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Introducción: La automedicación es definida como “el propio tratamiento de los signos y síntomas de enfermedad que las personas padecen y ha sido la forma más utilizada para el mantenimiento de la salud”. El objetivo del presente trabajo es caracterizar la automedicación en los estudiantes de la carrera de Enfermería. Materiales y Métodos: Estudio cuantitativo, prospectivo, en el que se utilizó una encuesta virtual con preguntas sobre automedicación a 383 estudiantes. Resultados: El 56% de los estudiantes se automedican, los que más se automedican son de noveno ciclo de la carrera con el 73,3%, sexto (65,6%) y cuarto ciclo (63,8%). El grupo etario que más se automedica es el de 18 a 23 años (56,7%), el sexo femenino con el 53,3% y aquellos que viven en zonas urbanas (55,4%). Las manifestaciones clínicas más comunes que llevaron a automedicarse fueron: malestar general (16%), cefalea (16%) y manifestaciones alérgicas (10%). Los analgésicos fueron los medicamentos más utilizados (30,73%), seguido por antinflamatorios (11,92%) y antibióticos (11,55%). El 74% tenía conocimiento de las complicaciones de la automedicación. Entre los factores causales se encontraron: influencia de familia y amigos (65,80%), economía baja (43,60%), falta de tiempo para chequeos médicos (38,12%). Conclusiones: Los estudiantes de enfermería, en su mayoría, se automedican, independientemente del conocimiento y de las consecuencias de esta. La venta libre de medicamentos sin prescripción médica es un factor condicionante para la automedicación. Por otra parte, los resultados deben ser tomados por la academia para reforzar el conocimiento de las complicaciones y efectos adversos.

29 p.2 fig.-3 tab.-1 graph.abst.+Sup. Inf. 4 p._4 tab., The Ames mutagenicity test constitutes the most frequently used assay to estimate the mutagenic potential of drug candidates. While this test employs experimental results using various strains of Salmonella typhimurium, the vast majority of the published in silico models for predicting mutagenicity do not take into account the test results of the individual experiments conducted for each strain. Instead, such QSAR models are generally trained employing overall labels (i.e., mutagenic and nonmutagenic). Recently, neural-based models combined with multitask learning strategies have yielded interesting results in different domains, given their capabilities to model multitarget functions. In this scenario, we propose a novel neural-based QSAR model to predict mutagenicity that leverages experimental results from different strains involved in the Ames test by means of a multitask learning approach. To the best of our knowledge, the modeling strategy hereby proposed has not been applied to model Ames mutagenicity previously. The results yielded by our model surpass those obtained by single-task modeling strategies, such as models that predict the overall Ames label or ensemble models built from individual strains. For reproducibility and accessibility purposes, all source code and datasets used in our experiments are publicly available., This work was partially supported by the Argentinean National Council of Scientific and Technological Research (CONICET for its acronym in Spanish) [Grant No.PIP 112-2017-0100829], by the National Agency for the Promotion of Research, Technological Development and Innovation of Argentina (AGENCIA I+D+i in Spanish),through the Fund for Scientific and Technological Research (FONCyT for its acronym in Spanish) [Grant No. PICT 2019-03350], by the Universidad Nacional del Sur (UNS), Bahía Blanca, Argentina [Grant No. PGI 24/N042], Ministerio de Economía, Industria y Competitividad, Gobierno de España, under Grant No. RTI2018-096100B-100, and by a Google Latin America Research Award 2021−2022.

The Ames mutagenicity test constitutes the most frequently used assay to estimate the mutagenic potential of drug candidates. While this test employs experimental results using various strains of Salmonella typhimurium, the vast majority of the published in silico models for predicting mutagenicity do not take into account the test results of the individual experiments conducted for each strain. Instead, such QSAR models are generally trained employing overall labels (i.e. mutagenic and non-mutagenic). Recently, neural-based models combined with multi-task learning strategies have yielded interesting results in different domains, given their capabilities to model multi-target functions. In this scenario, we propose a novel neural-based QSAR model to predict mutagenicity that leverages experimental results from different strains involved in the Ames test by means of a multi-task learning approach. To the best of our knowledge, the modeling strategy hereby proposed has not been applied to model Ames mutagenicity previously. The results yielded by our model surpass those obtained by single-task modeling strategies, such as models that predict the overall Ames label or ensemble models built from individual strains. For reproducibility and accessibility purposes, all source code and datasets used in our experiments are publicly available.

