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Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

World Journal of Gastroenterology 2009年第9期15卷 1065-1071页

作者： Nora A mohamad Graciela P Cricco Lorena A Sambuco máximo Croci Vanina A medina Alicia S Gutiérrez rosa m bergoc Elena S Rivera Gabriela A martín Laboratory of Radioisotopes School of Pharmacy and BiochemistryUniversity of Buenos AiresJunín 954 (C1113AAB)Buenos AiresArgentina Institute of Immunooncology Dr. Ernesto Crescenti Av. Córdoba 3200 (C1187AAS)Buenos AiresArgentina National Research Council (CONICET) Av. Rivadavia 1917 (C1033AAJ)Buenos AiresArgentina

AIm:To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation,apoptosis,redox status and vascularization.mETHODS:Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups:control and aminoguanidine treated. Tumor growth,survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS),catalase,copper-zinc superoxide dismutase (CuZnSOD),manganese superoxide dismutase (mnSOD) and glutathione peroxidase (GPx). Finally,vascularization was determined by massons trichromic staining,and by VEGF and CD34 expression.RESULTS:Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P median survival of AG mice was significantly greater than control animals (P molateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells,intratumoral vascularization (trichromic stain) and the expression of Ki-67,Bax,eNOS,CD34,VEGF,catalase,CuZnSOD and mnSOD were diminished in AG treated mice (P moral action of aminoguanidine is associated with decreased cell proliferation,reduced angiogenesis,and reduced expression of antioxidant enzymes.

关键词：细胞生长氨基胍癌肿瘤胰腺癌内皮型一氧化氮合酶铜锌超氧化物歧化酶转移血管内皮生长因子

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Rheological and stability analysis of cement pastes incorporating silica-based wastes

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Particuology 2024年第6期89卷 144-152页

作者： Julia da rosa martins Janaíde Cavalcante Rocha Dachamir Hotza Luciano Senff Graduate Program in materials Science and Engineering(PPGmAT) Federal University of Santa Catarina(UFSC)Florianópolis88040-900SCBrazil Graduate Program in Civil Engineering(PPGEC) Federal University of Santa Catarina(UFSC)Florianópolis88040-900SCBrazil Graduate Program in Chemical Engineering(POSENQ) Federal University of Santa Catarina(UFSC)Florianópolis88040-900SCBrazil Department of mobility Engineering Federal University of Santa Catarina(UFSC)Joinville89219-600SCBrazil

This study investigates the influence of waste characteristics,especially zeta potential,on the properties of cement pastes and solutions.The focus is to evaluate the impact of the zeta potential of cement particles and waste materials on the sedimentation speed,rheology,and hardening time of stabilized cement pastes.Portland Cement II F 40,retarder additive,silica,and fly ash were used in the research.The pastes were prepared,and during the stabilization period,their rheological properties and pH were evaluated.The zeta potential and sedimentation speed of the cement and waste particles were measured at the pH that the pastes presented during the entire stabilization period.After the stabilization period,the pastes were subjected to the hardening time test.The zeta potential analyses revealed diverse values for the different powder types,with the cement particles exhibiting a zeta potential of−3.0 mV,the silica particles exhibiting−10.5 mV,and the fly ash particles exhibiting−20.3 mV.The influence of the high zeta potential modulus was observed on the sedimentation speed,with the solution containing fly ash exhibiting a speed of 40.01μm/s,whereas the solution containing only cement exhibited a speed of 99.38μm/s.In the pastes,the results indicate that the presence of fly ash particles with a significantly negative zeta potential led to a 16%reduction in hardening time compared to particles with a lower modulus of zeta potential.Rheometry tests showed that the inclusion of fly ash particles prevented the formation of agglomerates.Although the zeta potential influenced agglomerate formation and hardening time,it was found to have no effect on yield stress or viscosity.

