No description available.

Au décours d'une première embolie pulmonaire (EP), certains patients présentent un syndrome post EP : un tiers des patients ont une obstruction persistante de la vascularisation pulmonaire, associée à la persistance d'une dyspnée et une limitation des performances à l'effort. Certains patients présenteront une récidive d'EP ou, plus rarement, une hypertension pulmonaire, dont les séquelles perfusionnelles sont un critère diagnostique indispensable. Le rôle et la physiopathologie des séquelles perfusionnelles au cours du syndrome post EP est incomprise. Ce travail a mis en évidence l'existence d'un risque majoré de récidive d'EP (odds ratio 1,9) chez les patients présentant des séquelles perfusionnelles >10% à la vascularisation pulmonaire. L'analyse des propriétés fonctionnelles du fibrinogène purifié à partir du plasma de patients suivis pour une première EP améliore la prédiction de séquelles perfusionnelles confirmant le rôle clé de celui-ci dans la physiopathologie de la maladie. Ainsi, une forte proportion de chaine Bβ porteuse d'un seul résidu acide sialique majore le risque de séquelles. L'étude des cellules endothéliales circulantes à la phase aigüe et après une EP montre que les patients qui développeront des séquelles mobilisent peu de cellules endothéliales, témoignant d'une forte altération des processus de réparation de l'endothélium pulmonaire. L'interaction de la fibrine avec les progéniteurs endothéliaux dans cette anomalie de la régulation est possible : les progéniteurs expriment le récepteur VLDLr dont l'épitope β15-42 de la fibrine est un ligand impliqué dans la régulation du cycle cellulaire et l'inhibition de l'angiogenèse. / Pulmonary vascular sequels after pulmonary embolism: prognosis, prediction and physiopathologyAbstract: Post Pulmonary Embolism (PE) syndrome is not rare after PE: one third of the patients presents residual pulmonary vascular obstruction (RPVO) traducing sequels associated with increased dyspnea and impaired exercise capacity. Some of these patients will suffer PE recurrence or, more rarely, chronic thromboembolic pulmonary hypertension, whose one the diagnosis criteria is persistent perfusion defect. Prognosis value and mechanisms underlying vascular sequels are still unclear. The present work shows that RPVO > 10% after a first PE is associated with an increased risk for venous thromboembolism recurrence (odds ratio 1.9). Secondly, fibrinogen properties were investigated in PE patients. Patients with RPVO >10% presented more monosialiated Bβchain form. Prediction models for RPVO that include fibrinogen analysis were more accurate than those without fibrinogen data; This results highlights the key role of fibrin in the pathophysiology of chronic venous thromboembolism. Interestingly, the present work shows that patient who will present RPVO had an impaired endothelial cells mobilization. Compared to patients without RPVO, patients with RPVO had lower circulating endothelial cells at the acute phase of PE. This endothelial dysfunction is probably triggered by endothelial progenitors that expressed the very low density lipoprotein receptor (VLDLr), implicated in the inhibition of angiogenesis and able to bind the β15-42 N terminal sequence of the fibrin Bβ chain.

Introduction: The high transmissibility and lethality of the novel coronavirus SARS-CoV-2 (COVID-19) have been catastrophic. Acute kidney injury (AKI) is one of the frequent complications in patients with respiratory insufficiency caused by the virus. The pathogenic mechanism is based on the binding of its S-proteins to the angiotensin-converting enzyme (ACE) receptors, which will trigger a cellular damage. A podocyte and tubular compromise are found in the kidneys which can lead to tubular necrosis and the consequent AKI. Objectives: The objective of this report is to identify the main risk factor to develop AKI in patients infected with SARS-CoV-2 with critical acute respiratory distress. Patients and Methods: We performed this report study, collecting data from 48 ICU patients. Data from 13 of them who developed AKI and needed renal replacement therapy (RRT)were analyzed. Clinical characteristics and laboratory findings were reported using STATA 10.0. Results: AKI was present in 27.08% of patients, mostly male (92.3%) with a mean age of 63.8 years old. Hypertension, diabetes and obesity were the main comorbidities in those patients. Additionally, the meantime between admission and AKI diagnosis was 2.69 days. All patients showed fibrinogen, D-dimer, ALT and values above normal range. Mortality was seen in 61.5% of patients. Conclusion: This report tries to show AKI as an important clinical manifestation in critically ill patients infected with SARS-CoV-2, with high mortality. Further studies are needed to demonstrate if there are independent risk factors. / Revisión por pares