[SPA] La Sierra Minera Cartagena-La Unión fue uno de los principales focos de la actividad extractiva hasta finales del siglo pasado, lo cual generó gran cantidad de residuos que se abandonaron en forma de depósitos de estériles mineros con altas concentraciones de elementos traza. Estos elementos, principalmente metal(oid)es, tienen un fuerte impacto en los suelos y la hidrología, y por extensión en la biota y la salud humana. Para evaluar esa transferencia, esta tesis se ha centrado en cuatro escenarios situados en sus proximidades: una zona forestal, una zona marítima situada en la desembocadura de una rambla con los depósitos en su cabecera, zonas agrícolas y una zona urbana con afección por material particulado. Para la zona forestal se han seleccionado cinco especies vegetales: Olea europaea, Pistacia lentiscus, Chamaerops humilis, Lavandula multifida y Rhamnus lycioides. Se ha estudiado la influencia de la rizosfera en las propiedades del suelo, el contenido en metal(oid)es y su distribución en la fracción química, concluyendo no existe una influencia significativa de la vegetación y que existe un riesgo por incorporación de As y Cd a los tejidos vegetales al presentar los mayores porcentajes de las fracciones lábiles. Todas las especies se desarrollan en suelos con altas concentraciones de As, Cd, Pb y Zn pudiendo usarse para labores de recuperación de suelos basadas en la fitoextracción (Lavandula multifida) y la fitoestabilización (Pistacia lentiscus). A su vez, al acumular estos elementos, existe un riesgo de incorporarlos a la cadena trófica mediante ingesta de las partes edibles por la fauna local. Para estudiar la transferencia al medio marítimo, se ha elegido la desembocadura de una rambla con los depósitos en su cabecera, que arrastra el material que contienen en episodios de lluvias torrenciales. Los resultados obtenidos muestran un aumento significativo en la concentración de metal(oid)es al sedimento, sin transferencia a las aguas, con respecto a otra zona sin influencia de la actividad minera. La especiación química muestra que el Cd es el elemento a tener más en cuenta, al tener unas fracciones lábiles más importantes, en torno al 20% del Cd presente en el sedimento está biodisponible para ser incoporado al medio marino. El análisis de la biota marina muestra que igualmente existe una influencia de la actividad minera con respecto a la de la zona control. La influencia de los depósitos mineros en los cultivos agrícolas de la zona ha sido estudiada en tres zonas seleccionadas de las que se ha usado el suelo para cultivar tres variedades de lechugas en invernadero destinadas a consumo humano para ver el contenido de metal(oid)es. Se han obtenido concentraciones de Pb en los tejidos foliares muy superiores a los límites establecidos por la legislación. Para el Cd, las concentraciones obtenidas se han situado ligeramente por encima de los valores límite, sin embargo, los altos valores de translocación observados hacen necesario un control más estricto ya la mayor parte del Cd que entra en la planta acaba acumulándose en sus hojas. Para la zona urbana se ha caracterizado el material particulado recogido en captadores, el contenido en metal(oid)es y su procedencia. Los resultados indican que no se superan los límites establecidos en la legislación y la Organización Mundial de la Salud para las fracciones de menor tamaño y más fácilmente inhalables (PM2.5-PM10) por lo que no supone un riesgo directo para la salud de la población del municipio. Sin embargo, a las partículas de menor tamaño son a las que más se asocian los metal(oid)es y son las que más fácilmente entran por las vías respiratorias, por lo que hay que estudiar en detalle la concentración de estos elementos en el material particulado y el aire, así como conocer la fuente de estos. [ENG] Cartagena-La Union mining district was one of the main areas of extractive industry in the Iberian Peninsula until last years of past century, which generated large amounts of wastes accumulated in tailing ponds with high concentrations of trace elements. These elements, mainly metal(loid)s, have an impact in soils, hydrology, biota and human Health. To assess the transfer, this thesis has focused in four places close to tailings ponds: forest area, marine area located in the mouth of a stream, agricultural area and urban area affected by particulate matter. In forest area five vegetal species have been selected: Olea europaea, Pistacia lentiscus, Chamaerops humilis, Lavandula multifida y Rhamnus lycioides. Influenceof rhizosphere in soil properties, metal(loid)s content and distribution in chemical fractions of soils have been studied. Conclusions reveal there is no influence of vegetation and there is a risk for incorporation of As and Cd to vegetal tissues because of labile fractions high percentages. All species have developed in soils with large amounts of As, Cd, Pb and Zn, so they can be used in remediation works as phytoextractor species (Lavandula multifida) or phytostabilization (Pistacia lentiscus). As well as a risk of incorporation to food chain by fauna intake must be considered. To evaluate transfer to marine environment, the mouth of a stream with influence of tailings ponds have been selected. There is an increase in metal(loid)s sediment concentration, without seawater transfer, in relation to control area without mining activities influence. Sediment chemical fractions shows Cd is risky because of importance of labile fractions (20%), so can be easily transfer to marine environment. Marine biota metal(loid)s concentrations reveal influence of tailings ponds. Transfer to agricultural crops has been studied in three selected areas, using in situ soils to grow in greenhouse three varieties of lettuces for human consumption to show metal(loid)s concentrations. Pb and Cd in leaf tissues limits have been exceeded, so it is necessary to monitor closely in crops with mining activities influence. Particulate matter has been characterized after filters particle collection, metal(loid)s content and its origin. Results have shown particulate matter is below limits defined by legislation and World Health Organization for smaller particles (PM2.5-PM10), easily respirable by population, so there is no risk for human health. Nevertheless, fine particles trend to assimilate metal(loid)s, so it is necessary to monitor the concentration of these trace elements and their origin Esta tesis doctoral ha sido ejecutada en el marco del proyecto “Soil take care” financiado por European Union Interreg V Sudoe (Ref. SOE1/P4/F0023). El soporte económico del autor durante el período predoctoral para la realización de esta tesis ha sido gracias a la beca de especialización asociada a actividades de I+D+I de la Universidad Politécnica de Cartagena (UPCT) y el grupo de Investigación Gestion y Aprovechamiento de Suelos y Aguas (GARSA). Referencia: R 529/15. Escuela Internacional de Doctorado de la Universidad Politécnica de Cartagena Universidad Politécnica de Cartagena Programa de Doctorado en Tecnología y Modelización en Ingeniería Civil, Minera y Ambiental