关键词： Wastes Zeta potential Setting time Rheometry

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Hypothalamic circuits and aging:keeping the circadian clock updated

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Neural Regeneration Research 2024年第9期19卷 1919-1928页

作者： rosa Vázquez-Lizarraga Lucia mendoza-Viveros Carolina Cid-Castro Sareni Ruiz-montoya Erick Carreño-Vázquez Ricardo Orozco-Solis Instituto Nacional de medicina Genómica(INmEGEN) México CityMéxico Centro de Investigacíon sobre el Envejecimiento Centro de Investigacíon y de Estudios Avanzados(CIE-CINVESTAV)México CityMéxico Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México UNAMMéxico CityMéxico

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

关键词： aging astrocytes cellular stress responses circadian clock hypothalamus intranasal drug administration metabolic control nutrient sensor SIRT1 sleep homeostasis

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Dietary(poly)phenol intake is associated with cardiometabolic health parameters in adolescents

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Food Science and Human Wellness 2024年

作者： Emily P.Laveriano-Santos Sara Castro-Barquero Camila Arancibia-Riveros Ana maría Ruiz-León rosa Casas Ramón Estruch Patricia Bodega mercedes de miguel Amaya de Cos-Gandoy Jesús martínez-Gómez Gloria Santos-Beneit Juan m.Fernández-Alvira Rodrigo Fernández-Jiménez rosa m.Lamuela-Raventós Anna Tresserra-Rimbau The Zena and michael A.Wiener Cardiovascular Institute Icahn School of medicine at mount Sinai Department de Nutrició Ciències de l'Alimentació I Gastronomia XIA Facultat de Farmàcia i Ciències de l'alimentació Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB) Universitat de Barcelona Department of Internal medicine Hospital Clínic Institutd'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) University of Barcelona Consorcio CIBER m.P.Fisiopatología de la Obesidad y Nutrición (CIBERObn) Instituto de Salud Carlos III (ISCIII) mediterranean Diet Foundation 5. Foundation for Science Health and Education (SHE) 6. Centro Nacional de Investigaciones Cardiovasculares (CNIC) CIBER de Enfermedades Cardiovasculares (CIBERCV) 9. Hospital Universitario Clínico San Carlos

Background: The protective role of (poly)phenols against metabolic disorders has been extensively studied in adults but not in adolescents.Objective: To assess associations of dietary (poly)phenols and their subclasses with cardiometabolic health parameters in adolescents. methods: A cross-sectional study was conducted in 944 individuals aged 11 to 14 years enrolled in the SI! Program for Secondary Schools trial (NCT03504059). (Poly)phenol intake was assessed using semi-quantitative food frequency questionnaires and the Phenol-Explorer database. The measured cardiometabolic parameters were waist circumference (WC) age-sex z-score， blood pressure (BP) age-sex z-score， blood glucose (BG)， triglycerides (TG)， and high-density lipoprotein cholesterol (HDL-c). multilevel mixed-effect linear regression models were applied to examine the association between (poly)phenol quintiles and cardiometabolic health parameters.Results: Compared to the lowest quintile， adolescents in the highest quintile of total (poly)phenol intake had lower WC z-scores (β=-0.09， 95%CI=-0.09;-0.08， P-for trend=0.002)， mean arterial pressure z-scores (β =-0.11， 95%CI=-0.12;-0.09， P-for trend=0.206)， and HDL-c (β=-1.52， 95%CI=-2.90;-0.14， P-for trend=0.108)， after multivariable adjustment. The WC z-scores (β=-0.11， 95%CI=-0.19;-0.03， P-for trend=0.013) and HDL-c (β=-2.16， 95%CI=-3.78;-0.53， P-for trend=0.046) were lower in the highest quintile of flavonoid intake compared to the lowest quintile. The highest quintile of phenolic acid intake was associated with a lower WC z-score (β=-0.14， 95%CI=-0.26;-0.02， P-for trend=0.011) and TG levels (β=-8.83， 95%CI=-12.37;-5.30， P-for trend mpared to the lowest quintile. Conclusion: A higher intake of (poly)phenols， especially flavonoids， phenolic acids， and stilbenes

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Histopathological impact of SARS-CoV-2 on the liver:Cellular damage and long-term complications

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World Journal of Gastroenterology 2024年第22期30卷 2866-2880页

作者： Alfonso Rodriguez-Espada moises Salgado-de la mora Briana mariette Rodriguez-Paniagua Nathaly Limonde la rosa monica Itzel martinez-Gutierrez Santiago Pastrana-Brandes Nalu Navarro-Alvarez Department of molecular Biology Universidad Panamericana School of MedicineCampus MéxicoMexico 03920Mexico Department of Internal medicine Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico 14080Mexico Department of Surgery University of Colorado Anschutz Medical CampusDenverCO 80045United States PECEm Facultad de MedicinaUniversidad Nacional Autónoma de MéxicoMexico 04360Mexico Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico 14080Mexico

