Infectious agents in atherosclerotic cardiovascular diseases through oxidative stress

Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis-induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research

Computers and students’ achievement: An analysis of the One Laptop per Child program in Catalonia

We analyse the impact of a One Laptop per Child program introduced by the Catalan government on student achievement. Using longitudinal population data for students in secondary education during the period 2009–2016, our identification strategy exploits variations across cohorts within schools. Although participation into the program was not random, we control for a number of school characteristics that influenced school participation. The empirical results consistently indicate that this program had a negative impact on student performance in Catalan, Spanish, English and mathematics. Test scores fell by 0.20–0.22 standardised points, which represent 3.8–6.2% of the average test score. This negative effect was stronger among boys than it was among girls (differences ranging from 10% to 42%)

Exploring heterocyclic scaffolds in the development of multi-target anti-Alzheimer and multi-trypanosomatid compounds

[eng] The aim of this PhD thesis consists of the synergistic combination of both highly efficient synthetic approaches and molecular modelling tools for the structure-based drug design and synthesis of novel bioactive heterocyclic compounds. The work carried out has followed two main research lines, namely the development of novel disease-modifying anti-Alzheimer agents and still unexplored chemical entities for the treatment of Neglected Tropical Diseases (NTDs). The results obtained have been presented as a compendium of publications and draft manuscripts. In the framework of the anti-Alzheimer research line, first the hit-to-lead optimization of a practically inactive propidium-related compound easily accessed via a Povarov multicomponent reaction (MCR) approach (Di Pietro O. et al. Eur. J. Med. Chem., 2014, 73, 141), and the subsequent molecular hybridization with a 6-chlorotacrine unit through a molecular dynamics-driven tether length optimization, overall led to one of the most potent non-covalent dual binding site acetylcholinesterase inhibitor (AChEI) ever described in the literature (Di Pietro O. et al. Eur. J. Med. Chem., 2014, 84, 107). Second, the combined recourse to the highly versatile click-chemistry strategy, through the well-known Cu-catalyzed azide-alkyne cycloaddition reaction, and convenient computational chemistry tools, allowed the rational design and synthesis of a novel series of 1,4-disubstituted triazole-based propargylamines as irreversible MAO-B inhibitors (draft manuscript) with the perspective to be further linked to a second pharmacophoric moiety to derive novel MTDLs as potential anti-Alzheimer drug candidates. Furthermore, an extensive computation of the BACE-1 apo conformational ensemble by means of combined molecular dynamics technique and Principal Component Analysis (PCA) method, allowed to carry out an exhaustive study of a secondary transient druggable pocket (draft manuscript) and a virtual screening of 500,000 commercially available fragments for further drug discovery purposes. Finally, in the framework of the NTDs research line, 2−4-step sequences involving as the key step an initial Povarov MCR gave easy access to a small library of quinolones and tricyclic heterofused quinolines, which were subjected to phenotypic whole-cell screenings, leading to the individuation of several low micromolar multi-trypanosomatid hit compounds (Di Pietro et al. Eur. J. Med. Chem. 2015, accepted with minor revision)

Tactile thresholds are preserved yet complex sensory function is impaired over the lumbar spine of chronic non-specific low back pain patients: A preliminary investigation

Evidence indicates that chronic non-specific low back pain (CNSLBP) is associated with alteration in the brain’s cortical representation of the back, resulting in body perception disturbance and contributing to the condition [1,2]. This study investigated perception via ‘cortical’ sensory tests, in this case two-point discrimination and graphaesthesia—whose results partly depend on the integrity of cortical representation [2]. The hypothesis was dysfunction in these higher-order tasks, with simple tactile thresholds remaining unchanged. Furthermore a relationship between cortical sensation and severity of the condition was predicted