Introduction: In patients with heart failure, global longitudinal strain (GLS) early detects decreased ventricular contractility, with prognostic value, but there is no evidence that GLS properly differentiates etiologies in patients with left ventricular ejection fraction

Paclitaxel (Taxol®) is a taxane and a first-line chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the current lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect the drug’s mechanism of action. Here, we solved the crystal structure of the core baccatin III moiety of paclitaxel lacking the C13 side chain in complex with tubulin at 1.9 Å resolution. Based on this information, we engineered two tailor-made taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects along with those of paclitaxel, docetaxel, and baccatin III on the microtubule lattice by X-ray fiber diffraction. We then compared high-resolution structures of ligand-bound tubulin and microtubule complexes with apo forms and used molecular dynamics simulations to understand the consequences of taxane binding to tubulin as well as to simplified protofilament and microtubule-lattice models. Our combined approach sheds light on three mechanistic questions. Firstly, taxanes bind better to microtubules as compared to unassembled tubulin due to a dual structural mechanism: Tubulin assembly is linked to a conformational reorganization of the βM loop, which otherwise occludes ligand access to the taxane site, while the bulky C13 side chains preferentially recognize the microtubule-assembled over the unassembled conformational state of tubulin. Second, the occupancy of the taxane site by a ligand has no influence on the straightness of tubulin protofilaments. Finally, binding of the taxane core to the taxane site displaces the S9-S10 loop of β-tubulin resulting in microtubule expansion. Our results provide detailed new insights into the mechanism of microtubule-stabilization by taxanes.

