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Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1644-1664页

作者： Gabriela Seplovich Yazan Bouchi Juan pablo de Rivero Vaccari Jennifer C.Munoz Pareja Andrew Reisner laura Blackwell Yehia Mechref Kevin K.Wang J.Adrian Tyndall Binu Tharakan Firas Kobeissy Department of Surgery Morehouse School of MedicineAtlantaGAUSA Department of Neurobiology Center for NeurotraumaMultiomics&Biomarkers(CNMB)Neuroscience InstituteMorehouse School of MedicineAtlantaGAUSA Department of Neurological Surgery and the Miami Project to Cure Paralysis University of Miami Miller School of MedicineMiamiFLUSA Division of Pediatric Critical Care Department of PediatricsUniversity of Miami Miller School of MedicineMiamiFLUSA Department of Pediatrics Emory UniversityAtlantaGAUSA Department of Neurosurgery Children’s Healthcare of AtlantaAtlantaGAUSA Department of Chemistry and Biochemistry Texas Tech UniversityLubbockTXUSA Morehouse School of Medicine AtlantaGAUSA

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

关键词： Alzheimer's disease caspase-1 chronic traumatic encephalopathy inflammasomes neurodegeneration neuroinflammation NlRP1 NlRP3 pyroptosis tauopathy traumatic brain injury

Diversification of SUMO-Activating Enzyme in Arabidopsis： Implications in SUMO Conjugation

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Molecular Plant 2013年第5期6卷 1646-1660页

作者： laura castano-Miquel Josep Segui Silvia Manrique Ines Teixeira lorenzo Carretero-Paulet Felix Atencio l. Maria lois Center for Research in Agricultural Genomics CRAG (CSIC-IRTA-UAB-UB) Edifici CRAG-Campus UAB Bellaterra (Cerdanyola del Valles) 08193 Barcelona Spain Department of Biological Sciences SUNY-University at Buffalo North Campus 109 Cooke Hall Buffalo NY 14260 USA

Sumoylation is an essential posttranslational modification that participates in many biological processes including stress responses. However, little is known about the mechanisms that control Small Ubiquitin-like MOdifier （SUMO） conjugation in vivo. We have evaluated the regulatory role of the heterodimeric E1 activating enzyme, which catalyzes the first step in SUMO conjugation. We have established that the E1 large SAE2 and small SAE1 subunits are encoded by one and three genes, respectively, in the Arabidopsis genome. The three paralogs genes SAEla, SAElbl, and SAElb2 are the result of two independent duplication events. Since SAElbl and SAElb2 correspond to two identical cop- ies, only two E1 small subunit isoforms are present in vivo： SAEla and SAElb. The E1 heterodimer nuclear localization is modulated by the C-terminal tail of the SAE2 subunit. In vitro, SUMO conjugation rate is dependent on the SAE1 isoform contained in the E1 holoenzyme and our results suggest that downstream steps to SUMO-E1 thioester bond formation are affected. In vivo, SAEla isoform deletion in T-DNA insertion mutant plants conferred sumoylation defects upon abi- otic stress, consistent with a sumoylation defective phenotype. Our results support previous data pointing to a regula- tory role of the E1 activating enzyme during SUMO conjugation and provide a novel mechanism to control sumoylation in vivo by diversification of the E1 small subunit.

关键词： E1 activating enzyme conjugation rate subcellular localization regulation abiotic stress gene duplication.

Self-powered smart patch for sweatconductivity monitoring

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Microsystems & Nanoengineering 2019年第1期5卷 672-681页

作者： laura Ortega Anna llorella Juan pablo Esquivel Neus Sabate Instituto de Microelectronica de Barcelona IMB-CNM(CSIC)C/del Til·lers.Campus Universitat Autonoma de Barcelona(UAB)08193 BellaterraBarcelonaSpain Catalan Institution for Research and Advanced Studies(ICREA) Passeig Lluís Companys 2308010 BarcelonaSpain

A self-powered skin patch for the measurement of sweat conductivity is *** key component of the patch consists of a paper battery that is activated upon absorption of *** body fluid acts as the battery electrolyte,the conductivity of which has a direct impact on the battery-generated output power and *** particular behaviour enables the operation of a very simple and robust conductivity sensor in direct current mode without needing an external power *** device presented in this paper takes advantage of this new measurement method to develop a sweat patch for screening cystic fibrosis that operates with an extremely simple electronic circuit that minimizes its cost and environmental *** patch provides an unambiguous digital result that can be read in an electrochromic display and yields 95%sensitivity and 100%specificity when tested with artificial eccrine perspiration samples.

