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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong miao michael S.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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Genetic analyses of ancient tea trees provide insights into the breeding history and dissemination of Chinese Assam tea(Camellia sinensis ***)

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Plant Diversity 2024年第2期46卷 229-237页

作者： miao-miao Li Muditha K.Meegahakumbura Moses C.Wambulwa Kevin S.Burgess michael Möller Zong-Fang Shen De-Zhu Li Lian-Ming Gao CAS Key Laboratory for Plant Diversity and Biogeography of East Asia Kunming Institute of BotanyChinese Academy of ScienceKunming650201China Germplasm Bank of Wild Species Kunming Institute of BotanyChinese Academy of ScienceKunming650201China Kunming College of Life Science University of Chinese Academy of SciencesKunming650201YunnanChina Department of Export Agriculture Faculty of Animal Science and Export AgricultureUva Wellassa UniversityBadulla90000Sri Lanka Department of Life Sciences School of Science and ComputingSouth Eastern Kenya University170-90200KituiKenya Department of Biology Columbus State UniversityUniversity System of GeorgiaColumbusGA31907-5645USA Royal Botanic Garden Edinburgh 20A Inverleith RowEdinburghEH35LRScotlandUK Lijiang Forest Biodiversity National Observation and Research Station Kunming Institute of BotanyChinese Academy of SciencesLijiang674100YunnanChina

Chinese Assam tea(Camellia sinensis ***)is an important tea crop with a long history of cultivation in Yunnan,*** its potential value as a genetic resource,its genetic diversity and domestication/breeding history remain *** address this issue,we genotyped 469 ancient tea plant trees representing 26 *** *** populations,plus two of its wild relatives(six and three populations of *** and ***,respectively)using 16 nuclear microsatellite *** showed that Chinese Assam tea has a relatively high,but comparatively lower gene diversity(H_(S)=0.638)than the wild relative ***(H_S=0.658).Clustering in STRUCTURE indicated that Chinese Assam tea and its two wild relatives formed distinct genetic groups,with considerable interspecific *** Chinese Assam tea accessions clustered into three gene pools,corresponding well with their geographic ***,New Hybrids analysis indicated that 68.48%of ancient Chinese Assam tea plants from Xishuangbanna were genetic intermediates between the Puer and Lincang gene *** addition,10%of the ancient Chinese Assam tea individuals were found to be hybrids between Chinese Assam tea and *** results suggest that Chinese Assam tea was domesticated separately in three gene pools(Puer,Lincang and Xishuangbanna)in the Mekong River valley and that the hybrids were subsequently selected during the domestication *** the domestication history of Chinese Assam tea in southwestern Yunnan remains complex,our results will help to identify valuable genetic resources that may be useful in future tea breeding programs.

关键词： Tea plant Hybrid origin Genetic diversity Domestication history Camellia sinensis var.assamica Camellia taliensis

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Knock-out of BnHva22c reduces the susceptibility of Brassica napus to infection with the fungal pathogen Verticillium longisporum

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The Crop Journal 2024年第2期12卷 503-514页

作者： Wanzhi Ye Roxana Hossain michael Prbsting Abdallah Abdelmegid Mohamed Ali Lingyue Han Ying miao Steffen Rietz Daguang Cai Dirk Schenke Department of Molecular Phytopathology and Biotechnology Institute of PhytopathologyChristian-Albrechts-University of KielKielGermany Institut für Zuckerrübenforschung GöttingenGermany Plant Pathology Department Faculty of Agriculture and Natural ResourcesAswan UniversityAswanEgypt Fujian Provincial Key Laboratory of Plant Functional Biology College of Life SciencesFujian Agriculture and Forestry UniversityFuzhou 350002FujianChina Hohenlieth-Hof NPZ Innovation GmbHHoltseeGermany

