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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

Atrial fibrillation in the elderly

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Journal of Geriatric Cardiology 2019年第1期16卷 49-53页

作者： pablo díez-Villanueva Fernando Alfonso department of Cardiology Hospital Universitario de la Princesa

Atrial fibrillation(AF)is the most common arrhythmia in elderly population,with age being one of the most important factors involved in its *** disturbances may be present on the surface electrocardiogram before AF onset in some *** this arrhythmia is diagnosed,antithrombotic therapy is mandatory in most cases,as this is the only treatment that has demonstrated to improve *** increases both the risk of thromboembolic and bleeding complications,while benefits from anticoagulant therapy outweigh that from bleeding in most scenarios,also in very elderly ***,elderly patients with AF are often ***-vitamin K antagonist oral anticoagulants have emerged as an alternative to vitamin K antagonists,with significant less adverse events and better profile in terms of efficacy and *** conditions related to age should be carefully evaluated in these patients(including frailty,comorbidity and polypharmacy)to ensure an individualized clinical and therapeutic approach.

关键词： Atrial fibrillation Antithrombotic therapy Frailty Non-vitamin K antagonist oral anticoagulants The elderly

Importance of frailty and comorbidity in elderly patients with severe aortic stenosis

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Journal of Geriatric Cardiology 2017年第6期14卷 379-382页

作者： pablo díez-Villanueva Jorge Salamanca Antonio Rojas Femando Alfonso Cardiology department Hospital Universitario La Princesa Universidad Autónoma de Madrid Madrid Spain

The progressive aging of the population has risen awareness and concern about the impact of geriatric syndromes on both clinical outcomes and health-related quality of life in elderly patients, as well as issues regarding the rising economic burden associated with healthcare. Recent studies have demonstrated frailty and other geriatric syndromes such as functionality, dependency and comorbidity can identify the most vulnerable patients, thus allowing to better estimate the individual prognosis in terms of disability, readmission and mortality. Such information should also be considered in the decision making process, ensuring the benefit derived from each treatment in each patient, optimizing the resources and avoiding futility.

关键词： Aortic stenosis Frailty

Non-ST elevation acute coronary syndrome in the elderly

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Journal of Geriatric Cardiology 2020年第1期17卷 9-15页

作者： pablo díez-Villanueva César Jiménez Méndez Fernando Alfonso Cardiology department Hospital Universitario La Princesa Universidad Autónoma de Madrid

1 Introduction Societies are ageing at an accelerated *** scenario is a well-known challenge for health care systems,as chronic diseases,multiple comorbidities and dependency are all entities that often converge in the ***,there is an issue regarding a reduction in the general incidence of acute coronary syndrome(ACS)together with a delayed in the age of presentation,which,in sum,lead to an increase in both incidence and prevalence of ACS with age,especially non-ST elevation myocardial infarction(NSTEMI).

关键词： Acute coronary syndrome Myocardial infarction The elderly

South Asian dairy smallholders: A scoping review of practices and zoonoses

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Asian Pacific Journal of Tropical Medicine 2023年第10期16卷 446-452页

作者： Emily Schembri Angus J d Campbell Juan pablo Villanueva-Cabezas Melbourne School of Population and Global Health The University of MelbourneVictoriaAustralia The Nossal Institute for Global Health The University of MelbourneVictoriaAustralia The Peter doherty Institute for Infection and Immunity The University of Melbourne and the Royal Melbourne HospitalVictoriaAustralia

Objective: To identify and discuss on-farm management practices linked to bacterial zoonosis risk in smallholder dairy farmers in South Asia. Methods: This scoping review was conducted as per the PRISMA-ScR guidelines. Five hundred and two publications were retrieved from five online databases using a comprehensive search strategy. Studies were selected if they discussed a farm management practice which impacted human health within a South Asian country. Results: Twenty-two studies were included. Seven management practices relevant to farmers, livestock and their shared environment were identified including raw milk consumption, farm hygiene management, personal protective equipment uses, animal vaccination, cleaning udders, hand washing and disposal of afterbirth materials. Preventive practices were found to be utilized at lower frequencies compared to risk increasing practices. Awareness of bacterial zoonoses is particularly low within the region. Conclusions: Based on the results of this review, it was determined that improving farmer awareness of bacterial zoonotic diseases may favor several of the presented leverage points within the South Asian smallholder dairy system. Relying on formal school education to improve this awareness may not solve this problem, instead, more focus on accessible and affordable zoonoses education and farming programs is required.

关键词： Management practices Zoonoses dairy Smallholder system

Impact of source tissue and ex vivo expansion on the characterization of goat mesenchymal stem cells

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Journal of Animal Science and Biotechnology 2015年第2期6卷 230-251页

作者： Nuradilla Mohamad-Fauzi pablo J Ross Elizabeth A Maga James d Murray department of Animal Science University of California Institute of Ocean and Earth Sciences University of Malaya department of Population Health and Reproduction University of California

