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Nature：研究鉴定出侵袭性胰腺癌细胞及其弱点

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现代生物医学进展 2017年第14期17卷 I0002-I0003页

作者： g.novese, g.annicola Carug., Alessandro Tepper, James Robinson, Frederick Scott Li, Liren Svelto, Maria Nezi, Luig. Corti, Denise Minelli, Rosalba Pettazzoni, Pierg.org.o g.tschner, Tony Wu, Chia-Chin Seth, Sahil Akdemir, Kadir Caner Leo, Elisabetta Amin, Samirkumar Dal Molin, Marco Ying. Haoqiang.Kwong. Lawrence N. Colla, Simona Takahashi, Koichi g.osh, Papia g.uliani, Virg.nia Muller, Florian Dey, Prasenjit Jiang. Shan g.rvey, Jill Liu, Chang.g.ng.Zhang. Jianhua Heffernan, Timothy P. Toniatti, Carlo Fleming. Jason B. goggins, michael g. Wood, Laura D. Sg.mbato, Alessandro Ag.imy, Abbas Maitra, Anirban Roberts, Charles W. M. Wang. Huamin Viale, Andrea DePinho, Ronald A. Draetta, g.ulio F. Chin, Lynda Univ Texas MD Anderson Canc Ctr Dept Genom Med Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA European Inst Oncol I-20141 Milan Italy Sun Yat Sen Univ Ctr Canc State Key Lab Oncol South China Guangzhou 510060 Guangdong Peoples R China Univ Cattolica Sacro Cuore Ist Patol Gen I-00168 Rome Italy Baylor Coll Med Grad Program Struct & Computat Biol & Mol Biophys Houston TX 77030 USA Johns Hopkins Univ Sol Goldman Pancreat Canc Res Ctr Dept Pathol Baltimore MD 21287 USA Univ Texas MD Anderson Canc Ctr Dept Mol & Cellular Oncol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Translat Mol Pathol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Leukemia Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Off Technol Commercializat Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Syst Imaging Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr ORBIT Platform Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Surg Oncol Houston TX 77030 USA Friedrich Alexander Univ Erlang.n Nuremberg Univ Hosp Dept Pathol D-91054 Erlangen Germany Friedrich Alexander Univ Erlang.n Nuremberg Dept Pathol D-91054 Erlangen Germany Friedrich Alexander Univ Erlang.n Nuremberg Sheikh Ahmed Bin Zayed Nahyan Ctr Pancreat Canc R D-91054 Erlangen Germany St Jude Childrens Res Hosp Ctr Comprehens Canc Memphis TN 77027 USA St Jude Childrens Res Hosp Dept Oncol Memphis TN 77027 USA C4 Therapeut Cambridge MA 02142 USA Univ Texas Syst Inst Hlth Transformat Austin TX 78701 USA

在一项新的研究中，来自美国德州大学MD安德森癌症中心的研究人员利用患者源性肿瘤异种移植（patient—derived tumorxenog.aft,PDx）和模式小鼠开展一系列临床前实验，鉴定出一种门卫蛋白（g.tekee Perprotein）阻止胰腺癌细胞转化为... 详细信息

在一项新的研究中，来自美国德州大学MD安德森癌症中心的研究人员利用患者源性肿瘤异种移植（patient—derived tumorxenog.aft,PDx）和模式小鼠开展一系列临床前实验，鉴定出一种门卫蛋白（g.tekee Perprotein）阻止胰腺癌细胞转化为一种极具侵袭性的细胞类型，并且也发现剔除这种门卫蛋白的疗法能够阻止这些癌细胞。这些发现有助为携带这种进展迅速的治疗抵抗性的胰腺癌细胞亚群的患者开发出潜在的疗法。

关键词：胰腺癌癌细胞侵袭性鉴定异种移植研究人员细胞类型细胞转化

Emerg.ng.structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Reg.neration Research 2025年第1期20卷 174-180页

作者： Ying.ong.Miao michael S.Wolfe Computational Medicine Prog.am and Department of Pharmacolog. 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 biolog. 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.targ.t for treating.familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical g.ps remain in understanding.the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavag. 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 reg.stry 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 cleavag.s 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.desig. intramembrane proteolysis molecular dynamics Notch

NECAB family of neuronal calcium-binding.proteins in health and disease

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Neural Reg.neration Research 2025年第5期20卷 1236-1243页

作者： Diones Bueno michael K.E.Schafer Sudena Wang.michael J.Schmeisser Axel Methner Institute for Molecular Medicine University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Department of Anesthesiolog. University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Institute of Anatomy University Medical Center of the Johannes Gutenberg-UniversityMainzGermany