Indiana University-Purdue University Indianapolis (IUPUI) / Large protein molecules are abundant in biological cells but are very difficult to study in physiological conditions due to molecular disorder. For large proteins, most structural information is obtained in crystalline states which can be achieved in certain conditions at very low temperature. X-ray and neutron crystallography methods can then be used for determination of crystalline structures at atomic level. However, in solution at room or physiological temperatures such highly resolved descriptions cannot be obtained except in very few cases. Scattering methods that can be used to study this type of structures at room temperature include small-angle x-ray and neutron scattering. These methods are used here to study two distinct proteins that are both classified as glycoproteins, which are a large class of proteins with diverse biological functions. In this study, two specific plasma glycoproteins were used: Fibrinogen (340 kDa) and Alpha 1-Antitrypsin or A1AT (52 kDa). These proteins have been chosen based on the fact that they have a propensity to form very large molecular aggregates due to their tendency to polymerize. One goal of this project is to show that for such complex structures, a combination of scattering methods that include SAXS, SANS, and DLS can address important structural and interaction questions despite the fact that atomic resolution cannot be obtained as in crystallography. A1AT protein has been shown to have protective roles of lung cells against emphysema, while fibrinogen is a major factor in the blood clotting process. A systematic approach to study these proteins interactions with lipid membranes and other proteins, using contrast-matching small-angle neutron scattering (SANS), small angle x-ray scattering (SAXS) and dynamic light scattering (DLS), is presented here. A series of structural reference points for each protein in solution were determined by performing measurements under osmotic stress controlled by the addition of polyethylene glycol-1,500 MW (PEG 1500) in the samples. Osmotic pressure changes the free energy of the molecular mixture and has consequences on the structure and the interaction of molecular aggregates. In particular, the measured radius of gyration (Rg) for A1AT shows a sharp structural transition when the concentration of PEG 1500 is between 33 wt% and 36 wt%. Similarly, a significant structural change was observed for fibrinogen when the concentration of PEG 1500 was above 40 wt%. This analysis is applied to a study of A1AT interacting with lipid membranes and to a study of fibrinogen polymerization in the presence of the enzyme thrombin, which catalyzes the formation of blood clots. The experimental approach presented here and the applications to specific questions show that an appropriate combination of scattering methods can produce useful information on the behavior and the interactions of large protein systems in physiological conditions despite the lower resolution compared to crystallography.

No description available.

Introdução: A terapia antirretroviral (ART) mudou o curso da Aids, porém está associada a alterações metabólicas e aumento do risco de doenças cardiovasculares. Objetivo: Avaliar o efeito da suplementação com ácidos graxos ômega-3 de origem marinha no perfil lipídico, na homeostase da glicose, na distribuição de gordura corporal e nos marcadores inflamatórios de adultos com HIV em ART. Métodos: Artigo 1. Trata-se de uma revisão sistemática da literatura com metanálise. Realizou-se busca por ensaios clínicos na base de dados PubMed; 33 artigos foram localizados, seis cumpriram os critérios de inclusão e quatro apresentavam qualidade metodológica adequada. Foi realizada metanálise com efeitos fixos e descrição das diferenças de médias sumárias (DMS (IC95 por cento )). Artigos 2 e 3. Trata-se de um ensaio clínico aleatorizado e controlado. Foram recrutados 120 adultos com idade entre 19 e 64 anos, de ambos os sexos. Os indivíduos alocados no grupo intervenção foram suplementados por 24 semanas com 3g de óleo de peixe/dia (900mg de ácidos graxos ômega-3) e indivíduos alocados no