Background： There is considerable interest in using goats as models for genetically engineering dairy animals and also for using stem cells as therapeutics for bone and cartilage repair. Mesenchymal stem cells （MSCs） have been isolated and characterized from various species, but are poorly characterized in goats. Results： Goat MSCs isolated from bone marrow （BM-MSCs） and adipose tissue （ASCs） have the ability to undergo osteogenic, adipogenic and chondrogenic differentiation. Cytochemical staining and gene expression analysis show that ASCs have a greater capacity for adipogenic differentiation compared to BM-MSCs and fibroblasts. different methods of inducing adipogenesis also affect the extent and profile of adipogenic differentiation in MSCs. Goat fibroblasts were not capable of osteogenesis, hence distinguishing them from the MSCs. Goat MSCs and fibroblasts express Cd90, Cd105, Cd73 but not Cd45, and exhibit cytoplasmic localization of OCT4 protein. Goat MSCs can be stably transfected by Nucleofection, but, as evidenced by colony-forming efficiency （CFE）, yield significantly different levels of progenitor cells that are robust enough to proliferate into colonies of integrants following G418 selection. BM-MSCs expanded over increasing passages in vitro maintained karyotypic stability up to 20 passages in culture, exhibited an increase in adipogenic differentiation and CFE, but showed altered morphology and amenability to genetic modification by selection. Conclusions： Our findings provide characterization information on goat MSCs, and show that there can be significant differences between MSCs isolated from different tissues and from within the same tissue. Fibroblasts do not exhibit trilineage differentiation potential at the same capacity as MSCs, making it a more reliable method for distinguishing MSCs from fibroblasts, compared to cell surface marker expression.

关键词： Adipose Bone marrow Characterization differentiation Goat Mesenchymal stem cells

Heart failure in the elderly

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Journal of Geriatric Cardiology 2021年第3期18卷 219-232页

作者： pablo díez-Villanueva César Jiménez-Méndez Fernando Alfonso Cardiology department Hospital Universitario La PrincesaUniversidad Autónoma de MadridCIBER-CVMadridSpain

Heart failure(HF)is a clinical syndrome caused by structural and/or functional cardiac abnormalities,resulting in a reduced cardiac output and/or elevated intracardiac filling pressures at rest or during *** is a major public health problem with high prevalence and incidence,involving both high morbidity and mortality,but also high economic *** incidence of HF progressively increases with age,reaching around 20%among people over 75 years ***,HF represents the leading cause of hospitalization in patients older than 65 years in Western ***,some authors even consider HF a geriatric syndrome,entailing worse prognosis and high residual disability,and often associating some complex comorbidities,common in older population,that may further complicate the course of the *** the other hand,however,clinical course and prognosis may be often difficult to *** this article,main pathophysiological issues related to the aging heart are addressed,together with key aspects related to both diagnosis and prognosis in elderly patients with ***,main geriatric conditions,common in the elderly population,are reviewed,highlighting the importance of a comprehensive and multidisciplinary approach.

关键词： diagnosis elevated mortality

COVId-19 and Indirect Liver Injury:A Narrative Synthesis of the Evidence

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Journal of Clinical and Translational Hepatology 2021年第5期9卷 760-768页

作者： Francisco Idalsoaga Gustavo Ayares Juan pablo Arab Luis Antonio díaz departamento de Gastroenterología Escuela de MedicinaPontificia Universidad Católica de ChileSantiagoChile Centro de Envejecimiento y Regeneración(CARE) Facultad de Ciencias BiológicasPontificia Universidad Católica de ChileSantiagoChile

The liver is frequently affected by severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)*** most common manifestations are mildly elevated alanine aminotransferase and aspartate aminotransferase,with a prevalence of 16-53%among *** with severe coronavirus disease 2019(COVId-19)seem to have higher rates of acute liver dysfunction,and the presence of abnormal liver tests at admission signifies a higher risk of severe disease during *** with chronic liver diseases also have a higher risk of severe disease and mortality(mainly seen in patients with metabolic-associated fatty liver disease).Several pathways of damage have been proposed in the liver involvement of COVId-19 patients;although,the end-cause is most likely *** liver tests have been attributed to the expression of angiotensin-converting enzyme 2 receptors in SARS-CoV-2 *** enzyme is expressed widely in cholangiocytes and less in *** factors attributed to liver damage include drug-induced liver injury,uncontrolled release of proinflammatory molecules(“cytokine storm”),pneumonia-associated hypoxia,and direct damage by the *** steatosis,vascular thrombosis,fibrosis,and inflammatory features(including Kupffer cell hyperplasia)are the most common liver histopathological findings in deceased COVId-19 patients,suggesting important indirect mechanisms of liver *** this translational medicinebased narrative review,we summarize the current data on the possible indirect mechanisms involved in liver damage due to COVId-19,the histopathological findings,and the impact of these mechanisms in patients with chronic liver disease.

关键词： COVId-19 SARS-CoV-2 Liver hepatitis Liver injury Novel coronavirus

Weak Gravity Conjecture and extremal black holes

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Science China(Physics,Mechanics & Astronomy) 2019年第11期62卷 69-86页

作者： William Cottrell Gary Shiu pablo Soler department of Physics University of WisconsinMadison WI53706USA Institut fur Theoretische Physik Universitat HeidelbergPhilosophenweg19Heidelberg D-69120Germany

Motivated by the desire to improve our understanding of the Weak Gravity Conjecture, we compute the one-loop correction of charged particles to the geometry and entropy of extremal black holes in 4d. We use the entropy function formalism to extend previous analysis that dealt with neutral particles, and obtain the corrections to the horizon entropy for different regimes of black hole masses. These corrections are small in general. They are furthermore reduced when supersymmetry is present, and disappear in N = 4 supergravity. We provide some speculative arguments that in a theory with only sub-extremal particles, classical Reissner-Nordstrom black holes actually possess an infinite microcanonical entropy, though only a finite amount is visible to an external observer, as shown by the horizon entropy computation.

关键词： black holes string theory entropy