Verticillium longisporum(Vl43)is a soilborne hemibiotrophic fungal pathogen causing stem striping on oilseed rape(OSR)and severe yield *** for resistant varieties is the most promising approach to control this ***,we report the identification of Hva22c as a novel susceptibility factor and its potential for improving OSR ***22c is a member of the Hva22 gene family,originally described for barley(Hordeum vulgare).Several Hva22 members have been located at the endoplasmic ***22c is up-regulated in response to Vl43 in both Arabidopsis and *** demonstrate that knock-out of Hva22c in OSR by CRISPR/Cas9 and its homolog in Arabidopsis by T-DNA insertion reduced plants’susceptibility to Vl43 infection and impaired the development of disease *** understand the underlying mechanism,we analysed transcriptomic data from infected and non-infected roots of hva22c knock-out and wild type *** identified a homozygous mutant with frame-shifts in all four BnHva22c loci displaying a vastly altered transcriptional landscape at 6 ***,a large set of genes was suppressed under mock conditions including genes related to the endomembrane *** the up-regulated genes we found several defense-related and phytohormone-responsive genes when comparing mutant to the wild *** results demonstrate that Hva22c is functionally required for a fully compatible plant-fungus *** loss of function reduces plant susceptibility,most likely due to endoplasmatic reticulum and Golgi dysfunction accompanied by additionally activated defense *** findings can help improve OSR resistance to *** infection.

关键词： Hva22c Susceptibility factor CRISPR/Cas9 Brassica napus Arabidopsis Verticillium longisporum Resistance breeding

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High formability Mg-Zn-Gd wire facilitates ACL reconstruction via its swift degradation to accelerate intra-tunnel endochondral ossification

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Journal of Magnesium and Alloys 2024年第1期12卷 295-315页

作者： Xuan He Ye Li Hongwei miao Jiankun Xu michael Tim-yun Ong Chenmin Wang Lizhen Zheng Jiali Wang Le Huang Haiyue Zu Zhi Yao Jie Mi Bingyang Dai Xu Li Patrick Shu-hang Yung Guangyin Yuan Ling Qin Musculoskeletal Research Laboratory of Department of Orthopaedics&Traumatology and Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory of Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongHong KongChina National Engineering Research Center of Light Alloy Net Forming School of Materials Science&EngineeringShanghai Jiao Tong UniversityShanghaiChina Department of Orthopaedics and Traumatology Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Orthopaedic Department Peking University Third HospitalBeijingChina Department of Rehabilitation Sciences The Hong Kong Polytechnic UniversityHong KongChina

After reconstructing the anterior cruciate ligament(ACL),unsatisfactory bone tendon interface healing may often induce tunnel enlargement at the early healing *** good biological features and high formability,Magnesium-Zinc-Gadolinium(ZG21)wires are developed to bunch the tendon graft for matching the bone tunnel during ***,tensile strength,degradation,and cytotoxicity of ZG21 wire are *** rabbit model is used for assessing the biological effects of ZG21 wire by Micro-CT,histology,and mechanical *** SEM/EDS,immunochemistry,and in vitro assessments are performed to investigate the underlying *** tests demonstrate the high formability of ZG21 wire as surgical ***-CT shows ZG21 wire degradation accelerates tunnel bone formation,and histologically with earlier and more fibrocartilage regeneration at the healing *** mechanical test shows higher ultimate load in the ZG21 *** SEM/EDS presents ZG21 wire degradation triggered calcium phosphate(Ca-P)*** results demonstrate upregulation of Wnt3a,BMP2,and VEGF at the early phase and TGFβ3 and Type II collagen at the late phase of *** vitro tests also confirmed the Ca-P in the metal extract could elevate the expression of Wnt3a,βcatenin,ocn and opn to stimulate *** vivo tests of clinical samples indicated suturing with ZG21 wire did not weaken the ultimate loading of human tendon *** conclusion,the ZG21 wire is feasible for tendon graft *** degradation products accelerated intra-tunnel endochondral ossification at the early healing stage and therefore enhanced bone-tendon interface healing in ACL reconstruction.

