Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization

The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (A beta) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low mu molar range) and are moderate/good inhibitors of A beta self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the p-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu2+ and Zn2+ (pCu = 14.3, pZn = 6.4, pH 7.4, C-I/C-M = 10, C-M = 10(-6) M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Ali-induced cell toxicity

Variação intra e interpessoal como fatores determinantes para o cálculo do número de observações para estimar a ingestão dietética habitual de adolescentes

This cross-sectional study describes the variation in the dietary intake of energy and macronutrients based on estimated coefficients of within- and between-person variation and intends to calculate the number of days required to evaluate the dietary intake of adolescents in Piracicaba, Brazil. The sample was made up by ninety-two adolescents aged between eleven and sixteen years. Interviews were performed to assess demographic, anthropometric and dietary variables, which were evaluated by the answers obtained through two 24-hour recalls. Descriptive analyses were performed and variances and Coefficients of variation within- and between-person were obtained by results of one-way ANOVA. The mean energy intake observed was 2,326.2 kilocalories; mean macronutrient intake came to 89.0 grams of fatty acids, 305.3 grams of carbohydrates and 82.2 grams of proteins. Coefficients of within-person variation ranged from 36% to 45%, while between-person coefficients varied from 26% to 31%. Variance ratios ranged from 1.35 (carbohydrate) to 2.62 (protein). The lowest number of observations required to correctly evaluate the usual diet calculated (r = 0.90) was six days, for carbohydrates while the highest was eleven, for proteins. Coefficients of variation were similar to those observed in international studies. We conclude that, in this study, two observations were sufficient to obtain reasonable correlations. However, six evaluations are necessary for these adolescents in order to obtain excellent correlations.Este estudo transversal descreve a variabilidade do consumo alimentar de energia e macronutrientes a partir da estimativa dos coeficientes de variação intra e interpessoal e calcula o número de dias necessários para se avaliar a ingestão dietética de adolescentes de Piracicaba, Brasil. A amostra foi constituída por 92 adolescentes com idade entre 11 e 16 anos. Por meio de entrevistas, foram avaliadas variáveis demográficas, antropométricas e de ingestão dietética, levantada por meio de dois Recordatórios de 24h. Foram realizadas análises descritivas, sendo que as variâncias e os coeficientes de variação intra e interpessoal foram obtidos a partir dos resultados da ANOVA com um fator de classificação. O consumo médio de energia observado foi de 2.326,2 Kcal, e em relação aos macronutrientes foram observados valores de 89,0g de lipídios, 305,3g de carboidratos e 82,2g de proteínas. Os coeficientes de variação intrapessoal variaram de 36% a 45% enquanto os coeficientes de variação interpessoal variaram de 26% a 31%. A razão entre as variâncias variou de 1,35 (carboidrato) a 2,62 (proteína). O menor número de observações necessárias para avaliar corretamente (r = 0,90) a dieta habitual foi de 6 dias para carboidratos. O maior número foi para proteínas (11 dias). Os coeficientes de variação foram semelhantes aos observados em estudos internacionais. Conclui-se que, para o presente estudo, duas observações foram suficientes para a obtenção de coeficientes de correlação razoáveis. No entanto, para se obter ótimos coeficientes de correlação, são necessárias no mínimo seis avaliações destes adolescentes.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Environmental Risk Assessment Based on High-Resolution Spatial Maps of Potentially Toxic Elements Sampled on Stream Sediments of Santiago, Cape Verde

