1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

La renda mínima d'inserció: una eina útil d���inserció social en el món local

La crisi actual ha agreujat la situació socioeconòmica de nombroses persones i famílies , esdevenint una realitat social cada vegada més complexa . Aquest nou context, ha portat a que aquesta nova bossa de persones hagin de recórrer a demanar suport als serveis socials bàsics. Persones que fins aquest moment havien estat en una situació normalitzada i en aquests moments estan en el llindar de l’exclusió social. El treball Sorgeix de la necessitat del món local, concretament de l’Àrea Bàsica de Serveis Socials del Consell Comarcal de l’Alt Pened��s, de disposar d���eines d���inserció social per a les persones perceptores de la renda mínima d���inserció de la comarca, que formen part d���aquest col·lectiu en risc d���exclusió. Planteja la importància que des del món local es creïn aliances amb entitats , associacions diverses i de diferents àmbits , per tal d���adequar les respostes i les mesures d���inserció social segons la realitat de cada persona i família a través de diferents tasques col·laboratives, dins la seva comunitat, el seu entorn més immediat. Presenta la renda mínima com una via útil i necessària per lluitar contra la pobresa i a favor de la inclusió social

Entorn al testament de Brunissèn d'Alentorn i alguns costums funeraris de la Lleida medieval

In this research from the late medieval period, we want to analyze diferent aspects related to funerary world through Brunissèn d���Alentorn’s will. The document is compared with other wills from Lleida’s area that acquire knowledge to these customs, for instance, the draps d���or’s uses. These were provided of deceased��� heraldry, and were comissioned to cover the tomb. Also, in Lleida’s case, they were used to decorate the ancient cathedral’s presbitery during the main festivities, and the patrons’ wedding bed. Artistic patronage, social prestige, family arms ostentation, pomp and devotion are other aspects that would be emphasized in this tour, just as the private devotions in the chapels and altars that were founded regarding this topic.

Noves aportacions a l'arbre genealògic de la família Montcada, senyors de la Baronia d'Aitona

Montcada’s family had in Middle Ages the Baronia d���Aitona in the land known as Baix Segre, in Lleida. His properties included the villages of Serós, Aitona, Mequinensa, Faió, Vallobar and Maials. This part of the family, who lived in Lleida, is really unknown. Documents from the Arxiu Ducal de Medinaceli a Catalunya have shown new members of this part of the family unknown since now. This new information has allowed to complete the genealogical trees of the Montcada’s family in Lleida.

Anàlisi del recurs pilot "cases d'infants: nou paradigma d'atenció i tractament a la infància i l'adolescència".

El treball que es presenta a continuació és una recerca aplicada, consistent en l’anàlisi descriptiva d���una mostra d���infants i adolescents de 5 a 19 anys atesos al projecte “Cases d���Infants” des del desembre de 2010 fins al juliol de 2013. Aquesta investigació pretén donar a conèixer la nova perspectiva o paradigma d���atenció a la infància i l’adolescència a Catalunya que neix de la Llei dels Drets i les Oportunitats de la Infància i l’Adolescència (LDOIA, maig de 2010): basada en la prevenció, el model sistèmic i de complexitat, la col·laboració de la família com a element de canvi, el treball en xarxa i interprofessionalitat, la participació dels infants i adolescents, i la territorialitat, principalment. Un cop feta aquesta aproximació teòrica, s’ha concretat identificant aquesta nova perspectiva al projecte pilot “Cases d���Infants” (nascut al setembre de 2010), el qual desplega les actuacions que sorgeixen d���aquesta filosofia de treball i suport. Per a elaborar aquesta recerca s’ha emprat un disseny d���investigació no experimental descriptiu, on s’han associat i comparat variables per tal d���identificar interferències en les relacions –a través de proves estad��stiques-, i proposar una certa tend��ncia i pronòstic de les característiques del perfil atès al projecte i les interferències d���algunes variables amb el recurs final de l’infant o adolescent. Finalment, s’extreuen unes conclusions en relació a la bibliografia inicial i els resultats obtinguts en l’anàlisi de la mostra estudiada.