关键词： Magnesium wire ACL reconstruction Magnesium alloy Biomaterials Endochondral ossification

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Yes-associated protein contributes to magnesium alloy-derivedinflammation in endothelial cells

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Regenerative Biomaterials 2022年第1期9卷 130-142页

作者： Hongchi Yu Zhe Hou Nuoya Chen Rifang Luo Li Yang michael miao Xiaoyi Ma Lifeng Zhou Fugui He Yang Shen Xiaoheng Liu Yunbing Wang National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610065China Institute of Biomedical Engineering West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China Division of Oral&Craniofacial Health Sciences University of North Carolina Adams School of DentistryChapel HillNC 27599USA Beijing Key Laboratory of Cardiac Drug Device Technology and Evidence Based Medicine Beijing 100021China

Magnesium alloy(Mg alloy)has attracted massive attention in the potential applications of cardiovascular stents because of its good biocompatibility and ***,whether and how the Mg alloy induces inflammation in endothelial cells remains *** the present work,we investigated the activation of Yes-associated protein(YAP)upon Mg alloy stimuli and unveiled the transcriptional function in Mg alloy-induced *** RT–PCR,western blotting and immunofluorescence staining showed that Mg alloy inhibited the Hippo pathway to facilitate nuclear shuttling and activation of YAP in human coronary artery endothelial cells(HCAECs).Chromatin immunoprecipitation followed sequencing was carried out to explore the transcriptional function of YAP in Mg alloy-derived *** led to the observation that nuclear YAP further bonded to the promoter region of inflammation transcription factors and co-transcription *** binding event activated their transcription and modified mRNA methylation of inflammation-related genes through regulating the expression of N6-methyladenosine modulators(METTL3,METTL14,FTO and WTAP).This then promoted inflammation-related gene expression and aggravated inflammation in *** YAP deficiency cells,Mg alloy-induced inflammation was ***,our data suggest that YAP contributes to the Mg alloy-derived inflammation in HCAECs and may provide a potential therapeutic target that alleviates inflammation after Mg alloy stent implantation.

关键词： magnesium alloy Yes-associated protein inflammation

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Fabrication of sub-20 nm MoS_(2) horizontal nanowire on silicon substrates by inclusion of precursors into polystyrene-bpolyethylene oxide nanopatterns: Detailed structural investigation

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Nano Research 2024年第3期17卷 2145-2153页

作者： Tandra Ghoshal michael A.Morris School of Chemistry AMBER and CRANNTrinity College DublinDublinIrelandD02 AK60

Herein,we demonstrate the fabrication of sub-20 nm MoS_(2) horizontal nanowire arrays on silicon substrates using a self-assembled block copolymer assisted in situ inclusion *** separated long-range ordered polystyrene-b-polyethylene oxide(PS-b-PEO)block copolymer(BCP)line-space nanopatterns were achieved through thermo-solvent *** patterns produced had long-range order and domain sizes>1μ*** BCP structures were lightly etched and modified by anhydrous ethanol to facilitate insertion of molybdenum precursor within the film maintaining the parent BCP *** ordered molybdenum oxide nanowire arrays were then fabricated by ultraviolet(UV)/ozone treatment at room *** oxides were converted to sulphides by thermal evaporation at different temperatures in Ar/H_(2) environment.X-ray photoelectron spectroscopy revealed the composition and phases of the molybdenum oxide and sulphide *** mapping was performed to investigate the interfaces between the oxide and sulphide nanowires with the substrate *** formation and stability of the sulphide nanowires were studied at different *** photoluminescence and Raman properties were studied at different formation temperatures to investigate defects and estimate the number of layers.

关键词： MoS_(2) block copolymer nanowires inclusion X-ray photoelectron spectroscopy(XPS) mapping photoluminescence

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A GHz chirped amplitude-modulated laser for high-contrast plasma gratings

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High Power Laser Science and Engineering 2024年第1期12卷 74-83页

作者： michael Valdman Amir Hen Gilad Marcus Applied Physics Institute Hebrew University of JerusalemJerusalemIsrael

The generation and control of large amplitude plasma gratings and other plasma structures is of paramount importance for the realization of plasma photonics. Autoresonant excitation of such structures by means of chirped amplitude-modulated lasers has been recently discussed and analyzed theoretically. Here we discuss the parameter space for the realization of such a scheme and describe the laser system that was built towards this goal. We also expand our earlier theoretical study to account for the more realistic case of a moderately focused laser beam, instead of the simplified plane wave approximation.