关键词： battery conductivity patch

SUMOylation Inhibition Mediated by Disruption of SUMO El-E2 Interactions Confers Plant Susceptibility to Necrotrophic Fungal Pathogens

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Molecular Plant 2017年第5期10卷 709-720页

作者： laura castano-Miquel Abraham Mas Ines Teixeira Josep Segui Anna Perearnau Bhagyasree N. Thampi Arnaldo l. Schapire Natalia Rodrigo Gaelle la Verde Silvia Manrique Maria Coca l. Maria lois Center for Research in Agricultural Genomics - CRAG Edifici CRAG-Campus UAB Bellaterra (Cerdanyola del Vall~s) 08193 Barcelona Spain

Protein modification by SUMO modulates essential biological processes in eukaryotes. SUMOylation is facilitated by sequential action of the El-activating, E2-conjugating, and E3-1igase enzymes. In plants, SUMO regulates plant development and stress responses, which are key determinants in agricultural productivity. To generate additional tools for advancing our knowledge about the SUMO biology, we have developed a strategy for inhibiting in vivo SUMO conjugation based on disruption of SUMO El-E2 interactions through expression of E1 SAE2uFDct domain. Targeted mutagenesis and phylogenetic analyses revealed that this inhibition involves a short motif in SAE2uFDct highly divergent across kingdoms. Transgenic plants expressing the SAE2UFDCt domain displayed dose-dependent inhibition of SUMO conjugation, and have revealed the existence of a post-transcriptional mechanism that regulates SUMO E2 conjugating enzyme levels. Interestingly, these transgenic plants displayed increased suscep- tibility to necrotrophic fungal infections by Botrytis cinerea and Plectosphaerella cucumerina. Early after fungal inoculation, host SUMO conjugation was post-transcriptionally downregulated, suggesting that targeting SUMOylation machinery could constitute a novel mechanism for fungal pathogenicity. These findings support the role of SUMOylation as a mechanism involved in plant protection from environmental stresses. In addition, the strategy for inhibiting SUMO conjugation in vivo described in this study might be applicable in important crop plants and other non-plant organisms regardless of their genetic complexity.

关键词： SUMQ inhibition development flowering necrotrophic fungi El-activating enzyme El-E2interaction disruption

Spontaneous and Bleomycin-Induced <i>γ</i>H2AX Signals in CHO9 Metaphase Chromosomes

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Advances in Bioscience and Biotechnology 2014年第7期5卷 603-616页

作者： María Vittoria Di Tomaso Silvia Basso laura lafon-Hughes Gustavo Saona Beatriz lópez-Carro Ana laura Reyes-ábalos pablo liddle Environmental Quality Evaluation and Control Service Municipality of Montevideo Montevideo Uruguay Genetics Department Instituto de Investigaciones Biológicas Clemente Estable Montevideo Uruguay

In eukaryotes, a cascade of events named DNA damage response (DDR) has evolved to handle DNA lesions. DDR engages the recruitment of signaling, checkpoint control, repair and chromatin remodeling protein complexes, allowing cell cycle delay, DNA repair or induction of apoptosis. An early DDR event involves the phosphorylation of the histone variant γH2AX on serine 139 (H2AX139 phosphorylation) originating the so-called γH2AX. DDR-related H2AX139 phosphorylation have been extensively studied in interphase nuclei. More recently, γH2AX signals on mitotic chromosomes of asynchronously growing cell cultures were observed. We performed a quantitative analysis of γH2AX signals on γH2AX immunolabeled cytocentrifuged metaphase spreads, analyzing the γH2AX signal distributions of CHO9 chromosomes harboring homologous regions both in control and bleomycin (BlM)-treated cultures. We detected γH2AX signals in CHO9 chromosomes of controls which significantly increase after BlM-exposure. γH2AX signals were uniformly distributed in chromosomes of controls. However, the γH2AX signal distribution in BlM exposed cells was significantly different between chromosomes and among chromosome regions, with few signals near the centromeres and a tendency to increase towards the telomeres. Interestingly, both basal and BlM-induced γH2AX signal distribution were statistically equal between CHO9 homologous chromosome regions. Our results suggest that BlM exerts an effect on H2AX139 phosphorylation, prevailing towards acetylated and gene-rich distal chromosome segments. The comparable H2AX139 phosphorylation of homologous regions puts forward its dependence on chromatin structure or function and its independence of the position in the karyotype.

关键词： H2AX Phosphorylation on Serine 139 γH2AX Signals Metaphase Chromosomes Homologous Chromosome Regions CHO9 Chinese Hamster Cell line

Scale dependency of liolaemus lizards＇ home range in response to different environmental variables

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Current Zoology 2016年第6期62卷 521-530页

作者： Oscar Anibal STEllATEllI Carolina BlOCK Debora lina MORENO-AZOCAR laura Estela VEGA Juan pablo ISACCH Felix Benjamin CRUZ laboratorio de Vertebrados Departamento de Biologia Instituto de Investigaciones Marinas y Costeras (IIMyC) CONICET-Facultad de Ciencias Exactas y Naturales Universidad Nacional de Mar del Plata. Defin Funes 3250 (B7602AYJ) Mar del Plata Buenos Aires Argentina Instituto de Investigaciones en Biodiversidad y Medioambiente (INIBIOMA) CONICET-Universidad Nacional del Comahue. Quintral 1250 (8400) San Carlos de Bariloche Rio Negro Argentina.

