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Sustained activation of P2X7 induces MMP-2- evoked cleavage and functional purinoceptor inhibition

Journal of Molecular Cell Biology 2018年第3期10卷 229-242页

作者： Christopher N. J. Young Natalia Chira Justyna Róg Rasha Al-Khalidi Magalie Benard Ludovic Galas Philippe Chan david vaudry Krzysztof Zablocki Dariusz C. Górecki School of Allied Health Sciences Faculty of Health and Life Sciences De Montfort University Leicester LE1 5RR UK Molecular Medicine Laboratory Institute of Biomedical and Biomolecular Sciences School of Pharmacy and Biomedical Sciences University of Portsmouth Portsmouth PO1 2DT UK Laboratory of Cellular Metabolism Department of Biochemistry Nencki Institute of Experimental Biology of the Polish Academy of Sciences Pasteur Str. 02- 093 Warsaw Poland PRIMACEN Cell Imaging Platform of Normandy Inserm IBiSA and PISSARO Proteomic Platform Institute for Research and Innovation in Biomedicine University of Rouen 76821 Mont-Saint-Aignan France

P2X7 purinoceptor promotes survival or cytotoxicity depending on extraceUular adenosine triphosphate （ATP） stimulus Intensity controlling its ion channel or P2X7-dependent large pore （LP） functions. Mechanisms governing this operational divergence and functional idiosyncrasy are ill-understood. We have discovered a feedback loop where sustained activation of P2X7 triggers release of active matrix metalloproteinase 2 （MMP-2）, which halts ion channel and LP responses via the MMP-2-dependent receptor cleavage. This mechanism operates in cells as diverse as macrophages, dystrophic myoblasts, P2X7-transfected HEK293, and human tumour cells. Given that serum-born MMP-2 activity also blocked receptor functions, P2X7 responses in vivo may decrease in organs with permeable capillaries. Therefore, this mechanism represents an Important fine-tuning of P2X7 functions, reliant on both cell-autonomous and extraneous factors. Indeed, it allowed evasion from the ATP-induced cvtotoxicity in macrophages and human cancer ceils with high P2X7 expression levels. Finally, we demonstrate that P2X7 ablation eliminated getatinase activity in inflamed dystrophic muscles in vivo. Thus, P2X7 antagonists could be used as an alternative to highly toxic MMP inhibitors in treatments of inflammatory diseases and cancers.

关键词： P2X7 MMP-2 DMD macrophage β-dystroglycan CD44 cancer

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Fluorescence Resonance Energy Transfer Competitive Binding Assay for Secretin Receptor （Class B-GPCR）

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Journal of Pharmacy and Pharmacology 2014年第5期2卷 295-303页

作者： Vijayalakshmi Senthil Jerome Leprince david vaudry Billy Kwok Chong Chow Department of Zoology University of Hong Kong Hong Kong Department of Federative Institute for Multidisciplinary Research on Peptides (IFRMP23) University of RouenMont-Saint-Aignan 76821 France

Human secretin is responsible for carrying a number of physiological functions including energy and water homeostasis, thus making secretin receptor a promising target for drug development. For GPCRs （G protein-coupled receptors）, radioactive ligands are usually used in conventional binding assays to characterize the binding affinities of the ligands. An alternative non-hazardous fluorescence based binding assay is lucrative over the radio-ligand assays. Here, we have developed a FRET （fluorescence resonance energy transfer） competitive binding assay for human secretin receptor. The receptor gene sequence is cloned in the SNAP （single nucleotide amplified polymorphisms） tag-plasmid and expressed in CHO （chinese hamster ovary）-K1 cells. Its expression and function is confirmed with immunofluorescence localization and receptor activation. The receptor and the ligand are labeled with fluorescent donor （Tb） and acceptor （Alexa488）. FRET signals are produced when the labeled ligand is bound to the receptor and the same drop when it is displaced by the test compounds. The saturation concentration of the receptor labeling is 100 nM, and the ligand Kd value is 500 nM. At these concentrations, the IC50 of unlabeled secretin is 1.63 4- 3.55 nM. Additionally, few class-B ligands are screened and hold good correlation with traditional radio-ligand assay. Henceforth, this FRET binding assay can be efficiently used as a primary screening tool for peptide analogs.