关键词： amplitude modulation high-frequency modulation autoresonance ion acoustic wave

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Neuronal trafficking as a key to functional recovery in immune-mediated neuropathies

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Neural Regeneration Research 2024年第11期19卷 2331-2332页

作者： Felix Kohle michael Schroeter Department of Neurology University of Cologne and University Hospital CologneCologneGermany

Immune-mediated neuropathies are rare diseases of the peripheral nervous system(PNS),substantially affecting patients’functionality and quality of *** are amenable to immunomodulatory treatments,which in many cases stabilize disease progression,but long-term deficits persist in many *** long-term deficits are particularly observed in monophasic autoimmune neuropathies like Guillain-Barrésyndrome and also in chronic variants,e.g.,chronic inflammatory demyelinating neuropathy(Fadia et al.,2019).

关键词： diseases autoimmune

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Transcranial photobiomodulation for the brain: a wide range of clinical applications

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Neural Regeneration Research 2024年第3期19卷 483-484页

作者： michael R.Hamblin Laser Research Centre Faculty of Health ScienceUniversity of Johannesburg-Doornfontein CampusDoornfonteinSouth Africa

Photobiomodulation therapy(PBMT)is a rapidly growing approach to the healing,stimulation,protection,and regeneration of many human organs and tissue *** started in the 1960s as low-level laser therapy for wound healing,but since then the introduction of light-emitting diodes(LEDs)has dramatically increased the number of applications and reports of positive *** generally uses red(620-700 nm)and/or near-infrared(780-1270 nm)wavelengths of light at an intensity that causes no tissue heating,and its activity is based on well-established biological and cellular mechanisms(de Freitas and Hamblin,2016).While laser therapists continue to use various types of laser in their office practice,LEDs are ideally suited for home use devices because they are completely safe and without any known significant adverse *** the various body parts on which PBMT has been shown to exert beneficial effects,the brain stands out as perhaps the most promising *** has been shown to reduce neuroinflammation,while increasing mitochondrial function,oxygen consumption,and blood flow within the brain(Hamblin,2016).Moreover,PBMT can stimulate the processes of synaptogenesis,neurogenesis,and neuroplasticity thus helping the brain to heal itself.

关键词： healing stimulation wound

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A Tropical View on Landau-Ginzburg Models

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Acta Mathematica Sinica,English Series 2024年第1期40卷 329-382页

作者： michael CARL Max PUMPERLA Bernd SIEBERT Alfred-Delp-Str.2 73430 AalenGermany IU Internationale Hochschule Juri-Gagarin-Ring 15299084 ErfurtGermany AnyscaleInc.2080 Addison St Ste 7BerkeleyCA 94704USA Department of Mathematics The Univ.of Texas at Austin2515 SpeedwayAustinTX 78712USA

This paper,largely written in 2009/2010,fits Landau-Ginzburg models into the mirror symmetry program pursued by the last author jointly with Mark Gross since *** point of view transparently brings in tropical disks of Maslov index 2 via the notion of broken lines,previously introduced in two dimensions by Mark Gross in his study of mirror symmetry for P2.A ma jor insight is the equivalence of properness of the Landau-Ginzburg potential with smoothness of the anticanonical divisor on the mirror *** obtain proper superpotentials which agree on an open part with those classically known for toric *** include mirror LG models for non-singular and singular del Pezzo surfaces,Hirzebruch surfaces and some Fano threefolds.

关键词： Landau-Ginzburg model mirror symmetry tropical disk broken line wall structure scattering diagram Gross-Siebert program del Pezzo surface toric degeneration

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