Family Size Evolution in Drosophila Chemosensory Gene Families: A Comparative Analysis with a Critical Appraisal of Methods

Gene turnover rates and the evolution of gene family sizes are important aspects of genome evolution. Here, we use curated sequence data of the major chemosensory gene families from Drosophila-the gustatory receptor, odorant receptor, ionotropic receptor, and odorant-binding protein families-to conduct a comparative analysis among families, exploring different methods to estimate gene birth and death rates, including an ad hoc simulation study. Remarkably, we found that the state-of-the-art methods may produce very different rate estimates, which may lead to disparate conclusions regarding the evolution of chemosensory gene family sizes in Drosophila. Among biological factors, we found that a peculiarity of D. sechellia's gene turnover rates was a major source of bias in global estimates, whereas gene conversion had negligible effects for the families analyzed herein. Turnover rates vary considerably among families, subfamilies, and ortholog groups although all analyzed families were quite dynamic in terms of gene turnover. Computer simulations showed that the methods that use ortholog group information appear to be the most accurate for the Drosophila chemosensory families. Most importantly, these results reveal the potential of rate heterogeneity among lineages to severely bias some turnover rate estimation methods and the need of further evaluating the performance of these methods in a more diverse sampling of gene families and phylogenetic contexts. Using branch-specific codon substitution models, we find further evidence of positive selection in recently duplicated genes, which attests to a nonneutral aspect of the gene birth-and-death process.

The awr gene family encodes a novel class of Ralstonia solanacearum type III effectors displaying virulence and avirulence activities

We present here the characterization of a new gene family, awr, found in all sequenced Ralstonia solanacearum strains and in other bacterial pathogens. We demonstrate that the five paralogues in strain GMI1000 encode type III-secreted effectors and that deletion of all awr genes severely impairs its capacity to multiply in natural host plants. Complementation studies show that the AWR (alanine-tryptophanarginine tryad) effectors display some functional redundancy, although AWR2 is the major contributor to virulence. In contrast, the strain devoid of all awr genes (¿awr1-5) exhibits enhanced pathogenicity on Arabidopsis plants. A gain-of-function approach expressing AWR in Pseudomonas syringae pv. tomato DC3000 proves that this is likely due to effector recognition, because AWR5 and AWR4 restrict growth of this bacterium in Arabidopsis. Transient overexpression of AWR in nonhost tobacco species caused macroscopic cell death to varying extents, which, in the case of AWR5, shows characteristics of a typical hypersensitive response. Our work demonstrates that AWR, which show no similarity to any protein with known function, can specify either virulence or avirulence in the interaction of R. solanacearum with its plant hosts.

Anàlisi de la competència del professorat d'educació física davant l'alumnat amb discapacitat

La present investigació es fonamenta en l’anàlisi de la competència del professorat d���educació física envers un alumnat amb discapacitat. L’objectiu és tenir coneixement de com el professorat assoleix aquesta competència i detectar possibles mancances a través de la formació adquirida, la figura de suport a les classes i/o la implicació de la família de l’alumnat. S’han analitzat 4 professors que han tingut estudiants amb discapacitat entre el seu alumnat amb l’objectiu de relacionar les seves vivències i punts de vista amb les idees dels investigadors més rellevants que presento en el marc teòric. Els resultats obtinguts demostren, d���una banda, que a les universitats catalanes hi ha poca formació en aquest àmbit, de l’altra, que a la figura de suport tot i ser de gran ajut si l’administració la concedeix li manquen coneixements d���educació física i, finalment, que la implicació de la família de l’alumnat és, sovint, imprescindible. D���altra banda, també s’ha detectat que la formació universitària va enfocada a un alumnat “estàndard���, i, respecte la figura de suport, cal destacar la reivindicació del professorat per exercir el dret a decidir sobre la necessitat o no d���aquesta figura.

Functional and evolutionary analysis of DXL1, a non-essential gene encoding a 1-deoxy-D-xylulose 5-phosphate synthase like protein in Arabidopsis thaliana

The synthesis of 1-deoxy-D-xylulose 5-phosphate (DXP), catalyzed by the enzyme DXP synthase (DXS), represents a key regulatory step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis. In plants DXS is encoded by small multigene families that can be classified into, at least, three specialized subfamilies. Arabidopsis thaliana contains three genes encoding proteins with similarity to DXS, including the well-known DXS1/CLA1 gene, which clusters within subfamily I. The remaining proteins, initially named DXS2 and DXS3, have not yet been characterized. Here we report the expression and functional analysis of A. thaliana DXS2. Unexpectedly, the expression of DXS2 failed to rescue Escherichia coli and A. thaliana mutants defective in DXS activity. Coherently, we found that DXS activity was negligible in vitro, being renamed as DXL1 following recent nomenclature recommendation. DXL1 is targeted to plastids as DXS1, but shows a distinct expression pattern. The phenotypic analysis of a DXL1 defective mutant revealed that the function of the encoded protein is not essential for growth and development. Evolutionary analyses indicated that DXL1 emerged from DXS1 through a recent duplication apparently specific of the Brassicaceae lineage. Divergent selective constraints would have affected a significant fraction of sites after diversification of the paralogues. Furthermore, amino acids subjected to divergent selection and likely critical for functional divergence through the acquisition of a novel, although not yet known, biochemical function, were identified. Our results provide with the first evidences of functional specialization at both the regulatory and biochemical level within the plant DXS family.