The participation of students in scientific articles represents a bibliometric indicator that describes the scientific production of a University. Objective: to describe the scientific production of articles with student presence in dental journals indexed in the SciELO database around Latin America and the Caribbean Region. Method: Bibliometric study that analyzed the scientific articles of 20 dental scientific journals from 2005 to 2017. The articles with student authorship and/or co-authorship were evaluated according to university affiliation, subject of the article, type of article and citation index. Results: Out of a total of 8747 articles, 2.09% (183) presented the participation of dentistry students. About half (50.3%) were from Brazil, and 78.1% corresponded to original articles. The main theme of the studies was related to cariology (12.6%). The journal with the highest student participation was the Journal of Applied Oral Science (32.2%) Conclusions: Student scientific production in dental journals in Latin America and the Caribbean is low, with the countries with the greatest participation being Brazil, Colombia and Chile.

19 p.-5 fig.-1 graph. abst., The introduction of a new drug to the commercial market follows a complex and long process that typically spans over several years and entails large monetary costs due to a high attrition rate. Because of this, there is an urgent need to improve this process using innovative technologies such as artificial intelligence (AI). Different AI tools are being applied to support all four steps of the drug development process (basic research for drug discovery; pre-clinical phase; clinical phase; and postmarketing). Some of the main tasks where AI has proven useful include identifying molecular targets, searching for hit and lead compounds, synthesising drug-like compounds and predicting ADME-Tox. This review, on the one hand, brings in a mathematical vision of some of the key AI methods used in drug development closer to medicinal chemists and, on the other hand, brings the drug development process and the use of different models closer to mathematicians. Emphasis is placed on two aspects not mentioned in similar surveys, namely, Bayesian approaches and their applications to molecular modelling and the eventual final use of the methods to actually support decisions., This work was supported by and supported through the Spanish Ministry of Science and Innovation (RTI2018-096100-B-I00); MTM2017-86875-C3-1-R AEI/FEDER,UE; AXA -ICMAT Chair on Adversarial Risk Analysis; Adversarial Machine Learning: Methods, Computations and Applications to Malware, Fake News and Autonomous Vehicles– Ayudas Fundación BBVA a Equipos de Investigación Científca 2019. AItenea Biotech wants to thank Madrid Emprende for the Madrid Impacta 2020 award.

22 p.-5 fig., Introduction: Glycogen synthase kinase 3 (GSK-3) was identified in the late 1970s and is a constitutively active, ubiquitous expressed serine/threonine kinase that is involved in a large number of signaling pathway such as insulin, Wnt, Reelin, Notch, Hedgehog signaling, among others. GSK-3 is a key target of a remarkably large number of cellular processes and diseases such as diabetes type II, bipolar disorder, chronic inflammatory disease, cancer, immune disorder, neurodegenerative pathologies among others diseases and surely in regenerative medicine. During the last decades the scientific community has been working trying to understand the role of GSK-3 different disorders with the aim in mind of design efficient and selectivity GSK-3 inhibitors. However so far clinical and preclinical GSK-3 inhibitors have been both sub-optimal regarding potency, poor GSK-3 selectivity over other CNS targets and closely related kinases, low CNS exposure and chronic toxicity. Research into GSK inhibitors relay primarily on identification of the new use of the know GSK-3 inhibitors and the development of them in order to improve selectivity and toxicity., Areas covered: This review covers patent literature on GSK-3 inhibitors and their application published between 2016-2019., Expert opinion: Thanks to the past, present and future research, in the next few years we will see progress in the treatment of some diseases with GSK-3 inhibitors, for instance in regenerative medicine immunotherapy applications among others., This work was supported by the Ministerio de Ciencia e Innovación under Grant RTI2018-096100B-100.

