Machine Learning to Predict Enzyme-Substrate Interactions in Elucidation of Synthesis Pathways: A Review.

Enzyme-substrate interactions play a fundamental role in elucidating synthesis pathways and synthetic biology, as they allow for the understanding of important aspects of a reaction. Establishing the interaction experimentally is a slow and costly process, which is why this problem has been addressed using computational methods such as molecular dynamics, molecular docking, and Monte Carlo simulations. Nevertheless, this type of method tends to be computationally slow when dealing with a large search space. Therefore, in recent years, methods based on artificial intelligence, such as support vector machines, neural networks, or decision trees, have been implemented, significantly reducing the computing time and covering vast search spaces. These methods significantly reduce the computation time and cover broad search spaces, rapidly reducing the number of interacting candidates, as they allow repetitive processes to be automated and patterns to be extracted, are adaptable, and have the capacity to handle large amounts of data. This article analyzes these artificial intelligence-based approaches, presenting their common structure, advantages, disadvantages, limitations, challenges, and future perspectives.

Enhancing the physicochemical stability and antioxidant activity of cape gooseberry calyx extract through nanoencapsulation in soy lecithin liposomes.

The focus of this study was on the development, physicochemical characterisation and evaluation of the antioxidant activity of cape gooseberry calyx extract loaded into nanoliposomal systems. Various nanoliposomes were prepared and optimised using the ethanol injection method and characterised based on particle size, polydispersity and zeta potential measurements. Subsequently, the encapsulation efficiency and in vitro release profile of the natural antioxidant extract (NAE) were evaluated, and its antioxidant activity was assessed using the oxygen radical absorbance capacity assay. The results revealed that NAE-loaded nanoliposomes described desired quality features (e.g., particle size of < 200 nm, polydispersity index of < 0.3, zeta potential of > -40 mV and encapsulation efficiency of ∼70%). Furthermore, it was found that NAE release is controlled by various stages, and its antioxidant activity improves by around 30% when loaded into the nanoliposomes, suggesting that it could be a promising antioxidant functional raw material.

El ultrasonido gástrico en la determinación del estado prandial preoperatorio

Introducción: La aspiración de contenido gástrico representa la principal causa de muerte relacionada con la anestesia. El ultrasonido gástrico parece ser útil para el estudio del contenido gástrico, en especial en situaciones donde no existen o se desconocen las condiciones de ayuno. Objetivo: Describir la utilidad del ultrasonido para la valoración del contenido gástrico preoperatorio. Metodología: Se realizó una búsqueda estructurada en las bases de datos Pubmed, Embase, SciELO y Cochrane Library con los descriptores fasting; anesthesia; anesthesia, general; ultrasonics, ultrasonography, stomach (MeSH) Resultados: Se encontraron alrededor de 29 artículos con información relevante para el desarrollo de la presente revisión. Conclusiones: Aunque el ultrasonido gástrico parece ser una técnica útil para el estudio del contenido gástrico, se desconoce su impacto en la incidencia de aspiración neumónica, por lo que se necesitan más estudios para promover su uso rutinario en la práctica clínica.

Introduction: Gastric content aspiration represents the main cause of death related to anesthesia. Gastric ultrasound seems to be useful for studying gastric content, especially in situations where fasting conditions do not exist or are unknown. Objetive: To describe the utility of ultrasound for the evaluation of gastric content. Methods: A structured search was carried out with the descriptors: fasting; anesthesia; general anesthesia; ultrasounds, ultrasonography, stomach (MeSH), in the databases: Pubmed, Embase, SciELO and Cochrane Library. Results: 29 articles were found with relevant information for the development of this review. Conclusions: Although gastric ultrasound seems to be a useful technique for the study of gastric content, the impact that this may have on the incidence of pneumonic aspiration is unknown, so more studies are needed to promote its routine use in clinical practice.

Development, Characterization, and Antimicrobial Evaluation of Ampicillin-Loaded Nanoparticles Based on Poly(maleic acid-co-vinylpyrrolidone) on Resistant Staphylococcus aureus Strains.

