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Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration

Neural Regeneration Research 2023年第6期18卷 1196-1202页

作者： Instituto de Salud Carlos III Irene Villalón-García Suleva Povea-Cabello MónicaÁlvarez-Córdoba Marta Talaverón-Rey Juan MSuárez-Rivero Alejandra Suárez-Carrillo Manuel Munuera-Cabeza Diana Reche-López Paula Cilleros-Holgado Rocío Piñero-Pérez JoséA.Sánchez-Alcázar Centro Andaluz de Biología del Desarrollo(CABD-CSIC-Universidad Pablo de Olavide de Sevilla) and Centro de Investigación Biomédica en Red:Enfermedades RarasInstituto de Salud Carlos IIISevillaSpain

Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases,such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,or neurodegeneration with brain iron accumulation disorders.Mitochondrial dysfunction,lipofuscin accumulation,autophagy disruption,and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders.Currently,the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear.In this review,we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation,and the effect of iron overload on lipid peroxidation and cellular function.The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration.Therefore,the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration.In addition,we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration,particularly in PLA2G6-associated neurodegeneration,a rare neurodegenerative disease with autosomal recessive inheritance,which belongs to the group of neurodegeneration with brain iron accumulation disorders.

关键词： 4-hidroxynonenal ferroptosis iron lipid peroxidation lipofuscin neurodegeneration neurodegeneration with brain iron accumulation oxidative stress PLA2G6-associated neurodegeneration

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The uPA/uPAR system in astrocytic wound healing

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Neural Regeneration Research 2022年第11期17卷 2404-2406页

作者： manuel Yepes Division of Neuropharmacology and Neurologic Diseases Yerkes National Primate Research CenterAtlantaGAUSA Department of Neurology Emory University School of MedicineAtlantaGAUSA Department of Neurology Veterans Affairs Medical CenterAtlantaGAUSA

The repair of injured tissue is a highly complex process that involves cell prolife ration,differentiation,and migration.Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area.Urokinase-type plasminogen activator(u PA)is a serine proteinase found in multiple cell types including endothelial cells,smooth muscle cells,monocytes,and macrophages.A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor(uPAR)on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix.In contrast,although uPA and uPAR are abundantly found in astrocytes and u PA binding to uPAR triggers astrocytic activation,it is unknown if uPA also plays a role in astrocytic migration.Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell conta cts between astrocytes.More specifically,while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells,its intracellular domain binds toβ-catenin,which in turn links the complex to the actin cytos keleton.Glycogen synthase kinase 3βis a serine-threonine kinase that prevents the cytoplasmic accumulation ofβ-catenin by inducing its phosphorylation at Ser33,Ser37,and Ser41,thus activating a sequence of events that lead to its proteasomal degradation.The data discussed in this perspective indicate that astrocytes release u PA following a mechanical injury,and that binding of this u PA to uPAR on the cell membrane induces the detachment ofβ-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650.Remarkably,this is followed by the cytoplasmic accumulation ofβ-catenin because uPA-induced extracellular signalregulated kinase 1/2 activation also phosphorylates lipoprotein receptor-r

关键词： astrocytes lipoprotein receptor-related protein 6 plasmin urokinase receptor urokinase-type plasminogen activator Wnt-β-catenin pathway wound healing β-catenin

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The plasminogen activating system in the pathogenesis of Alzheimer’s disease

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Neural Regeneration Research 2021年第10期16卷 1973-1977页

作者： manuel Yepes Department of Neurology Emory University School of MedicineAtlantaGAUSA Department of Neurology Veterans Affairs Medical CenterAtlantaGAUSA Division of Neuropharmacology and Neurologic Diseases Yerkes National Primate Research CenterAtlantaGAUSA

Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published t

关键词： Alzheimer’s disease amyloid precursor protein amyloidβ neuroserpin plasmin plasminogen activating system plasminogen activator inhibitor-1 synapse tissue-type plasminogen activator urokinase-type plasminogen activator

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The complex Maxwell stress tensor theorem:The imaginary stress tensor and the reactive strength of orbital momentum.A novel scenery underlying electromagnetic optical forces

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Light(Science & Applications) 2022年第11期11卷 2655-2675页

作者： manuel Nieto-Vesperinas Xiaohao Xu Instituto de Ciencia de Materiales de Madrid Consejo Superior de Investigaciones Cintificas.Campus de CantoblancoMadrid 28049Spain State Key Laboratory of Transient Optics and Photonics Xi'an Institute of Optics and Precision MechanicsChinese Academy of SciencesXi'an 710119China Institute of Nanophotonics Jinan UniversityGuangzhou 511443China