Animal habitat-use patterns cannot be isolated from scale issues. Consequently, multi-scale studies provide a complete characterization of ecological patterns that can further explain the observed variation. liolaemus constitutes the world＇s second most speciose lizard genus. In this study, we assessed the relationships between home range size and environmental variables at 3 different spatial scales. The study at a local and regional scale was focused on the habitat specialist liolaemus multimaculatus. The lizard＇s home range was calculated using the minimum convex polygon method in populations from grassland sites of the coastal sand dunes of the Argentinean Pampas under 2 different conditions, with or without forestations of Acacia Iongifolia. On the other hand, at a geographical scale we considered the evolutionary implications of 20 species of liolaemus. Home range size, phylogeny, ecological, environmental, and climatic data were ob- tained from the literature and remote sensing. l. multimaculatus home range varied from 12.66 to 570.00 m. Regionally, this species had smaller home ranges in forested habitats （X： 94.02 m2） com- pared with the non-forested sites （X： 219.78m2）. Habitat structure, vegetation types, and food availability would explain the space use at finer scales. When the 20 species of liolaernus were considered, high mean air temperature and broad thermal amplitudes showed an inverse relationship with home range size. Neither net primary productivity nor phylogeny was good predictors for home range variation at geographical scale. This study highlights the scale dependence of the explicative capability of a set of environmental and intrinsic variables on home range patterns.

关键词： environmental factors home range liolaemus lizard scales

Acceptance of living liver donation among medical students: A multicenter stratified study from Spain

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World Journal of Gastroenterology 2016年第25期22卷 5800-5813页

作者： Antonio Ríos Ana Isabel lópez-Navas Ana Isabel lópez-lópez Francisco Javier Gómez Jorge Iriarte Rafael Herruzo Gerardo Blanco Francisco Javier llorca Angel Asunsolo Pilar Sánchez-Gallegos Pedro Ramón Gutiérrez Ana Fernández María Teresa de Jesús laura Martínez-Alarcón Alberto lana lorena Fuentes Juan Ramón Hernández Julio Virseda José Yelamos José Antonio Bondía Antonio Miguel Hernández Marco Antonio Ayala pablo Ramírez Pascual Parrilla International Collaborative Donor Project ('Proyecto Colaborativo Internacional Donante' 30007 Casillas Murcia Spain Department of Surgery Paediatrics Obstetrics and Gynaecology University of Murcia Avenida de las Fuerzas Armadas 30800 Espinardo Murcia Spain Transplant Unit Surgery Service IMIB - Virgen de la Arrixaca University Hospital Carretera Madrid-Cartagena s/n 30120 El Palmar Murcia Spain Regional Transplant Centre Consejeria de Sanidad y Consumo de la Region de Murcia 30008 Ronda de Levante Murcia Spain Hospital Clinico Universitario Virgen de la Arrixaca Departamento de Cirugia General y del Aparato Digestivo Unidad de Trasplantes 30007 Casillas Murcia Spain Department of Psychology Universidad Catolica San Antonio (UCAM) Avenida de los Jeronimos 30107 Guadalupe Murcia Spain Department of Urology San Juan University Hospital of Alicante 03010 Calle Pintor Baeza Alicante Spain Universidad de Granada Avenida del Hospicio s/n 18010 Granada Spain Universidad de Navarra Campus Universitario 31080 Pamplona Navarra Spain Universidad Autonoma de Madrid Ciudad Universitaria de cantoblanco 28049 Madrid Spain Servicio de Cirugia HBP y Trasplante Hepatico Complejo Hospitalario Universitario de Badajoz Hospital Infanta Cristina Avenida Elvas s/n 06006 Badajoz Spain Universidad de Cantabria Avenida los Castros s/n 39005 Santander Cantabria Spain Departamento de Cirugia Ciencias Medicas y Sociales Facultad de Medicina y Ciencias de la Salud Universidad de Alcala Campus Cientifico-Tecnologico Plaza de San Diego s/n 28801 Alcala de Henares Madrid Spain Facultad de Medicina Universidad de Malaga 29071 Avenida de Cervantes Malaga Spain Servicio de Urologia (Complejo Hospitalario Universitario de Canarias CHUC) y Departamento de Cirugia (Universidad de La Laguna ULL) Calle Molinos de Agua s/n 38207 San Cristobal de La Laguna Santa Cruz de Tenerife Spain Departamento de Ciencias Biomedicas Basicas Facultad de Ciencias Biomedicas Universidad Europea de