2,7-Disubstituted oxazolo[5,4-f]quinoxalines were synthesized from 6-amino-2-chloroquinoxaline in four steps (iodination at C5, substitution of the chloro group, amidation and copper-catalysed cyclization) affording 28 to 44% overall yields. 2,8-Disubstituted oxazolo[5,4-f]quinoxaline was similarly obtained from 6-amino-3-chloroquinoxaline (39% overall yield). For the synthesis of other oxazolo[5,4-f]quinoxalines, amidation was rather performed before substitution; moreover, time-consuming purification steps were avoided between the amines and the final products (38 to 54% overall yields). Finally, a more efficient method involving merging of the last two steps in a sequential process was developed to access more derivatives (37 to 65% overall yields). Most of the oxazolo[5,4-f]quinoxalines were evaluated for their activity on a panel of protein kinases, and a few 2,8-disubstituted derivatives proved to inhibit GSK3 kinase. While experiments showed an ATP-competitive inhibition on GSK3β, structure-activity relationships allowed us to identify 2-(3-pyridyl)-8-(thiomorpholino)oxazolo[5,4-f]quinoxaline as the most potent inhibitor with an IC value of about 5 nM on GSK3α., We thank the Université de Rennes 1 and the Centre National de la Recherche Scientifique for supporting this research. We acknowledge the support from the Fonds Européen de Développement Régional (FEDER; D8 VENTURE Bruker AXS diffractometer). A. M. acknowledges financial support from Spanish Ministry of Innovation, Science and Universities (MICU, grant no. SAF2016-76693-R) and ISCiii (CIBERNED, grant no. CB18/05/00040). S. B. and S. R. also thank the Cancéropôle Grand Ouest (axis: Natural Sea Products in Cancer Treatment), IBiSA (French Infrastructures en sciences duvivant: biologie, santé et agronomie) and Biogenouest (Western France Life Science and Environment Core Facility Network) for supporting KISSf screening facility. We also thank Aurélie Assicot for her contribution to the study and Ludovic Paquin for the generous gift of secondary amines

68 p.-17 fig.-1 tab. Chierrito, Talita P. C. et al., The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD., Financial support of this research provided by the Fundação de Pesquisa e Amparo do Estado de São Paulo-FAPESP (Proc. 12/04054-5; 12/14114-5; 13/50788-3; 14-10414-0); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), CSIC (grant no. i-LINK-0801) and MINECO (grants no. SAF2016-76693-R to A.M., and CTQ2015-64597-C2-1 to J.J.B. and F.J.C.) is acknowledged

13 p.-6 fig.-5 tab., Alzheimer's disease is one of the most common neurodegenerative disorders in elder population. The β-site amyloid cleavage enzyme 1 (BACE1) is the major constituent of amyloid plaques and plays a central role in this brain pathogenesis, thus it constitutes an auspicious pharmacological target for its treatment. In this paper, a QSAR model for identification of potential inhibitors of BACE1 protein is designed by using classification methods. For building this model, a database with 215 molecules collected from different sources has been assembled. This dataset contains diverse compounds with different scaffolds and physical-chemical properties, covering a wide chemical space in the drug-like range. The most distinctive aspect of the applied QSAR strategy is the combination of hybridization with backward elimination of models, which contributes to improve the quality of the final QSAR model. Another relevant step is the visual analysis of the molecular descriptors that allows guaranteeing the absence of information redundancy in the model. The QSAR model performances have been assessed by traditional metrics, and the final proposed model has low cardinality, and reaches a high percentage of chemical compounds correctly classified., This work is kindly supported by CONICET, grant PIP 112–2012–0100471, by UNS, grants PGI 24/N042 and PGI 24/ZM17, Ministerio de Economía y Competitividad (CTQ2015-66313-R) and by MINCYT, for their economic support given to IP in the “6° Programa de Movilidad Docente a Madrid”.

Multitarget cannabinoids could be a promising therapeutic strategic to fight against Alzheimer's disease. In this sense, our group has developed a new family of indazolylketones with multitarget profile including cannabinoids, cholinesterase and BACE-1 activity. A medicinal chemistry program that includes computational design, synthesis and in vitro and cellular evaluation has allowed to us to achieve lead compounds. In this work, the synthesis and evaluation of a new class of indazolylketones have been performed. Pharmacological evaluation includes functional activity for cannabinoid receptors on isolated tissue. In addition, in vitro inhibitory assays in AChE/BuChE enzymes and BACE-1 have been carried out. Furthermore, studies of neuroprotective effects in human neuroblastoma SH-SY5Y cells and studies of the mechanisms of survival/death in lymphoblasts of patients with Alzheimer's disease have been achieved. The results of pharmacological tests have revealed that some of these derivatives (5, 6) behave as CB2 cannabinoid agonists and simultaneously show BuChE and/or BACE-1 inhibition., The authors gratefully acknowledge the financial support of Ministerio Español de Economía y Competitividad (CTQ2015- 66313-R) and would like to thank to Guadalupe Pablo and Carmen Merino for their excellent technical assistant. The work of MLC was supported by the Centre for Biomedical Research on Neurodegenerative Diseases (CIBERNED). GV was supported by a fellowship from SENECYT (Ecuador). Work dedicated in memoriam to Mercedes González Hormaizteguy, a great women scientist and wonderful person