Vinculando la danza y la educación: el caso del internado Beatriz Hernández

Informe que muestra el proceso de sistematización y teorización de gestión del conocimiento realizado para instalar el proyecto “La danza clásica desde la mirada educativa: una propuesta para la educación del cuerpo” en el internado para niñas de bajos recursos Beatriz Hernández, el cual depende de la Secretaría de Educación Jalisco (SEJ). Este proyecto tuvo el objetivo de diseñar un método educativo basado en la danza y en la conversación para incidir en el conocimiento del cuerpo, el desarrollo cognitivo y el socioafectivo de las alumnas del internado y lograr instalar este método como parte del currículo de la institución. Los resultados de este proyecto permiten tener un nuevo acercamiento al conocimiento de la práctica de la danza como herramienta metodológica para favorecer, por su naturaleza física, expresiva y cognitiva, la integración de mente, cuerpo y emociones. Además, posibilita abrir espacios para ampliar la visión tradicional de los procesos de cognición, aporta nuevos recursos a los normalmente utilizados en el currículo escolar, abre la reflexión sobre el cuerpo como medio de exploración y apropiación de los conocimientos y contribuye a la vinculación de la educación y el arte al proponer la danza como estrategia de formación en el currículo escolar. *A lo largo de este trabajo, la autora hace referencia a entrevistas y registros de clases en audio y video, los cuales no están agregados en este registro

Ultra rapid in vivo screening for anti-Alzheimer anti-amyloid drugs

More than 46 million people worldwide suffer from Alzheimer's disease. A large number of potential treatments have been proposed; among these, the inhibition of the aggregation of amyloid β-peptide (Aβ), considered one of the main culprits in Alzheimer's disease. Limitations in monitoring the aggregation of Aβ in cells and tissues restrict the screening of anti-amyloid drugs to in vitro studies in most cases. We have developed a simple but powerful method to track Aβ aggregation in vivo in realtime, using bacteria as in vivo amyloid reservoir. We use the specific amyloid dye Thioflavin-S (Th-S) to stain bacterial inclusion bodies (IBs), in this case mainly formed of Aβ in amyloid conformation. Th-S binding to amyloids leads to an increment of fluorescence that can be monitored. The quantification of the Th-S fluorescence along the time allows tracking Aβ aggregation and the effect of potential antiaggregating agents

New cranial characters in the tribe Hydropsini (Serpentes: Dipsadidae: Xenodontinae)

We here describe the skull in four species of the three genera of the tribe Hydropsini (Serpentes: Dipsadidae: Xenodontinae): Helicops infrataeniatus, H. leopardinus, Hydrops caesurus and Pseudoeryx plicatilis. We compare them with several genera of Dipsadidae. We found that the unpaired foramen on the parabasisphenoid with anterior position is the only skull feature shared by all Hydropsini genera. This feature also occurs in semi-aquatic (Erythrolamphrus semiaureus) and fully-aquatic (Farancia abacura) dipsadids. All species of Hydrops with available skull descriptions and Pseudoeryx plicatilis share four features: (1) The anterior border of the angular is higher than the posterior border of the splenial, (2) the vomerine processes of the premaxilla are long, (3) the ascending process of the premaxilla overlaps the horizontal lamina of the nasals, and (4) an anterior projection of the prefrontal is present. All species of Helicops with available skull descriptions and Pseudoeryx plicatilis share three features: (1) A vertical lamina of the nasal with a notch, (2) a single foramen rotundum, and (3) the presence of a ventral projection of the transverse crista of the basioccipital. Finally, we found small, paired parietal foramina in most of the dipsadids studied here, which are filled with a Sudan-Black-positive tissue of possible nervous origin

Unveiling a Novel Transient Druggable Pocket in BACE-1 through Molecular Simulations: Conformational Analysis and Binding Mode of Multisite Inhibitors

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments - huprine and rhein - that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8-14, 154-169 and 307-318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable 'floppy' pocket would enable the binding of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligomethylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications introduced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans

Cerebellar metabolic involvement and its correlations with clinical parameters in vestibular neuritis

Although vestibular neuritis (VN) cortical models are described in the literature, there is lack of knowledge regarding the exclusive cerebellar involvement. The aim of the present study was to analyze, by [18F] fluorodeoxyglucose-positron emission tomography (FDGPET)/ computer tomography, regional cerebellar FDG uptake in eight right-handed VN patients (five females; three males; mean age 48 ? 7 years) during the first few days (PET0) and after 1 month (PET1) since symptoms onset. At both phases, patients underwent otoneurological examination and filled in a battery of validated questionnaires. Twenty-six cerebellar volumes of interest (VOI) were identified by the automated anatomical labeling library and normalized to thalamus FDG-PET uptake. Mean intensity within VOIs was calculated in both phases and processed by within-subjects ANOVA. A significantly lower (