grupo controle receberam placebo (óleo de soja). Resultados: Artigo 1. Após 8-16 semanas de intervenção com 900-3360mg de ácidos graxos ômega-3/dia, observou-se redução de -80,34mg/dL (IC 95 por cento : -129,08 a -31,60) nas concentrações de triglicérides. A análise agregada de estudos com média de concentração de triglicérides > 300mg/dL no baseline e intervenção com 1800-2900mg de ácidos graxos ômega-3/dia resultou em redução de -129,72mg/dL (IC95 por cento : -206,54 a -52,91). Artigos 2 e 3. Foram considerados nas análises dados de 83 sujeitos. Os modelos multinível não revelaram relação estatisticamente significante entre a suplementação com óleo de peixe e as mudanças longitudinais nas concentrações de triglicérides (p=0,335), LDL-C (p= 0,078), HDL-C (p=0,383), colesterol total (p=0,072), apo B (p=0,522), apo A1 (p=0,420), razão LDL-C/apo B (p=0,107), índice homa-2 IR (p=0,387), IMC (p=0,068), circunferência da cintura (p=0,128), relação cintura/quadril (p=0,359), PCR ultra sensível (p=0,918), fibrinogênio (p=0,148), e fator VIII (p=0,073). Conclusões: Artigo 1. Diferentes doses de ácidos graxos ômega-3 reduziram modo significativo as concentrações de triglicérides, confirmando a potencial aplicabilidade desse nutriente no tratamento da hipertrigliceridemia em pessoas que vivem com HIV em ART. Artigos 2 e 3. Uma dose relativamente baixa de óleo de peixe para pessoas que vivem com HIV em ART não alterou o perfil lipídico, a homeostase da glicose, a distribuição de gordura corporal e a concentração de marcadores inflamatórios. Recomenda-se, em estudos subseqüentes, a avaliação do efeito de doses mais elevadas, bem como a determinação de marcadores inflamatórios mais sensíveis / Background: Although the antiretroviral therapy (ART) revolutionized the care of HIV-infected subjects, it has been associated with metabolic abnormalities and increased risk of cardiovascular diseases. Aims: To review the effects of marine omega-3 fatty acids on lipid profile, insulin resistance and inflammatory markers in subjects living with HIV on ART. Methods: Paper 1. Thirty three articles were found in a PubMed search; six met the inclusion criteria; and four of them were considered of adequate quality and included. Meta-analysis with fixed effects was performed and weighted mean differences (WMD (95 per cent CI)) were described. Paper 2 and 3. The study was conducted in an HIV/Aids care centre affiliated to the Medical School, University of Sao Paulo. This was a randomized controlled trial that assessed the effects of 3g fish oil/day (900mg of omega-3 fatty acids) or 3g soy oil/day (placebo). A hundred and twenty subjects aged between 19 and 64 years were recruited. The statistical analyses were performed in Stata 9. Results: Paper 1. Data from 83 subjects were included in the analyses. The overall reduction on triglyceride concentrations after 8-16 weeks of treatment with 900-3360mg of omega-3/day was WMD=-80.34mg/dL (95 per cent CI: -129.08 to -31.60). The pooled result of studies with mean triglyceride > 300 mg/dL at baseline and 1800-2900mg omega-3/day was WMD=-129.72mg (95 per cent CI: -206.54 to -52.91). Paper 2 and 3. Multilevel analyses revealed no statistically significant relationships between fish oil supplementation and the longitudinal changes in triglyceride (p= 0.335), LDL-C (p= 0.078), HDL-C (p= 0.383), total cholesterol (p=0.072), apo B (p= 0.522), apo A1 (p=0.420), LDL-C/apo B ratio (p=0.107), homa-2 IR index (p=0.387), BMI (p=0.068), waist circumference (p=0.128), waist/hip ratio (p=0.359), hs-CRP (p=0.918), fibrinogen (p=0.148), and VIII factor (p=0.073). Conclusions: Paper 1. Different doses of omega-3 fatty acids reduced significantly triglyceride concentrations confirming the potential applicability of this nutrient on the management of hypertriglyceridemia in HIV-infected subjects on ART. Paper 2 and 3. A relatively low dose of fish oil for HIV subjects on ART did not change lipid profile, insulin resistance, body fat distribution, and inflammatory markers. Further investigations should considerer the assessment of higher doses and more sensitivity inflammatory markers