Coronavirus disease 2019(COVID-19),caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome,multiple organ failure,and death.Despite extensive studies on the pathogenicity of SARS-CoV-2,its impact on the hepatobiliary system remains unclear.While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels,the exact source of this damage is not fully understood.Proposed mechanisms for injury include direct cytotoxicity,collateral damage from inflammation,drug-induced liver injury,and ischemia/hypoxia.However,evidence often relies on blood tests with liver enzyme abnormalities.In this comprehensive review,we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients,drawing from liver biopsies,complete autopsies,and in vitro liver analyses.We present evidence of the direct impact of SARS-CoV-2 on the liver,substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes,including mitochondrial swelling,endoplasmic reticulum dilatation,and hepatocyte apoptosis.Additional ly,we describe the diverse liver pathology observed during COVID-19 infection,encompassing necrosis,steatosis,cholestasis,and lobular inflammation.We also discuss the emergence of long-term complications,notably COVID-19-related secondary sclerosing cholangitis.Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

关键词： Liver SARS-CoV-2 COVID-19 Angiotensin-converting enzyme 2 Histopathology Liver biopsies Liver autopsy In vitro

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Anomalous negative magnetoresistance in quantum dot Josephson junctions with Kondo correlations

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Science China(Physics,mechanics & Astronomy) 2024年第8期Mechanics & Astronomy) .卷 7-17页

作者： mingtang Deng Chunlin Yu Guangyao Huang rosa López Philippe Caroff Sepideh Ghalamestani Gloria Platero Hongqi Xu Institute for Quantum Information & State Key Laboratory of High Performance Computing College of Computer Science and TechnologyNational University of Defense Technology NanoLund and Division of Solid State Physics Lund University Hefei National Laboratory China Greatwall Quantum Laboratory Institut de Física Interdisciplinària i de Sistemes Complexos IFISC Instituto de Ciencia de materiales de madrid Beijing Key Laboratory of Quantum Devices Key Laboratory for the Physics and Chemistry of Nanodevicesand Department of ElectronicsPeking University Beijing Academy of Quantum Information Sciences

The interplay between superconductivity and the Kondo effect has stimulated significant interest in condensed matter physics.They compete when their critical temperatures are close and can give rise to a quantum phase transition that can mimic majorana zero modes. Here, we have fabricated and measured Al-InSb nanowire quantum dot-Al devices. In the Kondo regime, a supercurrent-induced zero-bias conductance peak emerges. This zero-bias peak shows an anomalous negative magnetoresistance(NmR) at weak magnetic fields. We attribute this anomalous NmR to quasiparticle trapping at vortices in the superconductor leads as a weak magnetic field is applied. The trapping effect lowers the quasiparticle-caused dissipation and thus enhances the Josephson current. This work connects the vortex physics and the supercurrent tunneling in Kondo regimes and can help further understand the physics of Josephson quantum dot system.

关键词： quantum dot Kondo correlation InSb nanowire quasiparticle trapping

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microbial phenolic metabolites are associated with better frontal lobe cognition

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Food Science and Human Wellness 2024年

作者： Inés Domínguez-López Isabella Parilli-moser Anna Vallverdú-Queralt Anna Tresserra-Rimbau Cinta Valls-Pedret Zenaida Vázquez-Ruiz Olga Casta?er Ramon Estruch Emili Ros rosa m.Lamuela-Raventós Lipid Clinic Endocrinology and Nutrition Service Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic 08036 Barcelona Spain Unit of Cardiovascular Risk and Nutrition Institut Hospital del mar de Investigaciones médicas (ImIm) Department of Preventive medicine and Public Health University of Navarra Departament de Nutrició Ciències de l'Alimentació i Gastronomía Facultat de Farmacia Universitat de Barcelon (UB) Av.de Joan XXII Department of Endocrinology Hospital Clinic IDIBAPS Barcelona Spain Department of Internal medicine Hospital Clinic Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS) University of Barcelona CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Institut de Nutrició i Seguretat Alimentària (INSA) Universitat de Barcelona (UB)