Geochemical mapping is the base knowledge to identify the regions of the planet with critical contents of potentially toxic elements from either natural or anthropogenic sources. Sediments, soils and waters are the vehicles which link the inorganic environment to life through the supply of essential macro and micro nutrients. The chemical composition of surface geological materials may cause metabolic changes which may favor the occurrence of endemic diseases in humans. In order to better understand the relationships between environmental geochemistry and public health, we present environmental risk maps of some harmful elements (As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, V, and Zn) in the stream sediments of Santiago, Cape Verde, identifying the potentially harmful areas in this island. The Estimated Background Values (EBV) of Cd, Co, Cr, Ni and V were found to be above the Canadian guidelines for any type of use of stream sediments and also above the target values of the Dutch and United States guidelines. The Probably Effect Concentrations (PEC), above which harmful effects are likely in sediment dwelling organisms, were found for Cr and Ni. Some associations between the geological formations of the island and the composition of stream sediments were identified and confirmed by descriptive statistics and by Principal Component Analysis (PCA). The EBV spatial distribution of the metals and the results of PCA allowed us to establish relationships between the EBV maps and the geological formations. The first two PCA modes indicate that heavy metals in Santiago stream sediments are mainly originated from weathering of underlying bedrocks. The first metal association (Co, V, Cr, and Mn; first PCA mode) consists of elements enriched in basic rocks and compatible elements. The second association of variables (Zn and Cd as opposed to Ni; second PCA mode) appears to be strongly controlled by the composition of alkaline volcanic rocks and pyroclastic rocks. So, the second PCA mode is also considered as a natural lithogenic mode. The third association (Cu and Pb; third PCA mode) consists of elements of anthropogenic origin

A Hexanuclear Mixed-Valence Oxovanadium(IV,V) Complex as a Highly Efficient Alkane Oxidation Catalyst

The new hexanuclear mixed-valence vanadium complex [V3O3(OEt)(ashz)(2)(mu-OEt)](2) (1) with an N,O-donor ligand is reported. It acts as a highly efficient catalyst toward alkane oxidations by aqueous H2O2. Remarkably, high turnover numbers up to 25000 with product yields of up to 27% (based on alkane) stand for one of the most active systems for such reactions

A Prediction Algorithm For Drug Response In Patients With Mesial Temporal Lobe Epilepsy Based On Clinical And Genetic Information

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms ( SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner.121FAPESP [2013/07559-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

(2R)-Ethyl 2-(5-bromo-2,3-dioxoindolin-1-yl)propanoate

The title compound, C13H12BrNO4, was obtained from an optically active aniline derivative. The structure was characterized by 1H NMR, 13C NMR, MS and X-ray diffraction techniques. 86% of the atoms of the two independent mol­ecules in the asymmetric unit show non-crystallographic inversion symmetry

Dectin-1 Activation Exacerbates Obesity and Insulin Resistance in the Absence of MyD88

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant numbers 11/15682-4, 12/02270-2, 15/18121-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Regenera INCT Process Grant 465656/2014-5). JL is funded by the NIH/NIDDK R01DK106210. GDB is funded by the Wellcome Trust and the MRC Centre for Medical Mycology. Open access journalPeer reviewedPublisher PD

A genome-wide association study for morphometric traits in quarter horse

A genome-wide association study for morphometric traits was conducted in 184 Quarter Horses, 120 from a racing population, and 64 from a cutting population, which were genotyped using the Illumina EquineSNP50 chip. Association analysis was performed with 42,058 single-nucleotide polymorphisms (SNPs) (after quality control) using Qxpak5 software. The following traits were measured: weight (W), rump length (RL), and body length (BL). These morphometric traits are important for the best performance in race and cutting events. For weight, three SNPs associated (P < .0001) were found on chromosomes (Equus caballus autosomes [ECA]) 2 and 3. For rump length, eight SNPs associated (P < .0001) were found on ECA 2, 3, 6, 7, 9, 21, and 26. On ECA 3 and ECA 8, two SNPs were associated (P < .0001) with body length. So, a total of 13 important chromosomal regions were identified with Q values of 0.53 (SNPs for W), 0.40 (SNPs for RL), and 0.99 (SNPs for BL). Positional and functional candidate genes emerging from this study were WWOX and AAVPR1A. Further studies are required to confirm these associations in other populations. (c) 2014 Elsevier Inc. All rights reserved