This study was focused on synthesizing, characterizing, and evaluating the antimicrobial effect of polymer nanoparticles (NPs) loaded with ampicillin. For this, the NPs were produced through polymeric self-assembly in aqueous media assisted by high-intensity sonication, using anionic polymers corresponding to the sodium salts of poly(maleic acid-co-vinylpyrrolidone) and poly(maleic acid-co-vinylpyrrolidone) modified with decyl-amine, here named as PMA-VP and PMA-VP-N10, respectively. The polymeric NPs were analyzed and characterized through the formation of polymeric pseudo-phases utilizing pyrene as fluorescent probe, as well as by measurements of particle size, zeta potential, polydispersity index, and encapsulation efficiency. The antimicrobial effect was evaluated by means of the broth microdilution method employing ampicillin sensitive and resistant Staphylococcus aureus strains. The results showed that PMA-VP and PMA-VP-N10 polymers can self-assemble, forming several types of hydrophobic pseudo-phases with respect to the medium pH and polymer concentration. Likewise, the results described that zeta potential, particle size, polydispersity index, and encapsulation efficiency are extremely dependent on the medium pH, whereas the antimicrobial activity displayed an interesting recovery of antibiotic activity when ampicillin is loaded in the polymeric NPs.

A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer's disease.

Presenilin-1 (PSEN1) mutations cause familial Alzheimer's disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aß) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype-phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aß, there were no relevant differences between groups in generation and deposition of Aß. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin-proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aß accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aß pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.

Study of In Vitro and In Vivo Carbamazepine Release from Coarse and Nanometric Pharmaceutical Emulsions Obtained via Ultra-High-Pressure Homogenization.

In the past decade, pharmaceutical nanotechnology has proven to be a promising alternative for improving the physicochemical and biopharmaceutical features for conventional pharmaceutical drug formulations. The goal of this study was to develop, characterize, and evaluate the in vitro and in vivo release of the model drug carbamazepine (CBZ) from two emulsified formulations with different droplet sizes (coarse and nanometric). Briefly, oil-in-water emulsions were developed using (i) Sacha inchi oil, ultrapure water, TweenTM 80, and SpanTM 80 as surfactants, (ii) methyl-paraben and propyl-paraben as preservatives, and (iii) CBZ as a nonpolar model drug. The coarse and nanometric emulsions were prepared by rotor-stator dispersion and ultra-high-pressure homogenization (UHPH), respectively. The in vitro drug release studies were conducted by dialysis, whereas the in vivo drug release was evaluated in New Zealand breed rabbits. The results showed that nanoemulsions were physically more stable than coarse emulsions, and that CBZ had a very low release for in vitro determination (<2%), and a release of 20% in the in vivo study. However, it was found that nanoemulsions could significantly increase drug absorption time from 12 h to 45 min.

Franz Diffusion Cell Approach for Pre-Formulation Characterisation of Ketoprofen Semi-Solid Dosage Forms.

This study aimed to evaluate and compare, using the methodology of Franz diffusion cells, the ketoprofen (KTP) releasing profiles of two formulations: A gel and a conventional suspension. The second aim was to show that this methodology might be easily applied for the development of semi-solid prototypes and claim proof in pre-formulation stages. Drug release analysis was carried out under physiological conditions (pH: 5.6 to 7.4; ionic strength 0.15 M; at 37 °C) for 24 h. Three independent vertical Franz cells were used with a nominal volume of the acceptor compartment of 125 mL and a diffusion area of 2.5 cm². Additionally, two different membranes were evaluated: A generic type (regenerated cellulose) and a transdermal simulation type (Strat-M®). The KTP permeation profiles demonstrated that depending on the membrane type and the vehicle used, the permeation is strongly affected. High permeation efficiencies were obtained for the gel formulation, and the opposite effect was observed for the suspension formulation. Moreover, the permeation studies using Strat-M membranes represent a reproducible methodology, which is easy to implement for pre-formulation stage or performance evaluation of semi-solid pharmaceutical products for topical or transdermal administration.

Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains.

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

Amyloid-beta immunotherapy: the hope for Alzheimer disease? / Inmunoterapia beta-amiloide: ¿la esperanza para la enfermedad de Alzheimer?

Abstract Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

Resumen La enfermedad de Alzheimer (EA) es la forma más frecuente de demencia de inicio en el adulto, caracterizada por un deterioro progresivo en la cognición y la memoria. No hay cura para la enfermedad y los tratamientos actuales son sólo sintomáticos. El descubrimiento de fármacos es un proceso costoso y que consume mucho tiempo; en la última década no se han encontrado nuevos fármacos para la EA a pesar de los esfuerzos de la comunidad científica y las compañías farmacéuticas. La inmunoterapia contra Aβ es uno de los enfoques más prometedores para modificar el curso de la EA. Esta estrategia terapéutica utiliza péptidos sintéticos o anticuerpos monoclonales (mAb) para disminuir la carga de Aβ en el cerebro y retardar la progresión de la enfermedad. Por lo tanto, este artículo discutirá los principales aspectos de la neuropatogénesis de la EA, el tratamiento farmacológico clásico, así como la inmunización activa y pasiva describiendo los prototipos de fármacos evaluados en diferentes ensayos clínicos.