AIM: To analyze the attitude of Spanish medical students toward living liver donation (llD) and to establish which factors have an influence on this ***: Study type: A sociological, interdisciplinary, multicenter and observational study. Study population: Medical students enrolled in Spain (n = 34000) in the university academic year 2010-2011. Sample size: A sample of 9598 students stratified by geographical area and academic year. Instrument used to measure attitude: A validated questionnaire (PCID-DVH RIOS) was self-administered and completed anonymously. Data collection procedure: Randomly selected medical schools. The questionnaire was applied to each academic year at compulsory sessions. Statistical analysis: Student´s t test, χ2 test and logistic regression ***: The completion rate was 95.7% (n = 9275). 89% (n = 8258) were in favor of related llD, and 32% (n = 2937) supported unrelated llD. The following variables were associated with having a more favorable attitude: (1) age (P = 0.008); (2) sex (P l area (P = 0.013); (5) believing in the possibility of needing a transplant oneself in the future (P living kidney donation (P liver segment from a family member if one were needed (P ly (P ltruistic nature; and (12) fear of the possible mutilation of the body after donation (P lUSION: Spanish medical students have a favorable attitude toward llD.

关键词： Attitude living liver donation Medical students Transplantation Organ donation Psychosocial variables Spain

Tolerance in liver transplantation: Biomarkers and clinical relevance

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World Journal of Gastroenterology 2016年第34期22卷 7676-7691页

作者： Alberto Baroja-Mazo Beatriz Revilla-Nuin Pascual Parrilla laura Martínez-Alarcón pablo Ramírez José Antonio Pons Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU) 30120 Murcia Spain Division of Gastroenterology and Hepatology and liver Transplant Unit University Hospital Virgen de la Arrixaca 30120 Murcia Spain

Transplantation is the optimal treatment for end-stage organ failure,and modern immunosuppression has allowed important progress in short-term outcomes. However,immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus,a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor Fox P3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. likewise,other immune cells,such as dendritic cells,monocyte/macrophages or natural killer cells,have been described as part of the process known as "operational tolerance". However,translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way,a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multicenter clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

关键词： liver transplantation Operational tolerance Regulatory T cells Dendritic cells Biomarkers

End-of-life care in a cardiology department： have we improved？

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Journal of Geriatric Cardiology 2016年第7期13卷 587-592页

作者： Juan Rulz-Garcia pablo Dlez-Villanueva Ana Ayesta Vanessa Brufia lourdes M Figueiras-Graillet laura Gallego-Parra Francisco Fernandez-Aviles Manuel Martinez-Selles Department of Cardiology Hospital General Universitario Gregorio Maranon Calle Doctor Esquerdo Madrid Spain Department of Cardiology Hospital Universitario de Torrejon Calle Mateo Inurria Torrejon de Ardoz Madrid Spain Universidad Francisco de Vitoria Carretera Pozuelo a Majadahonda Pozuelo de Alareon Madrid Spain Department of Cardiology Hospital Universitario de la Princesa Calle de Diego de Leon Madrid Spain Departmet of Cardiology Hospital Universitario del Sureste Ronda del Sur Arganda del Rey Madrid Spain Universidad Complutense de Madrid Av. Seneca Madrid Spain Universidad Europea de Madrid Urbanizacion E1Bosque Calle Tajo Villaviciosa de Odon Madrid Spain

Background End-of-life care is not usually a priority in cardiology departments. We sought to evaluate the changes in end-of-life care after the introduction of a do-not-resuscitate （DNR） order protocol. Methods ＆ Results Retrospective analysis of all deaths in a cardiology department in two periods, before and after the introduction of the protocol. Comparison of demographic characteristics, use of DNR orders, and end-of-life care issues between both periods, according to the presence in the second period of the new DNR sheet （Group A）, a conven- tional DNR order （Group B） or the absence of any DNR order （Group C）. The number of deaths was similar in both periods （n = 198 vs. n = 197）. The rate of patients dying with a DNR order increased significantly （57.1% vs. 68.5%; P = 0.02）. Only 4% of patients in both periods were aware of the decision taken about cardiopulmonary resuscitation. Patients in Group A received the DNR order one day earlier, and 24.5% received it within the first 24 h of admission （vs. 2.6% in the first period; P 〈 0.001）. All patients in Group A with an implantable cardioverter defibrillator （ICD） had shock therapies deactivated （vs. 25.0% in the first period; P = 0.02）. Conclusions The introduction of a DNR order protocol may improve end-of-life care in cardiac patients by increasing the use and shortening the time of registration of DNR orders. It may also contribute to increase ICD deactivation in patients with these orders in place. However, the introduction of the sheet in late stages of the disease failed to improve patient participation.

关键词： Cardiology Cardiopulmonary resuscitation End-of-life Palliative care