristchurchNew Zealand College of Medicine University of VermontBurlingtonVTUSA Christchurch Radiology Group ChristchurchNew Zealand Department of Neurology Canterbury District Health BoardChristchurchNew Zealand

Background:The presence and extent of structural changes in the brain as a consequence of Parkinson’s disease(PD)is still poorly ***:High-resolution 3-tesla T1-weighted structural magnetic resonance images in sixty-five PD and 27 age-matched healthy control participants were ***,caudate,and intracranial volumes were manually traced in the axial plane of 3D reconstructed *** nuclei volumes were normalized to intracranial volume for statistical *** status was assessed using the Unified Parkinson’s Disease Rating Scale and Hoehn and Yahr *** status was assessed using global status tests and detailed neuropsychological ***:Both caudate and putamen volumes were smaller in PD brains compared to controls after adjusting for age and *** volumes were reduced by 11%(p=0.001)and putamen volumes by 8.1%(p=0.025).PD striatal volumes were not found to be significantly correlated with cognitive or motor ***:Small,but significant reductions in the volume of both the caudate and putamen occur in PD *** reductions are independent of the effects of age and gender,however the relation of these reductions to the functional loss of dopamine,which is characteristic of PD,remains unclear.

关键词： Magnetic resonance imaging Volumetry Caudate Putamen Parkinson’s disease

An investigation of the L-shell x-ray conversion efficiency for laser-irradiated tin foils

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Plasma Science and Technology 2020年第4期22卷 48-54页

作者： David BAILIE Cormac HYLAND Raj L SINGH Steven WHITE Gianluca SARRI Francis P keenan David RILEY Steven j ROSE Edward G HILL Feilu WANG Dawei YUAN Gang ZHAO Huigang WEI Bo HAN Baoqiang ZHU jianqiang ZHU Pengqian YANG Centre for Plasma Physics School of Mathematics and PhysicsQueen's University BelfastBelfastBT7 INNUnited Kingdom Astrophysics Research Centre School of Mathematics and PhysicsQueen's University BelfastBelfastBT7 INNUnited Kingdom Plasma Physics Group Blackett LaboratoryPrince Consort RoadLondonSW72AZUnited Kingdom Key Laboratory of Optical Astronomy National Astronomical ObservatoriesChinese Academy of SciencesBeijing 100012People's Republic of China Department of Astronomy Beijing Normal UniversityBeijing 100875People's Republic of China Shanghai Institute of Optics and Fine Mechanics Chinese Academy of Sciences.Shanghai 201800People's Republic of China

We have used the ShenguangⅡlaser in third harmonic(351 nm)to investigate the emission of L-shell radiation in the 3.3–4.4 ke V range generated using thin foils of Sn coated onto a parylene substrate with irradiation of order 1015 W cm-2 and nanosecond pulse *** our experiment,we have concentrated on assessing the emission on the non-laser irradiated side as this allows an experimental geometry relevant to experiments on photo-ionised plasmas where a secondary target must be placed close to the source,to achieve x-ray fluxes appropriate to astrophysical *** L-shell conversion efficiencies are estimated to be of order 1%,with little dependence on Sn thickness between 400 and 800 nm.

关键词： conversion efficiency laser plasma x-ray sources laboratory astrophysics

Simultaneous Release of a Hydroxy-Methylglutaryl Coenzyme A Reductase Inhibitor and a Glycoprotein IIb/IIIa Antagonist from a Thermoresponsive NiPAAm/NtBAAm Copolymer System

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journal of Biomaterials and Nanobiotechnology 2011年第1期2卷 18-27页

作者： j. A. Hickey I. Lynch K. A. Dawson D. Cox A. K. keenan 不详

While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothelial monolayer lining the vessel wall, leading to possible in-stent thrombosis. Local drug delivery from stent surfaces represents a means of delivering therapeutic doses of drug directly to the target site. The aim of this study was to elute fluvastatin, which can inhibit vascular smooth muscle cell proliferation, and xemilofiban, which prevents platelet adhesion and aggregation, together in bioactive concentrations from the same copolymer system. Combined elution from thermoresponsive N-isopropylacrylamide (NiPAAm)/N-tert-butylacrylamide (NtBAAm)-derived copolymer systems was achieved using microgels (NiPAAm/NtBAAm 65/35 wt/wt) randomly dispersed in 85/15 matrices. Fluvastatin elution from 5 mm films over a 14-day period showed initial burst release, which leveled off. Of the total incorporated (8.33 ± 0.21 nmol, n=4), 68.5 % was eluted during this period. Xemilofiban release was measured in terms of its ability to inhibit platelet adhesion, using a microfluidic system. To investigate the influence of location and hydrophobicity on elution of bioactivity, three separate systems were employed. While elution of anti-adhesive activity from the system containing xemilofiban-loaded matrices was more dramatic in the short term, a more sustained level of inhibition was achieved when xemilofiban had been incorporated into microgels. All samples investigated for anti-adhesive activity also decreased human coronary artery smooth muscle cell proliferation. Therefore xemilofiban has potential as an agent for preventing in-stent thrombosis. Our study has demonstrated the feasibility of using this novel matrix/microgel system to regulate simultaneous release of both agents in bioactive concentrations.

关键词： Fluvastatin Xemilofiban Nipaam/Ntbaam Microgels Local Drug Delivery

Exploring DFT+U parameter space with a Bayesian calibration assisted by Markov chain Monte Carlo sampling

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npj Computational Materials 2021年第1期7卷 1661-1669页

作者： Pedram Tavadze Reese Boucher Guillermo Avendaño-Franco keenan X.Kocan Sobhit Singh Viviana Dovale-Farelo Wilfredo Ibarra-Hernández Matthew B.johnson David S.Mebane Aldo H.Romero Department of Physics and Astronomy West Virginia UniversityMorgantownWVUSA Department of Mechanical and Aerospace Engineering West Virginia UniversityMorgantownWVUSA Department of Physics and Astronomy Rutgers UniversityPiscatawayNJUSA Facultad de Ingeniería Benemérita Universidad Autónoma de PueblaApdo.Postal J-39PueblaPue.72570México

The density-functional theory is widely used to predict the physical properties of ***,it usually fails for strongly correlated materials.A popular solution is to use the Hubbard correction to treat strongly correlated electronic ***,the values of the Hubbard U and j parameters are initially unknown,and they can vary from one material to *** this semi-empirical study,we explore the U and j parameter space of a group of iron-based compounds to simultaneously improve the prediction of physical properties(volume,magnetic moment,and bandgap).We used a Bayesian calibration assisted by Markov chain Monte Carlo sampling for three different exchange-correlation functionals(LDA,PBE,and PBEsol).We found that LDA requires the largest U *** has the smallest standard deviation and its U and j parameters are the most transferable to other iron-based ***,PBE predicts lattice parameters reasonably well without the Hubbard correction.

关键词： materials Hubbard parameter