We uncover the existence of a universal phenomenon concerning the electromagnetic optical force exerted by light or other electromagnetic waves on a distribution of charges and currents in general,and of particles in particular.This conveys the appearence of underlying reactive quantities that hinder radiation pressure and currently observed timeaveraged forces.This constitutes a novel paradigm of the mechanical effciency of light on matter,and completes the landscape of the optical,and generally electromagnetic,force in photonics and classical electrodynamics;widening our understanding in the design of both llumination and particles in optical manipulation without the need of increasing the illuminating power,and thus lowering dissipation and heating.We show that this may be accomplished through the minimization of what we establish as the reactive strength of orbital(or canonical)momentum,which plays against the optical force a role analogous to that of the reactive power versus the radiation effciency of an antenna.This long time overlooked quantity,important for current progress of optical manipulation,and that stems from the complex Maxwell theorem of conservation of complex momentum that we put forward,as well as its alternating flow associated to the imaginary part of the complex Maxwell stress tensor,conform the imaginary Lorentz force that we introduce in this work,and that like the reactive strength of orbital momentum,is antagonistic to the well-known time-averaged force;thus making this reactive Lorentz force indirectly observable near wavelengths at which the time-averaged force is lowered.The Minkowski and Abraham momenta are also addressed.

关键词： imaginary tensor orbital

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Urokinase-type plasminogen activator is a modulator of synaptic plasticity in the central nervous system:implications for neurorepair in the ischemic brain

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Neural Regeneration Research 2020年第4期15卷 620-624页

作者： manuel Yepes Division of Neuropharmacology and Neurologic Diseases Yerkes National Primate Research Center Department of Neurology Emory University School of Medicine Department of Neurology Veterans Affairs Medical Center

The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability.Unfortunately,the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients.Thus,understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific,social and economic implications.Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment.In agreement with these observations,experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke.Furthermore,it has become evident that synaptic plasticity is crucial not only during development and learning,but also for synaptic repair after an ischemic insult.The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin.However,recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation.Urokinase-type plasminogen activator(uPA)is a serine proteinase and one of the plasminogen activators,that upon binding to its receptor(uPAR)not only catalyzes the conversion of plasminogen into plasmin on the cell surface,but also activates cell signaling pathways that promote cell migration,proliferation and survival.The role of uPA is the brain is not fully understood.However,it has been reported while uPA and uPAR are abundantly found in the developing central nervous system,in the mature brain their expression is restricted to a limited group of cells.Remarkably,following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable

关键词： cerebral ischemia neurorepair plasminogen plasticity stoke synapse urokinase urokinase receptor

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Dissecting symbiosis cell by cell

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Molecular Plant 2023年第2期16卷 308-309页

作者： manuel Frank Dugald Reid Department of Molecular Biology and Genetics Aarhus UniversityUniversitetsbyen 818000Aarhus CDenmark Department of Animal Plant and Soil SciencesSchool of AgricultureBiomedicine and EnvironmentLa Trobe UniversityMelbourneVIC 3086Australia

Symbiotic nitrogen fixation in legumes occurs in specialized root organs called nodules.Their development requires coordination across tissues as infection progresses from the epidermis to growing nodules derived from the cortex or pericycle.Moreover,functional nodules include a variety of specialized cells,including those that house the nitrogen-fixing bacteria.This combination of developmental changes across tissues and specialized functions acquired by nodule cells makes dissecting the process difficult using bulk analysis of gene expression,proteins,and metabolites.

关键词： organs cortex specialized

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从计算机科学理论审视意识和通用人工智能

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Engineering 2023年第6期25卷 12-16页

作者： Lenore Blum manuel Blum Department of Computer Science School of Computer ScienceCarnegie Mellon UniversityPittsburghPA 15213USA Electrical Engineering and Computer Science Department University of CaliforniaBerkeleyCA 94720USA

1.Introduction We have defined the Conscious Turing Machine(CTM)for the purpose of investigating a theoretical computer science(TCS)approach to consciousness[1].For this,we have hewn to the TCS demand for simplicity and understandability.The CTM is consequently and intentionally a simple machine.It is not a model of the brain,though its design has greatly benefited—and continues to benefit—from neuroscience and psychology.