With increasing life expectancy， neurodegenerative diseases have become one of the leading causes of ill-health in the elderly. Preventive strategies include following healthy diets， such as the mediterranean diet， which is particularly rich in polyphenols， bioactive compounds with neuroprotective properties. The aim of this study was to assess the association of microbial phenolic metabolites (mPm) with cognition. This cross-sectional analysis was performed with 200 participants of the PREDImED trial (Barcelona-Clinic recruitment center). A novel method based on liquid chromatography coupled to mass spectrometry was used to identify urinary mPm (protocatechuic acid， enterodiol glucuronide， enterolactone glucuronide， urolithin B glucuronide， and vanillic acid glucuronide)， and cognitive function was evaluated with neuropsychological tests. multivariable-adjusted ordinary least squares regression was used to assess the associations between cognitive function and mPm， and a score was calculated as the weighted sum of mPm. A higher mPm score was associated with better frontal lobe function. Among individual metabolites， vanillic acid glucuronide was correlated with frontal cognitive performance. Participants with higher concentrations of vanillic acid glucuronide and urolithin B glucuronide obtained better scores in the Color Trail Test part 2. A higher score for urinary multi-mPm was associated with better frontal cognitive performance in an older mediterranean population.

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Superior antibody and membrane protein‑specific T‑cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents

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World Journal of Pediatrics 2024年第4期20卷 353-370页

作者： Jaime S.rosa Duque Samuel m.S.Cheng Carolyn A.Cohen Daniel Leung Xiwei Wang Xiaofeng mu Yuet Chung Tsun ming Lau manni Wang Wenyue Zhang Yanmei Zhang Howard H.W.Wong Leo C.H.Tsang Sara Chaothai Tsz Chun Kwan John K.C.Li Karl C.K.Chan Leo L.H.Luk Jenson C.H.Ho Wing Yan Li Amos m.T.Lee Jennifer H.Y.Lam Sau man Chan Wilfred H.S.Wong Issan Y.S.Tam masashi mori Sophie A.Valkenburg malik Peiris Wenwei Tu Yu Lung Lau Department of Paediatrics and Adolescent medicine The University of Hong KongHong KongChina School of Public Health The University of Hong KongHong KongChina HKU‑Pasteur Research Pole School of Public HealthThe University of Hong KongHong KongChina Research Institute for Bioresources and Biotechnology Ishikawa Prefectural UniversityNonoichiJapan Department of microbiology and Immunology Peter Doherty Institute for Infectionand ImmunityUniversity of MelbourneMelbourneVICAustralia Center for Immunology and Infection C2i Hong KongChina

Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(Im)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is unknown.This study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over Im administration in adolescents.methods Participants aged 11–17 years received two doses of Im or ID vaccine,followed by the 3rd dose 13–42 days later.Humoral and cellular immunogenicity outcomes were measured post-dose 2(Im-CC versus ID-CC)and post-dose 3(ImCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,respectively.Results Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNm[sum of individual(S),nucleocapsid protein(N),and membrane protein(m)peptide pool]-specific interleukin-2(IL-2)+CD4+,SNm-specific IL-2+CD8+,S-specific IL-2+CD8+,N-specific IL-2+CD4+,N-specific IL-2+CD8+and m-specific IL-2+CD4+responses fulfilled the superior and non-inferior criteria for ID-CC compared to Im-CC,whereas IgG avidity was inferior.For ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,m-specific IL-2+CD4+,interferon-γ+CD8+and IL-2+CD8+responses were superior and non-inferior to Im-CCC.The estimated vaccine efficacies were 49%,52%,66%and 79%for Im-CC,ID-CC,Im-CCC and ID-CCC,respectively.The ID groups reported more local,mild adverse reactions.Conclusion This is the first study to demonstrate superior antibody and m-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.

关键词： CoronaVac Coronavirus disease 2019 Immunity Intradermal Vaccine

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Concerns about the application of resistance exercise with blood-flow restriction and thrombosis risk in hemodialysis patients

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Journal of Sport and Health Science 2024年第4期13卷 548-558,F0003页