BACE1 RNAi Restores the Composition of Phosphatidylethanolamine-Derivates Related to Memory Improvement in Aged 3xTg-AD Mice.

ß-amyloid (Aß) is produced by the ß-secretase 1 (BACE1)-mediated enzymatic cleavage of the amyloid precursor protein through the amyloidogenic pathway, making BACE1 a therapeutic target against Alzheimer's disease (AD). Alterations in lipid metabolism are a risk factor for AD by an unknown mechanism. The objective of this study was to determine the effect of RNA interference against BACE1 (shBACEmiR) on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after 6 and 12 months of treatment compared to aged PS1KI mice. The shBACEmiR treatment induced cognitive function recovery and restored mainly the fatty acid composition of lysophosphatidylethanolamine and etherphosphatidylethanolamine, reduced the cPLA2's phosphorylation, down-regulated the levels of arachidonic acid and COX2 in the hippocampi of 3xTg-AD mice. Together, our findings suggest, for the first time, that BACE1 silencing restores phospholipids composition which could favor the recovery of cellular homeostasis and cognitive function in the hippocampus of triple transgenic AD mice.

Amyloid-ß Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.

The mechanisms leading to amyloid-ß (Aß) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Aß plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Aß precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Aß40 and Aß42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Aß accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Aß species.

Síndrome de Diógenes: aproximación actual de publicaciones en diversos abordajes y áreas de conocimiento / Hoarding: current approach of publication, in various approaches and areas of knowledge / Entesouramento: abordagem atual de publicaçoes, em várias abordagnes e áreas do conhecimento

El síndrome de Diógenes, tema de revisión de este artículo, constituye el trastorno deacumulación más conocido y con mayor impacto socio-ambiental. La importancia,extensión y complejidad de dicho trastorno ha determinado una considerable suma debibliografía científica, especialmente en los últimos años. La revisión bibliográficaefectuada, fue de modalidad integrativa, con el fin de obtener material científico para latesis de Doctorado en Ciencias de la Salud. De ella se desprende este artículo con elobjetivo: Identificar la producción bibliográfica acerca del Síndrome de Diógenes endiversos abordajes y área de conocimiento. El relevamiento de los datos, fue entre elperiodo 2006-2014. En dicha revisión de diferentes artículos, se destaca que el Síndromede Diógenes se asocia mayoritariamente a los adultos mayores, que viven solos, conescaso o nulo apoyo familiar y social. Otra característica de estas personas es quegeneralmente presentan trastornos psiquiátricos, sin conciencia de enfermedad yacompañados de apragmatismos. Mayoritariamente fueron captados a través de consultasmédicas realizadas por presencia de patologías orgánicas, siendo necesario en algunoscasos internaciones psiquiátricas o médicas, sin presentar antecedentes. Estas personastienen en común que en sus hogares practican la acumulación de los objetos más diversos,de los cuales no pueden desprenderse. La mayoría de las publicaciones comprueban lacomplejidad de aspectos referentes en este síndrome, que van desde lo psicológico, loambiental y social, entre otros. Surge consecuentemente, el abordaje interdisciplinar, quetrasvasa las áreas tradicionales de la salud...

Diogenes syndrome, or hoarding disorder, is named in honour to Diogenes of Sinope,representative of the Greek philosophy “cynicism”. "Cynicism is a philosophicalmovement that preaches non-attachment to material goods, believing that happiness doesnot depend on anything external to oneself”. This article systematically reviews theliterature, analysing a period from 2006 to 2014, including 18 clinical case studies, somealso reviewing the scientific literature on Diogenes syndrome, with conceptual definitionsand dimensions that cover the subject. The main signs of the disorder described by thestudies are that it mainly affects elderly people that live alone, with little or no family andpoor social support. They mostly have psychiatric disorders, unaware of the disease, andthe presence of apragmatisms. Mainly, the disorders were found when conductingmedical consultations for organic pathologies that required health services. In some casespsychiatric or medical hospitalization was needed and most patients didn`t havepsychiatric treatment before. At their houses, patients hoard different objects, books,newspaper clippings, paper, clothing, faeces, bottles and useless objects, from which theycannot detached. As it will be develop in this article, people with this disorder suffercomplex and diverse problems, and this obliges institutions and disciplines to have analso complex approach to each situation...