关键词： Class-B GPCR FRET binding assay human secretin receptor peptide analogs secretin.

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Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice

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World Journal of Gastroenterology 2022年第48期28卷 6935-6949页

作者： Karim Atmani Fabien Wuestenberghs Maximilien Baron Illona Bouleté Charlène Guérin Wafa Bahlouli david vaudry Jean Claude do Rego Jean-Nicolas Cornu Anne-Marie Leroi Moïse Coëffier Mathieu Meleine Guillaume Gourcerol Nutrition Gut and Brain Unit(Inserm U1073)Institute for Research and Innovation in BiomedicineUniversitéde Rouen NormandieRouen 76000France Department of Gastroenterology and Hepatology UniversitéCatholique de LouvainCHU UCL NamurYvoir 5530Belgium Department of Physiology CHU RouenUniversitéde Rouen NormandieRouen 76031France Department of Urology CHU RouenUniversitéde Rouen NormandieRouen 76000France Inserm UMR 1245Team Epigenetics and Pathophysiology of Neurodevelopmental DisordersUniversitéde Rouen NormandieRouen 76000France Behavioural Analysis Platform(SCAC) HeRacLeS Inserm US51-CNRS UAR2026Institute for Research and Innovation in BiomedicineUniversitéde Rouen NormandieRouen 76000France Department of Nutrition CHU RouenUniversitéde Rouen NormandieRouen 76000France Inserm U1107 NeuroDolClermont Auvergne UniversityClermont-Ferrand 63000France

BACKGROUND Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral *** pelvic organs share common sensory pathways,it is likely that those syndromes involve a cross-sensitization of the bladder and the *** precise pathophysiology remains poorly *** To develop a model of chronic bladder-colon cross-sensitization and to investigate the mechanisms *** Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane *** sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal ***,used as a marker of colorectal inflammation,was measured in the colon,and colorectal permeability was measured using chambers.c-Fos protein expression,used as a marker of neuronal activation,was assessed in the spinal cord(L6-S1 level)using *** fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal *** expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western *** Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline(P<0.0001).This effect started 1 h post-injection and lasted up to 7 d *** increased permeability or inflammation was shown in the bladder or colon 7 d *** hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord(P<0.0001).In green fluorescent protein on the fractalkine receptor-positive mice,intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord(P<0.0001).NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after

关键词： Cross-organ sensitization MAPK-p38 Microglia NK1 receptor Pain Visceral hypersensitivity

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Making bridges between preclinical and clinical insights into age-related cognitive decline

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Neural Regeneration Research 2025年第8期20卷 2321-2322页

作者： david VC Brito Clévio Nóbrega Algarve Biomedical Center-Research Institute(ABC-RI) Campus GambelasFaroPortugal Algarve Biomedical Center-(ABC) Campus GambelasFaroPortugal Faculty of Medicine and Biomedical Sciences(FMCB) University of AlgarveGambelas CampusFaroPortugal

With people living longer,the societal impact of age-related cognitive decline is becoming more pronounced(Crimmins,2015).Thus,it is increasingly important to comprehend the cognitive shifts linked to aging-whether th... 详细信息

关键词： bridges becoming insight

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Women in visual neural regeneration research

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Neural Regeneration Research 2025年第2期20卷 489-490页

作者： Tonia S.Rex david J.Calkins Vanderbilt Eye Institute Vanderbilt University Medical CenterNashvilleTNUSA

The year 2024 marks the 60^(th)anniversary of Title IX and 25 years since the New York Times revealed bias against female faculty members at the Massachusetts Institute of *** take an opportunity here to examine the state of gender bias in a relatively new yet already prominent field,neural regeneration in the visual system,for which there is a well-defined context useful for this *** National Eye Institute(NEI)provided the first round of research funding for its Audacious Goals Initiative(AGI)on visual neural regeneration in 2013 and the last round in ***,we focus on this *** sources included PubMed,the National Science Foundation(NSF),the NEI,the Blue Ridge Institute for Medical Research and data from the major professional organization for eye and vision research,the Association for Research in Vision and Ophthalmology(ARVO).