Evidências recentes sugerem que as doenças periodontais podem desempenhar um papel relevante na etiologia e patogênese de doenças cardiovasculares e hipertensão arterial. A resposta inflamatória, com conseqüente elevação de marcadores sistêmicos como proteína C-reativa, fibrinogênio e interleucina-6, e a disfunção endotelial, podem ser os responsáveis por essa associação. Alguns estudos têm relatado maiores níveis pressóricos, maior massa ventricular esquerda e disfunção endotelial em pacientes com doenças periodontais. Ao mesmo tempo, estudos clínicos vêm mostrando que a terapia periodontal pode levar à redução dos níveis plasmáticos dos marcadores de inflamação e redução do risco cardiovascular. O presente estudo teve como objetivo avaliar os efeitos da terapia periodontal não-cirúrgica em 26 pacientes (idade média de 53.68.0 anos) hipertensos refratários. Foram avaliados marcadores plasmáticos de inflamação (proteína C-reativa, fibrinogênio e interleucina-6), pressão arterial sistólica e diastólica, massa ventricular esquerda e rigidez arterial. A terapia periodontal foi eficaz na redução da média de todos os marcadores de risco cardiovascular avaliados. Os níveis de proteína C-reativa baixaram 0.7mg/dl 6 meses após a terapia periodontal, os de IL-6, 1.6pg/dl e os de fibrinogênio 55.3mg/dl (p<0.01). A pressão arterial sistólica apresentou redução média de 16.7mmHg e a diastólica de 9.6mmHg. A massa ventricular esquerda diminuiu em média 12.9g e a velocidade da onda de pulso, um marcador de rigidez arterial, e consequentemente de disfunção endotelial, apresentou redução de seus valores médios de 0.9m/s (p<0.01). Dessa forma, conclui-se que a terapia periodontal foi eficaz na redução dos níveis de proteína C-reativa, interleucina-6, fibrinogênio, pressão arterial, massa ventricular esquerda e rigidez arterial. / Recent evidences suggest that periodontal diseases may play a relevant role in the etiology and pathogenesis of cardiovascular diseases and hypertension. The inflammatory response, and the consequent elevation of systemic markers such as C-reactive protein, fibrinogen and interleukin-6, and endothelial dysfunction, may be responsible for this association. Some studies have reported higher blood pressure levels, left ventricle mass and endothelial dysfunction in patients presenting periodontal diseases. At the same time, clinical trials have been showing that periodontal therapy can lead to the reduction of plasmatic levels of inflammatory markers and reduction of the cardiovascular risk. The present study aims to evaluate the effects of non-surgical periodontal therapy in 26 patients (mean age: 53.68.0 years old) diagnosed as having refractory hypertension. The study measured plasmatic markers of inflammation (C-reactive protein, fibrinogen and interleukin-6), systolic and diastolic blood pressure, left ventricle mass and arterial stiffness. Periodontal therapy was effective in reducing all cardiovascular risk markers evaluated. The levels of C-reactive protein lowered 0.7mg/dl 6 months after periodontal therapy, the IL-6 levels, 1.6pg/dl and fibrinogen levels 55.3mg/dl (p<0.01). Systolic blood pressure lowered 16.7mmHg and diastolic 9.6mmHg (means). Left ventricle mass lowered 12.9g (means) and pulse wave velocity, a marker of arterial stiffness, and consequently endothelial dysfunction, presented reduction of 0.9m/s (means) (p<0.01). So, the study conclusion is that periodontal therapy was effective in reducing levels of C-reactive protein, interleukin-6, fibrinogen, blood pressure, left ventricle mass and arterial stiffness.

Introdução: A terapia antirretroviral (ART) mudou o curso da Aids, porém está associada a alterações metabólicas e aumento do risco de doenças cardiovasculares. Objetivo: Avaliar o efeito da suplementação com ácidos graxos ômega-3 de origem marinha no perfil lipídico, na homeostase da glicose, na distribuição de gordura corporal e nos marcadores inflamatórios de adultos com HIV em ART. Métodos: Artigo 1. Trata-se de uma revisão sistemática da literatura com metanálise. Realizou-se busca por ensaios clínicos na base de dados PubMed; 33 artigos foram localizados, seis cumpriram os critérios de inclusão e quatro apresentavam qualidade metodológica adequada. Foi realizada metanálise com efeitos fixos e descrição das diferenças de médias sumárias (DMS (IC95 por cento )). Artigos 2 e 3. Trata-se de um ensaio clínico aleatorizado e controlado. Foram recrutados 120 adultos com idade entre 19 e 64 anos, de ambos os sexos. Os indivíduos alocados no grupo intervenção foram suplementados por 24 semanas com 3g de óleo de peixe/dia (900mg de ácidos graxos ômega-3) e indivíduos alocados no grupo controle receberam placebo (óleo de soja). Resultados: Artigo 1. Após 8-16 semanas de intervenção com 900-3360mg de ácidos graxos ômega-3/dia, observou-se redução de -80,34mg/dL (IC 95 por cento : -129,08 a -31,60) nas concentrações de