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3β and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC values toward GSK-3β, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 μM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs., This work was supported by the University of Bologna (RFO2015_2016), European Cooperation of Science and Technology (EUCOST) Action CA15135, Ministerio de Economia y Competitividad (CTQ2015-66313-R), Italian Ministry of Health (GR-2013-02355724), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015). The authors thank E. De Cecco (PhD candidate, SISSA) for providing K18 and 2N4R protein samples for the in vitro assays.

This paper provides an overview of border control processes and how the inclusion of different biometric technologies contributes to its improvement. In particular, facial recognition is one of the latest biometric technology to have been added to this list of technologies. The Face Matching Tool (FMT), a system defined to assist border guards in the process of validating the identity of a travel document holder during the crossing border process, is presented in this paper. The system is built using advanced and high-performance deep learning models. Existing solutions for border control, such as the Automated Border Check gates (ABC gates), are possible thanks to the use of facial recognition as the main option for identity validation. These solutions imply a decrease in the queue time that a traveler expends crossing the border at airports around the globe. The FMT module, together with the rest of the iBorderCtrl system, reduces this waiting time while providing unconstrained and high facial recognition performances at the land borders.

15 p.-10 fig.-5 tab., Allosteric sites on proteins are targeted for designing more selective inhibitors of enzyme activity and to discover new functions. Acetylcholinesterase (AChE), which is most widely known for the hydrolysis of the neurotransmitter acetylcholine, has a peripheral allosteric subsite responsible for amyloidosis in Alzheimer's disease through interaction with amyloid β-peptide. However, AChE plays other non-hydrolytic functions. Here, we identify and characterise using computational tools two new allosteric sites in AChE, which have allowed us to identify allosteric inhibitors by virtual screening guided by structure-based and fragment hotspot strategies. The identified compounds were also screened for in vitro inhibition of AChE and three were observed to be active. Further experimental (kinetic) and computational (molecular dynamics) studies have been performed to verify the allosteric activity. These new compounds may be valuable pharmacological tools in the study of non-cholinergic functions of AChE., We thank to Ministerio de Educación, Cultura y Deporte (Grant of V.S.P, FPU15/01465 and Grant of N.E.C., Programa “Salvador de Madariaga” PR2015–00476).

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE., Financial support of this research provided by the Fundaç~ao de Pesquisa e Amparo do Estado de S~ao Paulo-FAPESP (Proc.12/04054- 5; 12/14114-5; 13/50788-3; 14/10414-0; 17/04695-4); Coordenaç~ao de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), CSIC (grant no. i-LINK-0801) and MINECO (grants no. SAF2016-76693-R to A.M., CTQ 2016-76263 to A.C. and CTQ 2015- 64597-C2-2 to F.J.C.) is acknowledged. Authors want to express their gratitude to Prof. G. Pepeu for the experimental work in target engagement.

34 p.-9 fig.-1 tab.-1 graph. abst., Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported., This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (grant 2012/14114-5, 2013/50788-3, 2014/04868-8), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Consejo Superior de Investigaciones Científicas – CSIC (grant i-Link0801) and MINECO (CTQ2015-66313-R).

Protein-protein interactions (PPIs) are known to play an essential role between the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to regulate synapse function, emerging as a druggable interface for synaptopathies such as the fragile X syndrome (FXS). Recently, the phenothiazine FD44 has been identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. Here, we have integrated advanced experimental and computational studies to obtain important structural insights into Drosophila NCS-1/FD44 recognition to understand the basis of its affinity and specificity and generate improved PPI regulators. This has allowed the identification of a new small drug-like molecule, IGS-1.76, which efficiently inhibits the human NCS-1/Ric8a complex with improved binding potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different from FD44, shares the same mechanism of action and constitutes a new hit candidate for FXS.