Síndrome de Diógenes, ou acumulação desordem, tem esse nome em homenagem aDiógenes de Sinope, representante do cinismo filósofo grego. "O cinismo é ummovimento filosófico que prega o desapego aos bens materiais, acreditando que afelicidade não depende de qualquer coisa externa a si mesmo. A revisão sistemática daliteratura período, revisão de análise 2006-2014 set, sendo 18 estudos de casos clínicos,alguns com revisão da literatura científica sobre a síndrome de Diógenes, a definiçãoconceitual e dimensões cobrindo o assunto. Os principais sinais, realizando os estudos éque eles são idosos, que vivem sozinhos, com pouco ou nenhum apoio familiar e social.É, sobretudo, as pessoas com transtornos psiquiátricos, sem saber da doença, bem comoa presença de apragmatismos. A descoberta desses usuários foi a realização de consultamédica para patologias orgânicas por isso foi necessário para ser levado para os serviçosde saúde, em alguns casos com internações psiquiátricas ou médicas, que não estavamem tratamento psiquiátrico...

Amyloid-beta immunotherapy: the hope for Alzheimer disease?

Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aß immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aß load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

La enfermedad de Alzheimer (EA) es la forma más frecuente de demencia de inicio en el adulto, caracterizada por un deterioro progresivo en la cognición y la memoria. No hay cura para la enfermedad y los tratamientos actuales son sólo sintomáticos. El descubrimiento de fármacos es un proceso costoso y que consume mucho tiempo; en la última década no se han encontrado nuevos fármacos para la EA a pesar de los esfuerzos de la comunidad científica y las compañías farmacéuticas. La inmunoterapia contra Aß es uno de los enfoques más prometedores para modificar el curso de la EA. Esta estrategia terapéutica utiliza péptidos sintéticos o anticuerpos monoclonales (mAb) para disminuir la carga de Aß en el cerebro y retardar la progresión de la enfermedad. Por lo tanto, este artículo discutirá los principales aspectos de la neuropatogénesis de la EA, el tratamiento farmacológico clásico, así como la inmunización activa y pasiva describiendo los prototipos de fármacos evaluados en diferentes ensayos clínicos.

Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis.

Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar ß-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aß aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aß precursor processing, leading to FAD and neurodegeneration.

Specific de-SUMOylation triggered by acquisition of spatial learning is related to epigenetic changes in the rat hippocampus.

Histone acetyltransferase activity by transcriptional cofactors such as CREB-binding protein (CBP) and post-translational modifications by small ubiquitin-like modifier-1 (SUMO-1) have shown to be relevant for synaptic and neuronal activity. Here, we investigate whether SUMOylation of CBP plays a role in spatial learning. We assessed protein levels of CBP/p300, SUMO-1, and CBP SUMOylation in the hippocampi of rats trained on the Morris water maze task. Furthermore, we evaluated the post-translational modifications at Zif268, BDNF, and Arc/Arg3.1 promoters using chromatin immunoprecipitation with anti-Acetyl-Histone H3-Lys14 (H3K14Ac) and SUMO-1. We found that CBP/p300 protein expression is unchanged in animals trained for 7 days. However, H3K14Ac-specific histone acetyltransferase activity showed specific hyperacetylation at promoters of Zif268 and BDNF-pI but not of Arc/Arg3.1 and BDNF-pIV. In naive animals, CBP is selectively SUMOylated and the Arc/Arg3.1 promoter is differentially occupied by SUMO-1, although SUMO-1 levels are unchanged. These results suggest a specific negative regulation by SUMO-1 on CBP function and its effect on epigenetic changes triggered by spatial learning and memory processes.

Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.

Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured ß-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPPß and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP ß-C-terminal fragment (ß-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP ß-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPß levels. Taken together, these data suggest that the physiopathological events underlying the chronic Aß production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.

Glycogen synthase kinase-3ß/ß-catenin signaling in the rat hypothalamus during the estrous cycle.

During the estrous cycle, a remodeling of synapses on somas and dendritic spines occurs in the rat hypothalamic arcuate nucleus. The synaptic remodeling is known to be induced by estradiol, but the molecular mechanisms involved still have not been fully clarified. ß-catenin is known to regulate synaptic plasticity, so we have assessed possible modifications of ß-catenin in the rat mediobasal hypothalamus during the estrous cycle. Our findings indicate that ß-catenin expression is increased during proestrus and estrus in comparison with diestrus day. This increase was accompanied by an enhanced phosphorylation of Akt in Ser473 and of glycogen synthase kinase-3ß (GSK3ß) in Ser9. Also, the association of ß-catenin with the synaptic protein PSD95 was increased during these same stages of the estrous cycle, whereas the levels of synapsin I were significantly decreased in proestrus. These findings suggest that Akt/GSK3ß/ß-catenin signaling is involved in the synaptic modifications that occur in the basal hypothalamus during the estrous cycle.