triglicérides. A análise agregada de estudos com média de concentração de triglicérides > 300mg/dL no baseline e intervenção com 1800-2900mg de ácidos graxos ômega-3/dia resultou em redução de -129,72mg/dL (IC95 por cento : -206,54 a -52,91). Artigos 2 e 3. Foram considerados nas análises dados de 83 sujeitos. Os modelos multinível não revelaram relação estatisticamente significante entre a suplementação com óleo de peixe e as mudanças longitudinais nas concentrações de triglicérides (p=0,335), LDL-C (p= 0,078), HDL-C (p=0,383), colesterol total (p=0,072), apo B (p=0,522), apo A1 (p=0,420), razão LDL-C/apo B (p=0,107), índice homa-2 IR (p=0,387), IMC (p=0,068), circunferência da cintura (p=0,128), relação cintura/quadril (p=0,359), PCR ultra sensível (p=0,918), fibrinogênio (p=0,148), e fator VIII (p=0,073). Conclusões: Artigo 1. Diferentes doses de ácidos graxos ômega-3 reduziram modo significativo as concentrações de triglicérides, confirmando a potencial aplicabilidade desse nutriente no tratamento da hipertrigliceridemia em pessoas que vivem com HIV em ART. Artigos 2 e 3. Uma dose relativamente baixa de óleo de peixe para pessoas que vivem com HIV em ART não alterou o perfil lipídico, a homeostase da glicose, a distribuição de gordura corporal e a concentração de marcadores inflamatórios. Recomenda-se, em estudos subseqüentes, a avaliação do efeito de doses mais elevadas, bem como a determinação de marcadores inflamatórios mais sensíveis / Background: Although the antiretroviral therapy (ART) revolutionized the care of HIV-infected subjects, it has been associated with metabolic abnormalities and increased risk of cardiovascular diseases. Aims: To review the effects of marine omega-3 fatty acids on lipid profile, insulin resistance and inflammatory markers in subjects living with HIV on ART. Methods: Paper 1. Thirty three articles were found in a PubMed search; six met the inclusion criteria; and four of them were considered of adequate quality and included. Meta-analysis with fixed effects was performed and weighted mean differences (WMD (95 per cent CI)) were described. Paper 2 and 3. The study was conducted in an HIV/Aids care centre affiliated to the Medical School, University of Sao Paulo. This was a randomized controlled trial that assessed the effects of 3g fish oil/day (900mg of omega-3 fatty acids) or 3g soy oil/day (placebo). A hundred and twenty subjects aged between 19 and 64 years were recruited. The statistical analyses were performed in Stata 9. Results: Paper 1. Data from 83 subjects were included in the analyses. The overall reduction on triglyceride concentrations after 8-16 weeks of treatment with 900-3360mg of omega-3/day was WMD=-80.34mg/dL (95 per cent CI: -129.08 to -31.60). The pooled result of studies with mean triglyceride > 300 mg/dL at baseline and 1800-2900mg omega-3/day was WMD=-129.72mg (95 per cent CI: -206.54 to -52.91). Paper 2 and 3. Multilevel analyses revealed no statistically significant relationships between fish oil supplementation and the longitudinal changes in triglyceride (p= 0.335), LDL-C (p= 0.078), HDL-C (p= 0.383), total cholesterol (p=0.072), apo B (p= 0.522), apo A1 (p=0.420), LDL-C/apo B ratio (p=0.107), homa-2 IR index (p=0.387), BMI (p=0.068), waist circumference (p=0.128), waist/hip ratio (p=0.359), hs-CRP (p=0.918), fibrinogen (p=0.148), and VIII factor (p=0.073). Conclusions: Paper 1. Different doses of omega-3 fatty acids reduced significantly triglyceride concentrations confirming the potential applicability of this nutrient on the management of hypertriglyceridemia in HIV-infected subjects on ART. Paper 2 and 3. A relatively low dose of fish oil for HIV subjects on ART did not change lipid profile, insulin resistance, body fat distribution, and inflammatory markers. Further investigations should considerer the assessment of higher doses and more sensitivity inflammatory markers