Neglected tropical diseases represent a significant health burden in large parts of the world. Drug discovery is currently a key bottleneck in the pipeline of these diseases. In this chapter, the in silico approaches used for the processes involved in drug discovery, identification and validation of druggable Leishmania targets, and design and optimisation of new anti-leishmanial drugs are discussed. We also provide a general view of the different computational tools that can be employed in pursuit of this aim, along with the most interesting cases found in the literature.

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure¿activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects., This work was financially supported by MINECO (grant no. SAF2012-37979-C03-01 and SAF2016-76693-R to A.M. and IJCI-2014-20767 to V.P.). CCHMC funds L.T. A.M. and C.G. are members of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET).

19 p.-12 fig.-5 tab. Ponzoni, Ignacio et al., Quantitative structure–activity relationship modeling using machine learning techniques constitutes a complex computational problem, where the identification of the most informative molecular descriptors for predicting a specific target property plays a critical role. Two main general approaches can be used for this modeling procedure: feature selection and feature learning. In this paper, a performance comparative study of two state-of-art methods related to these two approaches is carried out. In particular, regression and classification models for three different issues are inferred using both methods under different experimental scenarios: two drug-like properties, such as blood-brainbarrier and human intestinal absorption, and enantiomeric excess, as a measurement of purity used for chiral substances. Beyond the contrastive analysis of feature selection and feature learning methods as competitive approaches, the hybridization of these strategies is also evaluated based on previous results obtained in material sciences. From the experimental results, it can be concluded that there is not a clear winner between both approaches because the performance depends on the characteristics of the compound databases used for modeling. Nevertheless, in several cases, it was observed that the accuracy of the models can be improved by combining both approaches when the molecular descriptor sets provided by feature selection and feature learning contain complementary information., This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) [Grant number 112-2012-0100471 and PIP 114-2011-0100362], the Secretaría de Ciencia y Tecnología of the Universidad Nacional del Sur (UNS) [Grant numbers 24/N032, 24/ZN26] and MINECO (Spain) [project CTQ2015-66313-R and CTQ2015-66954-P MINECO/FEDER]. Dr. Ponzoni did this work as a visiting researcher at the Centro de Investigaciones Biológicas (CIB-CSIC) at Madrid (Spain). The authors would like to express their acknowledgment to the 6° Programa de Movilidad Docente a Madrid of the Secretaría de Políticas Universitarias (SPU), Ministerio de Educación de la República Argentina, for their economic support given for Dr. Ponzoni’s visit. Víctor Sebastián-Pérez acknowledges a predoctoral fellowship from MINECO [FPU15/01465].

La calcifilaxis constituye una de las entidades menos frecuente dentro de las complicaciones de la enfermedad renal crónica. Se presenta el caso de un paciente de 52 años, portador de una insuficiencia renal crónica en estadío terminal, secundaria a nefropatía hipertensiva, alcohólico crónico, operado de carcinoma de laringe, bajo régimen de hemodiálisis por 2 años y 6 meses. Las características de las lesiones dermatológicas más sobresalientes fueron las placas eritematovioláceas con evolución hacia la ulceración necrótica, presentes en la región distal de los miembros superiores e inferiores. El diagnóstico fue corroborado mediante estudios bioquímicos y la biopsia de piel.