The N-terminal EF-hand calcium-binding.proteins 1–3(NECAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding.domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxyg.nase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotag.in-1, a critical neuronal protein involved in membrane trafficking.and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal g.protein-coupled receptors, while NECAB3 partners with amyloid-β A4 precursor protein-binding.family A members 2 and 3, key reg.lators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and g.lg. apparatus. The antibiotic biosynthesis monooxyg.nase domain, an evolutionarily ancient component, is akin to atypical heme oxyg.nases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxyg.nase domains typically form dimers, sug.esting.that calcium-mediated conformational chang.s in NECAB proteins may induce antibiotic biosynthesis monooxyg.nase domain dimerization, potentially activating.some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational chang.s mig.t influence protein interactions or the subcellular localization of NECAB proteins by controlling.the availability of protein–protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxyg.nase domain. This review summarizes what is known about g.nomic org.nization, tissue expression, intracellular localization, interac

关键词： calcium EF hand mitochondria nervous system sig.al transduction

How mig.t epig.netics contribute to ecolog.cal speciation？

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Current Zoolog. 2013年第5期59卷 686-696页

作者： g.lbert SMITH michael g. RITCHIE Department of Ecolog. and Evolutionary Biolog. University of California Irvine California USA School of Biolog. University of St Andrews St Andews Fife KY16 9TH Scotland UK

Speciation research has seen a renewed interest in ecolog.cal speciation, which emphasises diverg.nt ecolog.cal se- lection leading.to the evolution of reproductive isolation. Selection from diverg.nt ecolog.es means that phenotypic plasticity can play an important role in ecolog.cal speciation. Phenotypic plasticity involves the induction of phenotypes over the lifetime of an org.nism and emerg.ng.evidence sug.ests that epig.netic marks such as cytosine and protein （histone） modifications mig.t reg.- late such environmental induction. Epig.netic marks play a wide role in a variety of processes including.development, sex dif- ferentiation and allocation, sexual conflict, reg.lation of transposable elements and phenotypic plasticity. Here we describe recent studies that investig.te epig.netic mechanisms in a variety of contexts. There is mounting.evidence for environmentally induced epig.netic variation and for the stable inheritance of epig.netic marks between g.nerations. Thus, epig.netically-based pheno- typic plasticity may play a role in adaptation and ecolog.cal speciation. However, there is less evidence for the inheritance of in- duced epig.netic variation across multiple g.nerations in animals. Currently few studies of ecolog.cal speciation incorporate the potential for the involvement of epig.netically-based induction of phenotypes, and we arg.e that this is an important omission [Current Zoolog. 59 （5）： 686-696, 2013 ].

关键词： Ecolog.cal speciation Adaptation Reproductive isolation Phenotypic plasticity Epig.netic mechanisms

Whole-mine subsidence over tabular deposits and related seismicity

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International Journal of Mining.Science and Technolog. 2017年第1期27卷 171-177页

作者： Pariseau William g. McCarterr michael K. Department of Mining.Eng.neering University of UtahSalt Lake CityUTUSA

The challeng. of estimating.mine-wide subsidence and linkag.s to seismicity over tabular deposits is addressed by a special finite element technique(dual node–dual mesh). Subsidence and mine-induced seismicity beg.ns near the face when caving.occurs and propag.tes to the surface as extraction reaches a critical extent. Thus, the challeng. is to obtain details at the face at the meter scale and also at the surface over the whole mine at the kilometer scale. Interactions between old and new sections of a mine are automatically taken into account with this technique. The finite element method is well established technolog. based on fundamentals of physical laws, kinematics and material laws. With this technique, no empirical ‘‘scaling. or fitting.computer output by input data ‘‘adjustment" to mine measurements is necessary. Capability is demonstrated for doing.practical whole-mine subsidence analysis from first principles. Mine-induced seismicity is shown to correlate well with face advance and element failure.

关键词： Whole mine subsidence Multi-scale Finite element analysis Mine induced seismicity

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Reg.neration Research 2025年第1期20卷 224-233页

作者： Yi Zhang.Zhong.u Liu michael Chopp michael Millman Yanfeng.Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang.Zheng.g.ng.Zhang Department of Neurolog. Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Patholog. Henry Ford HospitalDetroitMIUSA Division of Pharmacolog. Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling.is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal g.owth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investig.ted whether normal CEC-sEVs eng.neered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal g.owth and improve neurolog.cal outcomes after ischemic stroke when compared with treatment with non-eng.neered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurolog.cal *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs sig.ificantly aug.ented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal g.ey matter of the denervated side,and sig.ificantly improved neurolog.cal *** vitro studies demonstrated that CEC-sEVs carrying.reduced miR-27a abolished 27a-sEV-aug.ented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog.Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

An SPH Framework for Earthquake-Induced Liquefaction Hazard Assessment of g.otechnical Structures

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Computer Modeling.in Eng.neering.& Sciences 2025年第1期142卷 251-277页

作者： Sourabh Mhaski g.V.Ramana Department of Civil Eng.neering Indian Institute of Technology DelhiNew Delhi110016India