关键词： neural visual Times

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Software, Software Engineering and Software Engineering Research: Some Unconventional Thoughts

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Journal of Computer Science & Technology 2009年第2期24卷 189-197页

作者： david Notkin Computer Science and Engineering University of Washington Seattle

Software engineering is broadly discussed as falling far short of expectations. Data and examples are used to justify how software itself is often poor, how the engineering of software leaves much to be desired, and how research in software engineering has not made enough progress to help overcome these weaknesses. However, these data and examples are presented and interpreted in ways that are arguably imbalanced. This imbalance, usually taken at face value, may be distracting the field from making significant progress towards improving the effective engineering of software, a goal the entire community shares. Research dichotomies, which tend to pit one approach against another, often subtly hint that there is a best way to engineer software or a best way to perform research on software. This, too, may be distracting the field from important classes of progress.

关键词： software engineering/general software engineering process/life cycle

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts Christian Mustroph david Gimbel Jonathan Grossberg Daniel L.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick Heimel Markus Kerbl LászlóGál Sylvia Nürnberger Barbara Schaedl James Ferguson Nicole Swiadek Xavier Monforte Johannes C.Heinzel Antal Nógrádi Andreas H.Teuschl-Woller david Hercher Department Life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria Ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk-based nerve guidance conduit vascularization

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The functional properties of synapses made by regenerated axons across spinal cord lesion sites in lamprey

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Neural Regeneration Research 2022年第10期17卷 2272-2277页

作者： david Parker Department of Physiology Developmentand NeuroscienceUniversity of CambridgeCambridgeUK

While the anatomical properties of regenerated axons across spinal cord lesion sites have been studied extensively,little is known of how the functional properties of regenerated synapses compared to those in unlesioned *** study aims to compare the properties of synapses made by regenerated axons with unlesioned axons using the lamprey,a model system for spinal injury research,in which functional locomotor recovery after spinal cord lesions is associated with axonal regeneration across the lesion *** synapses below the lesion site did not differ from synapses from unlesioned axons with respect to the amplitude and duration of single excitatory postsynaptic *** also showed the same activity-dependent depression over spike ***,regenerated synapses did differ from unlesioned synapses as the estimated number of synaptic vesicles was greater and there was evidence for increased postsynaptic quantal *** axons above the lesion site,the amplitude and duration of single synaptic inputs also did not differ significantly from unlesioned ***,in this case,there was evidence of a reduction in release probability and inputs facilitated rather than depressed over spike *** inputs from single regenerated axons below the lesion site thus do not increase in amplitude to compensate for the reduced number of descending axons after functional ***,the postsynaptic input was maintained at the unlesioned level using different synaptic ***,the facilitation from the same initial amplitude above the lesion site made the synaptic input over spike trains functionally *** may help to increase propriospinal activity across the lesion site to compensate for the lesion-induced reduction in supraspinal *** animal experiments were approved by the Animal Ethics Committee of Cambridge University.

关键词： electrophysiology lamprey plasticity regeneration reticulospinal axon spinal cord spinal injury synapse

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Conversion of Solar Energy to Fuels by Inorganic Heterogeneous Systems

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催化学报 2011年第6期32卷 879-890页

作者： Kimfung LI david MARTIN Department of Chemical Engineering University College LondonTorrington PlaceLondonWC1E 7JEUK

Over the last several years,the need to find clean and renewable energy sources has increased rapidly because current fossil fuels will not only eventually be depleted,but their continuous combustion leads to a dramatic increase in the carbon dioxide amount in *** of the Sun's radiation can provide a solution to both *** fuel can be generated by using solar energy to split water,and liquid fuels can be produced via direct CO2 *** would create an essentially free carbon or at least carbon neutral energy *** this tutorial review,the current progress in fuels' generation directly driven by solar energy is *** mechanisms are discussed with suggestions for future research.

关键词：固体超强碱氧化钙硝酸钾氧化铝氧化锆氢氧化钾硝酸钙

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