Gleevec, an Abl family inhibitor, produces a profound change in cell shape and migration (in press)

The issue of how contractility and adhesion are related to cell shape and migration pattern remains largely unresolved. In this paper we report that Gleevec (Imatinib), an Abl family kinase inhibitor, produces a profound change in the shape and migration of rat bladder tumor cells (NBTII) plated on collagen-coated substrates. Cells treated with Gleevec adopt a highly spread D-shape and migrate more rapidly with greater persistence. Accompanying this more spread state is an increase in integrin-mediated adhesion coupled with increases in the size and number of discrete adhesions. In addition, both total internal reflection fluorescence microscopy (TIRFM) and interference reflection microscopy (IRM) revealed a band of small punctate adhesions with rapid turnover near the cell leading margin. These changes led to an increase in global cell-substrate adhesion strength, as assessed by laminar flow experiments. Gleevec-treated cells have greater RhoA activity which, via myosin activation, led to an increase in the magnitude of total traction force applied to the substrate. These chemical and physical alterations upon Gleevec treatment produce the dramatic change in morphology and migration that is observed.

Risk factors for colorectal cancer in subjects with family history of the disease.

The relationship between lifestyle factors, past medical conditions, daily meal frequency, diet and the risk of 'familial' colorectal cancer has been analysed using data from a case-control study conducted in northern Italy. A total of 1584 colorectal cancer patients and 2879 control subjects were admitted to a network of hospitals in the Greater Milan area and the Pordenone province. The subjects included for analysis were the 112 cases and the 108 control subjects who reported a family history of colorectal cancer in first-degree relatives. Colorectal cancer cases and control subjects with family history were similarly distributed according to sex, age, marital status, years of schooling and social class. Familial colorectal cancer was associated with meal frequency, medical history of diabetes (relative risk, RR = 4.6) and cholelithiasis (RR = 5.2). Significant positive trends of increasing risk with more frequent consumption were observed for pasta (RR = 2.5, for the highest vs the lowest intake tertile), pastries (RR = 2.4), red meat (RR = 2.9), canned meat (RR = 1.9), cheese (RR = 3.5) and butter (RR = 1.9). Significant inverse associations and trends in risk were observed for consumption of poultry (RR = 0.4), tomatoes (RR = 0.2), peppers (RR = 0.3) and lettuce (RR = 0.3). Significant inverse trends in risk with increasing consumption for beta-carotene and ascorbic acid were observed (RR = 0.5 and 0.4 respectively, highest vs lowest intake tertile). These results suggest that risk factors for subjects with a family history of colorectal cancer in first-degree relatives are not appreciably different from recognized risk factors of the disease in the general population.

Coneixements, actituds i percepció versus la infecció per Virus del Papil·loma Humà en els professionals d'infermeria : tend��ncies en salut pública

Actualment, s’evidencia una dificultat en el seguiment estricte de les infeccions de transmissió sexual (ITS). A nivell mundial, aquestes causen un problema de Salut Pública (SP) en termes de morbiditat i mortalitat per complicacions i seqüeles que es poden originar si no es diagnostiquen i no es tracten adequadament. Entre les ITS més comunes trobem la provocada pel Virus del Papil·loma Humà (VPH), la principal causant del càncer de cèrvix, entre altres complicacions La família de VPH compta amb més de 150 tipus virals. El coneixement de la situació epidemiològica de la infecció per VPH es veu dificultada per varis aspectes: el caràcter asimptomàtic; l’estigma social; les dificultats diagnòstiques; la falta de homogeneïtat dels sistemes de vigilància amb la infradeclaració de casos. Ens trobem en una inversemblança constant. Les intervencions des de SP, ja sigui a nivell nacional com regional, sónpròpiament enfocades a la prevenció de la malaltia. Paral·lelament, la incid��ncia de les ITS continua amb una tend��ncia ascendent, cosa que provoca una inquietant preocupació. Partint de la problemàtica exposada, el present estudi pretén identificar elsconeixements que tenen els professionals d���infermeria de l’atenció primària en relació a la infecció de transmissió sexual pel virus del papil·loma humà i quina és la seva percepció i actitud sobre l’atenció a l’usuari. Es tractarà d���un estudi multicèntric amb disseny descriptiu transversal. La instrumentació es farà mitjançant una enquesta totalment anònima sobre una mostra aproximada de 115 professionals d���infermeria que durant l’any 2013 que treballen a les àrees bàsiques de salut (ABS) de l’Institut Català de la Salut (ICS) del Gironès. Aquest estudi vol fer visible la necessitat d���incrementar la formació dels professionals d���infermeria en relació a la infecció VPH i el requeriment d���un consell addicional que promogui la salut encaminat a empoderar a la comunitat mitjançant educació per a la salut