La dynamique co-évolutive qui joue dans les systèmes hôte-parasite conduit à une véritable course aux armements entre les deux protagonistes qui se traduit, dans certaines interactions comme celle qui est traitée dans cette thèse, par un polymorphisme de compatibilité dont les bases moléculaires sont méconnues. L'objectif de cette thèse était de progresser dans la connaissance des mécanismes moléculaires sous-jacents à ce polymorphisme de compatibilité dans l'interaction Biomphalaria glabrata/Schistosoma mansoni. Une approche protéomique comparative entre des souches de parasites compatibles et incompatibles nous a permis d'identifier des déterminants moléculaires clés de l'interaction exprimés par le parasite. Il s'agit d'une part de mucines hautement polymorphes potentiellement antigéniques, les "Schistosoma mansoni Polymorphic Mucin" (SmPoMucs), et d'autre part de molécules anti-oxydantes ("ROS scavengers"). Afin d'aborder la question de la course aux armements de manière complète, nous avons également recherché la "contre-partie moléculaire" exprimée par le mollusque et susceptible d'exprimer ce polymorphisme de compatibilité. Dans ce but, des approches de co-précipitation ont été menées. Elles ont permis de montrer que les SmPoMucs interagissaient avec des récepteurs immunitaires diversifiés du mollusque, les Fibrinogen-related Proteins (FREPs). Nous montrons ainsi pour la première fois dans une interaction parasite/hôte invertébré l'intervention d'un "système de type antigène-anticorps" impliquant un répertoire individuel polymorphe d'antigènes potentiels du parasite (les SmPoMucs) et un répertoire individuel diversifié de récepteurs immunitaires de son hôte (les FREPs). Nous avons également montré que le complexe immun formé par les deux dernières molécules citées incluait un troisième partenaire, une thioester-containing protein (TEP) qui appartient à une classe de molécules connue pour son rôle dans la fagocytose ou l'encapsulation. La présence de ce troisième partenaire au sein d'un même complexe renforce le rôle potentiellement immunitaire de ce complexe dans la reconnaissance et l'élimination du parasite. Au travers de cette thèse, nous nous sommes également intéressés à la course aux armements jouant sur les mécanismes effecteurs de l'immunité du mollusque. Dans notre modèle, les effecteurs responsables de la destruction du parasite sont principalement des espèces réactives de l'oxygène (ROS). Dans ce cas aussi, nous avons montré qu'il existe une concordance phénotypique entre la production de ROS par l'hôte et le niveau de "ROS scavengers" produits par le parasite pour contrecarrer la réaction de l'hôte. Ainsi, les mécanismes moléculaires responsables du polymorphisme de compatibilité dans l'interaction B. glabrata/S. mansoni s'appuieraient au moins sur deux facteurs d'une part sur la confrontation de répertoires de molécules polymorphes et/ou diversifiées en ce qui concerne les mécanismes de reconnaissance immunitaire, et d'autre part sur une adaptation réciproque quantitative en ce qui concerne certains mécanismes effecteurs de l'immunité.

Nitric oxide (NO) is a neurotransmitter involved in memory processes. Currently, the only recognized physiological signalling pathway controlled by NO is the activation of guanylyl cyclase. In this thesis, we propose an alternative NO-signalling pathway that involves the Heme-regulated eukaryotic initiation factor-2a kinase (HRI) and eIF2a phosphorylation. We have found that the enzyme BACE1, a key protein in Alzheimer’s disease (AD), is controlled by this novel pathway. This pathway would be involved in the physiology of memory formation and learning processes. We have also studied how an external stress factor, the Herpes Simplex Virus 1, can disrupt this cascade leading to a pathological increase in BACE1 and amyloid ß-peptide (Aß) production. Aß aggregates forming fibrils that generate free radicals. These react with NO producing peroxynitrite, which contribute to AD progression. Since NO turns toxic when produced in a pro-oxidant environment we have also studied the effect of peroxynitrite in Stroke. / L’òxid nítric (NO) és un neurotransmissor involucrat en processos de memòria. Actualment, l’única cascada de senyalització fisiològica controlada per NO consisteix en l’activació de la guanilat ciclasa. En aquesta tesi, en proposem una d’alternativa que inclou la fosforilació de eIF2a per la Heme-regulated eukaryotic initiation factor-2a kinase (HRI). Hem mostrat com l’enzim BACE1, una proteïna clau en la malaltia d’Alzheimer (AD), és controlat per aquesta nova cascada de senyalització, que podria estar involucrada en la fisiologia de l’aprenentatge i la memòria. També hem estudiat com un factor d’estrès extern, l’ Herpes Simplex Virus 1, pot pertorbar aquesta cascada donant lloc a increments patològics en BACE1 i pèptid ß-amiloide (Aß). L’Aß agrega formant fibril·les que generen radicals lliures. Aquests reaccionen químicament amb NO produint peroxinitrit, que contribueix a la progressió de l’AD. Pel fet que l’NO esdevé tòxic quan és produït en un entorn pro-oxidant, hem estudiat també l’impacte que el peroxinitrit té en l’ictus.