作者： Hugo de Luca Correa Lysleine Alves Deus Dahan da Cunha Nascimento Nicholas Rolnick Rodrigo Vanerson Passos Neves Andrea Lucena Reis Thais Branquinho de Araujo Carmen Tzanno-martins Fernanda Silveira Tavares Luiz Sinesio Silva Neto Claudio Avelino Rodrigues Santos Paolo Lucas Rodrigues-Silva Fernando Honorato Souza Vitoria marra da motta Vilalva mestrinho Rafael Lavarini dos Santos rosangela Vieira Andrade Jonato Prestes Thiago dos Santos rosa Post-graduate Program of Physical Education Catholic University of BrasıliaBrasılia 71966-700Brazil The Human Performance mechanic Lehman CollegeNew YorkNY 10011USA Clinical Group Home Dialysis Center and RenalClass Sao Paulo 01239-040Brazil Department of medicine Catholic University of BrasıliaBrasılia 71966-700Brazil Faculty of medicine Federal University of TocantinsTocantins 77001-090Brazil Embrapa Genetic Resources and Biotechnology Brasılia 70770-917Brazil Graduate Program of Genomic Sciences and Biotechnology Brasılia 71966-700Brazil

Background:Hemodialysis(HD) per se is a risk factor for thrombosis.Considering the growing body of evidence on blood-flow restriction(BFR) exercise in HD patients,identification of possible risk factors related to the prothrombotic agent D-dimer is required for the safety and feasibility of this training model.The aim of the present study was to identify risk factors associated with higher D-dimer levels and to determine the acute effect of resistance exercise(RE) with BFR on this molecule.methods:Two hundred and six HD patients volunteered for this study(all with a glomerular filtration rate of mL/min/1.73 m2).The RE+BFR session consisted of 50% arterial occlusion pressure during 50 min sessions of HD(intradialytic exercise).RE repetitions included concentric and eccentric lifting phases(each lasting 2 s) and were supervised by a strength and conditioning specialist.Results:Several variables were associated with elevated levels of D-dimer,including higher blood glucose,citrate use,recent cardiovascular events,recent intercurrents,higher inflammatory status,catheter as vascular access,older patients(>70 years old),and HD vintage.Furthermore,RE+BFR significantly increases D-dimer after 4 h.Patients with borderline baseline D-dimer levels(400-490 ng/mL) displayed increased risk of elevating D-dimer over the normal range(≥500 ng/mL).Conclusion:These results identified factors associated with a heightened prothrombotic state and may assist in the screening process for HD patients who wish to undergo RE+BFR.D-dimer and/or other fibrinolysis factors should be assessed at baseline and throughout the protocol as a precautionary measure to maximize safety during RE+BFR.

关键词： Blood-flow restriction Chronic kidney disease Coagulation Hemodialysis Vascular occlusion exercises

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Role of vascular endothelial growth factor as a critical neurotrophic factor for the survival and physiology of motoneurons

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Neural Regeneration Research 2023年第8期18卷 1691-1696页

作者： Paula m.Calvo Rosendo G.Hernández rosa R.de la Cruz Angel m.Pastor Departamento de Fisiología Facultad de BiologíaUniversidad de SevillaSevillaSpain

Vascular endothelial growth factor(VEGF)was discovered by its angiogenic activity.However,during evolution,it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrates lacking a circulatory system.We aimed at reviewing recent evidence indicating that VEGF has neuroprotective effects in neurons exposed to a variety of insults.Of particular interest is the link established between VEGF and motoneurons,especially after the design of the VEGFδ/δmutant mice.These mice are characterized by low levels of VEGF and develop muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis.The administration of VEGF through several routes to animal models of amyotrophic lateral sclerosis delays motor impairment and motoneuron degeneration and increases life expectancy.There are new recent advances in the role of VEGF in the physiology of motoneurons.Our experimental aims use the extraocular(abducens)motoneurons lesioned by axotomy as a model for studying VEGF actions.Axotomized abducens motoneurons exhibit severe alterations in their discharge activity and a loss of synaptic boutons.The exogenous administration of VEGF to axotomized abducens motoneurons,either from the transected nerve or intraventricularly,fully restores the synaptic and discharge properties of abducens motoneurons,despite being axotomized.In addition,when an anti-VEGF neutralizing antibody is delivered from the muscle to intact,uninjured abducens motoneurons,these cells display alterations in their discharge pattern and a loss of synaptic boutons that resemble the state of axotomy.All these data indicate that VEGF is an essential neurotrophic factor for motoneurons.

关键词： abducens nucleus amyotrophic lateral sclerosis cell death extracellular single-unit recordings eye movements neurodegeneration oculomotor trophic factors

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