关键词： computer simplicity Turing

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Laser trimming for lithography-free fabrications of MoS_(2)devices

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Nano Research 2023年第4期16卷 5042-5046页

作者： Yong Xie OnurÇakıroğlu Wenshuai Hu Kexin He Sergio Puebla Thomas Pucher Qinghua Zhao Xiaohua Ma Carmen munuera Andres Castellanos-Gomez Key Laboratory of Wide Band-Gap Semiconductor Technology School of Advanced Materials and NanotechnologyXidian UniversityXi’an 710071China Materials Science Factory Instituto de Ciencia de Materiales de MadridConsejo Superior de Investigaciones Científicas28049 MadridSpain

Single-layer MoS_(2)produced by mechanical exfoliation is usually connected to thicker and multilayer regions.We show a facile laser trimming method to insulate single-layer MoS_(2)regions from thicker ones.We demonstrate,through electrical characterization,that the laser trimming method can be used to pattern single-layer MoS_(2)channels with regular geometry and electrically disconnected from the thicker areas.Scanning photocurrent microscope further confirms that in the as-deposited flake(connected to a multilayer area)most of the photocurrent is being generated in the thicker flake region.After laser trimming,scanning photocurrent microscopy shows how only the single-layer MoS_(2)region contributes to the photocurrent generation.The presented method is a direct-write and lithography-free(no need of resist or wet chemicals)alternative to reactive ion etching process to pattern the flakes that can be easily adopted by many research groups fabricating devices with MoS_(2) and similar twodimensional materials.

关键词： 2D materials transition metal dichalcogenides laser trimming differential reflectance

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Short-term effects of post-fire mulching with straw or wood chips on soil properties of semi-arid forests

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林业研究:英文版 2023年第6期34卷 1777-1790页

作者： manuel Esteban Lucas Borja Demetrio Antonio Zema Department of Agroforestry Technology Science and GeneticsSchool of Advanced Agricultural and Forestry EngineeringCampus Universitario s/nCastilla La Mancha UniversityE-02071 Castilla La ManchaAlbaceteSpain Department AGRARIA “Mediterranea”University of Reggio CalabriaLocalitàFeo di VitoI-89122 Reggio CalabriaItaly

Few studies have compared the variability of soil properties using different types of mulches in semi-arid forests.This study evaluated the changes in physico-chemical soil properties in a semi-arid forest of Central Eastern Spain,where straw and pine wood chips were distributed as mulch three months after a wildfire.Soils were sampled under burned and unmulched and burned and mulched plots three and nine months after the treatments.The data was processed using Principal Component Analysis(PCA)and Analytical Hierarchical Cluster Analysis(AHCA).Mulching with straw or wood chips did not have any significant effects on the texture and chemical properties of burned sites few months after the treatment.In contrast,significant changes are expected over time in organic matter,nutrients and many ions.There were no significant differences in soil properties between the two mulches.These low changes were confirmed by PCA coupled with AHCA,which did not show a clear distinction among the three soil conditions.However,a noticeable and significant variability of many of these properties over time was evident.This study shows that mulching does not degrade of soil properties in the short-term after a wildfire and after post-fire treatments,and thus helps protect semi-arid forest ecosystems against the negative impacts of high-severity fires.

关键词： Post-fire management High-severity fire Aridisols Erosion Vegetal residues incorporation Soil degradation

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Study and ICH validation of a reverse-phase liquid chromatographic method for the quantification of the intact monoclonal antibody cetuximab

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Journal of Pharmaceutical Analysis 2016年第2期6卷 117-124页

作者： Antonio Martinez-Ortega Agustin Herrera Antonio Salmeron-Garcia Jose cabeza Luis Cuadros-Rodriguez Natalia Navas Department of Analytical Chemistry University of Granada Faculty of Science Campus Fuentenueva s/n E-18071 Granada Spain UGC intercentro Interniveles Farmacia Granada San Cecilio Hospital Biomedical Research Institute ibs. GRANADA. Hospitales Universitarios de Granada University of Granada E-18012 Granada Spain Department of Analytical Chemistry Science Faculty Biomedical Research Institute ibis. GRANADA University of Granada Campus Fuentenuevo s/n E-18071 Granada Spain

Cetuximab （CTX） is a potent chimeric mouse/human monoclonal antibody （mAb） approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses per- formed for full study on this biopharmaceutic, the determination of the concentration preparations throughout manufacturing and subsequent handling in hospital is particularly relevant. In the present work, the study and validation of a method for quantifying intact CTX by reverse-phase high-perfor- mance liquid chromatography with diode array detection （（RP）HPLC/DAD） is presented. With that end, we checked the performance of a chromatographic method for quantifying CTX and conducted a study to validate the method as stability-indicating in accordance with the International Conference on Harmo- nization guidelines （ICH） for biotechnological drugs; therefore, we evaluated linearity, accuracy, preci- sion, detection and quantification limits, robustness and system suitability. The specificity of the method and the robustness of the mAb formulation against external stress factors were estimated by compre- hensive chromatographic analysis by subjecting CTX to several informative stress conditions. As de- monstrated, the method is rapid, accurate, and reproducible for CTX quantification. It was also suc- cessfully used to quantify CTX in a long-term stability study performed under hospital conditions.

关键词： Reverse-phase high performance liquidchromatography Diode detector Stress study Biopharmaceuticals Cetuximab

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