Fundamento: altos niveles de comorbilidad y el declinar funcional están estrechamente relacionados con la mortalidad a corto plazo y la pobre calidad de vida de las personas mayores institucionalizadas. Objetivo: determinar la asociación del deterioro cognitivo con la alta comorbilidad y el declinar funcional en personas mayores institucionalizadas. Métodos: estudio descriptivo de 156 pacientes ingresados en un hogar de ancianos ubicado en Mahé, Seychelles, entre el 2010 y el 2012. Se analizó el comportamiento de los adultos mayores en relación con: presencia de deterioro cognitivo y demencia, edad, sexo, enfermedades crónicas no transmisibles, niveles de comorbilidad, declinar funcional, filtrado glomerular estimado, polifarmacia, y años de escolaridad. En la evaluación de la comorbilidad se utilizó el Índice de Charlson en su versión abreviada y en la valoración funcional el Índice de Barthel. Resultados: el 57,7 % de los residentes presentaron deterioro cognitivo o demencia, de ellos el 66,7 % pertenecieron al sexo masculino. Los pacientes con deterioro cognitivo y demencia analizados en el estudio tuvieron una mayor probabilidad de padecer alta comorbilidad (OR: 5,88; intervalo de confianza del 95% [IC95]: 5,42-6,33) y peor desempeño funcional (OR: 20,53; IC95%: 19,54-21,29) que los casos institucionalizados sin estas entidades. Otras variables estudiadas en los casos con deterioro cognitivo como la edad, presencia de polifarmacia, filtrado glomerular estimado y años de escolaridad mostraron diferencias significativas en comparación con los adultos mayores sin deterioro cognitivo. Conclusiones: los pacientes con deterioro cognitivo tienen una comorbilidad y deterioro funcional superior a los casos sin deterioro cognitivo. Se constata asociación del deterioro cognitivo con la alta comorbilidad y un peor desempeño funcional.

AIM To determine whether a relationship exists between the markers of severe acidemia (SA) and the developmental, verbal, and behavioral characteristics of children with SA born at term 5 years previously, without apparent neurological impairment. METHODS A cohort of 76 children-38 with SA (pH < 7, base deficit ≥12 mmol/L) and 38 non-SA (pH ≥ 7.20)-were evaluated using the Battelle Developmental Inventory, McCarthy's Verbal Scale, the Token Test for Children, and the Conners 3rd Edition-Parent. The relationships between markers of SA and verbal and behavioral scores were analyzed with parametric correlations. Multiple regression analysis was used to determine the possible effect of these markers on verbal abilities, verbal memory, and attention. RESULTS Although none of the scores were in the "impaired" range, the SA group scored lower in verbal index (p = .000) and verbal memory (p = .004) on the McCarthy's Scales and in verbal comprehension (p = .001) on the Token Test for Children-2, and higher on the inattention (p = .003) and hyperactivity-impulsivity domains of the Conners Scales (p = .009) compared with the control group. There were no differences between the groups in the motor, personal-social, or cognitive domains on the Battelle Developmental Inventory. The SA markers were found to be predictors, accounting for 61.6% of verbal variability. CONCLUSIONS SA markers reflect mild long-term consequences regarding verbal abilities and inattentiveness among children born at term without apparent neurological impairment on discharge but do not suggest severe impairment to the 5-year development of children. The authors recommend that these children should be monitored to determine whether they need or might benefit from an early intervention program.

Fundamento: el deterioro cognitivo y la alta comorbilidad son problemas de salud frecuentes en pacientes con enfermedad cerebrovascular. Objetivo: describir el comportamiento del deterioro cognitivo y de la comorbilidad en pacientes con infarto cerebral hospitalizados. Método: estudio descriptivo de 77 pacientes con diagnóstico de enfermedad cerebrovascular isquémica, ingresados entre abril del 2010 y diciembre del 2011, en el hospital general de Seychelles. Se analizó el comportamiento de esta enfermedad en relación con variables como: edad, presencia de enfermedades crónicas no transmisibles, deterioro cognitivo, años de estudios terminados, hemisferio cerebral afectado y tiempo de evolución. Resultados: el 68,9 % de los pacientes presentó deterior cognitivo; la edad media de estos fue de 74,2(±9,19) años frente a un 62,4(±14,2) para los que no tuvieron deterioro cognitivo. Se encontró una mayor frecuencia de enfermedades crónicas no transmisibles en los pacientes con deterioro cognitivo, con un índice de comorbilidad de Charlson en 2,11(±0,97). Se diagnosticaron con depresión 18 pacientes con deterioro cognitivo y 23 pacientes sin deterioro cognitivo. Conclusiones: más de la mitad de los pacientes hospitalizados presentó deterioro cognitivo, la mayor parte previo a la enfermedad cerebrovascular. En este grupo de pacientes predominó el sexo masculino, se observó un incremento de la edad, de la severidad de la depresión, así como de la frecuencia de enfermedades crónicas no transmisibles, e infarto de tamaño considerable, con respecto a los pacientes sin deterioro cognitivo.