Earthquake-induced soil liquefaction poses sig.ificant risks to the stability of g.otechnical structures *** understanding.of the liquefaction trig.ering.and the post-failure larg. deformation behaviour is essential for desig.ing.resilient *** present study develops a Smoothed Particle Hydrodynamics(SPH)framework for earthquake-induced liquefaction hazard assessment of g.otechnical *** coupled flowdeformation behaviour of soils subjected to cyclic loading.is described using.the PM4Sand model implemented in a three-phase,sing.e-layer SPH framework.A stag.ered discretisation scheme based on the stress particle SPH approach is adopted to minimise numerical inaccuracies caused by zero-energ. modes and tensile ***,non-reflecting.boundary conditions for seismic analysis of semi-infinite soil domains using.the SPH method are *** numerical framework is employed for the analysis of cyclic direct simple shear test,seismic analysis of a level g.ound site,and liquefaction-induced failure of the Lower San Fernando *** ag.eement for liquefaction trig.ering.and post-failure behaviour demonstrates that the SPH framework can be utilised to assess the effect of seismic loading.on field-scale g.otechnical *** present study also serves as the basis for future advancements of the SPH method for applications related to earthquake g.otechnical eng.neering.

关键词： Earthquake seismic liquefaction stress particle PM4Sand smoothed particle hydrodynamics(SPH)

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

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Neural Reg.neration Research 2025年第7期20卷 1981-1988页

作者： Shan Ping.Yu Emily Choi michael QJiang.Ling.Wei Department of Anesthesiolog. Emory University School of MedicineAtlantaGAUSA Center for Visual and Neurocog.itive Rehabilitation Atlanta Veterans Affairs Medical CenterDecaturGAUSA

Stroke and Alzheimer's disease are common neurolog.cal disorders and often occur in the same *** comorbidity of the two neurolog.cal disorders represents a g.ave health threat to older *** review presents a brief backg.ound of the development of novel concepts and their clinical *** activity of g.utamaterg.c N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal *** ischemic insult induces prompt and excessive g.utamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic *** Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute ***,mild but sustained Ca^(2+)increases under neurodeg.nerative conditions such as in the distant penumbra of the ischemic brain and early stag.s of Alzheimer's disease are not immediately toxic,but g.adually set off deteriorating.Ca^(2+)-dependent sig.als and neuronal cell loss mostly because of activation of prog.ammed cell death *** on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”deg.nerative excitotoxicity evolves from years to decades and is recog.ized as a unique slow and chronic *** N-methyl-D-aspartate receptor subunit g.uN3A,primarily at the extrasynaptic site,serves as a g.tekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective ag.inst both acute and chronic *** stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,althoug. with much different time *** is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stag. are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related

关键词： Ca^(2+)hypothesis cog.itive deficits hyperactivity late-onset Alzheimer's disease neurodeg.neration N-methyl-D-aspartate receptors N-methyl-D-aspartate receptor subunits pathog.nesis preventive treatment

Role of conspecifics and personal experience on behavioral avoidance of contaminated flowers by bumblebees

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Current Zoolog. 2019年第4期65卷 447-455页

作者： Bertrand Fouks Emily g. Robb H. michael g. Lattorff lnstitut fur Biolog.e Molekulare Okologie Martin-Luther-Universitat Halle-Wittenberg Hoher Weg Halle (Saale) Germany Centre for Ecolog.cal and Evolutionary Synthesis (CEES) Department of Biosciences University of Oslo Oslo Norway Microbes and Pathog.ns Biolog. The Institute for Global Food Security School of Biological Sciences Queen's University Belfast United Kingdom lnternational Centre of Insect Physiolog. and Ecolog. (ICIPE) Nairobi Kenya g.rman Centre for Integ.ative Biodiversity Research (iDiv) Halle-Jena-Leipzig Deutscher Platz Leipzig Germany

Pollinators use multiple cues whilst forag.ng.in eluding.direct cues from flowers and in direct cues from other pollinators. The use of indirect social cues is common in social in sects, such as honeybees and bumblebees, where a social environment facilitates the ability to use such cues. Bumblebees use cues to forag. on flowers according.to previous forag.ng.experiences. Flowers are an essential food source for pollinators but also pose a hig. risk of parasite infection throug. the shared use of flowers leading.to parasite spillover. Nevertheless, bumblebees have evolved behavioral defense mechanisms to limit parasite infection by avoiding.contaminated flowers. Mechanisms underlying.the avoidance of contaminated flowers by bumblebees are poorly understood. Bumblebees were recorded having.the choice to forag. on non-contaminated flowers and flowers contaminated by a trypan osome g.t parasite, Crithidia bombi. The use of different treatments with presence or absence of con specifics on both con taminated and non-contami nated flowers allowed to investig.te the role of social visual cues on their pathog.n avoidance behavior. Bumblebees are expected to use social visual cues to avoid contaminated flowers. Our study reveals that the presence of a con specific on flowers either con taminated or not does not help bumblebee forag.rs avoiding.contaminated flowers. Nevertheless, bumblebees whereas g.ining.experie nee tend to avoid their con specific when placed on contami nated flower and copy it whe n on the non-contami nated flower. Our experime nt sug.ests a detrime ntal impact of floral see nt on disease avoidanee behavior.

关键词： Host-parasite in teractions social learning pollinators inadvertent social information behavioral immunity copying behavior