RESUMO
The aggregation of the 42-residue amyloid ß-protein (Aß42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aß42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Aß42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the Aß42-taxifolin adduct was suggested by mass spectrometry, Aß42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of Aß42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Aß42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-Aß42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Aß42 as well as Aß42. Furthermore, interaction of (+)-taxifolin with the ß-sheet region in Aß42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Aß42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of Aß42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.
Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Catecóis/química , Lisina/química , Fragmentos de Peptídeos/química , Quercetina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Catecóis/metabolismo , Humanos , Lisina/metabolismo , Norleucina/química , Norleucina/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Quercetina/química , Quercetina/metabolismoRESUMO
Silymarin, the seed extract of Silybium marianum, has preventive effects against Alzheimer's disease-like pathogenesis in vivo. We isolated (+)-taxifolin (4) from silymarin as an inhibitor of aggregation of the 42-residue amyloid ß-protein. Structure-activity relationship studies revealed the 3',4'-dihydroxyl groups to be critical to the anti-aggregative ability, whereas the 7-hydroxyl group and the stereochemistry at positions 2 and 3 were not important.
Assuntos
Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Quercetina/análogos & derivados , Silimarina/química , Estrutura Secundária de Proteína , Quercetina/química , Quercetina/isolamento & purificação , Quercetina/farmacologia , Relação Estrutura-AtividadeRESUMO
Given mounting aspirations to graduate from college and pervasive difficulties in obtaining a four-year degree, growing numbers of young people in the United States have become "underachievers." Using data from the ongoing Youth Development Study, the authors examine the prevalence of "holding on" and "letting go" of high aspirations and the precursors of these states as youth move from high school through their mid-twenties. They find that advantage stemming from the family of origin and changing occupational circumstances engender persistence or reappraisal of earlier educational goals.
Assuntos
Aspirações Psicológicas , Escolaridade , Motivação , Autoimagem , Baixo Rendimento Escolar , Escolha da Profissão , Emprego/estatística & dados numéricos , Características da Família , Feminino , Objetivos , Humanos , Acontecimentos que Mudam a Vida , Estudos Longitudinais , Masculino , Minnesota , Pais/educação , Meio Social , Fatores Socioeconômicos , Adulto JovemRESUMO
Aggregation of the 42-mer amyloid beta peptide (Abeta42) plays a pivotal role in the pathogenesis of Alzheimer's disease. Recent investigations suggested the isomerization and/or racemization of Asp at position 1, 7, or 23 to be associated with the pathological role of Abeta42. Our previous study indicated that the turn at positions 22 and 23 of Abeta42 is closely related to its neurotoxicity through the formation of radicals. To clarify the contribution of these modifications at Asp23 to the pathology, three isomerized and/or racemized Abeta42 mutants were prepared. l-isoAsp23- and d-Asp23-Abeta42 showed moderate aggregative ability similar to the wild type. However, d-Asp23-Abeta42 was less neurotoxic than the wild type, while l-isoAsp23-Abeta42 was as toxic as the wild type. In contrast, d-isoAsp23-Abeta42 showed weak aggregative ability without neurotoxicity. These results suggest the isomerization and/or racemization of Asp23 not to be related to the pathogenesis, but to be a consequence of chemical reactions during the long-term deposition of fibrils.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neurotoxinas/administração & dosagem , Neurotoxinas/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Animais , Sítios de Ligação , Dimerização , Isomerismo , Células PC12 , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Two-dimensional (2D) layered semiconductors are a novel class of functional materials that are an ideal platform for electronic applications, where the whole electronic states are directly modified by external stimuli adjacent to their electronic channels. Scale-up of the areal coverage while maintaining homogeneous single crystals has been the relevant challenge. We demonstrate that wafer-size single crystals composed of an organic semiconductor bimolecular layer with an excellent mobility of 10 cm2 V-1 s-1 can be successfully formed via a simple one-shot solution process. The well-controlled process to achieve organic single crystals composed of minimum molecular units realizes unprecedented low contact resistance and results in high-speed transistor operation of 20 MHz, which is twice as high as the common frequency used in near-field wireless communication. The capability of the solution process for scale-up coverage of high-mobility organic semiconductors opens up the way for novel 2D nanomaterials to realize products with large-scale integrated circuits on film-based devices.
RESUMO
OBJECTIVES: This study aimed to investigate ideal nurse involvement based on the expectations of patients. Data on conflicts between nurses and patients were obtained. The patient situation involved standard nursing treatment, rather than acute phase or palliative care. METHODS: Questionnaires were distributed among senior nurses attending a series of trainings in 2012 and 2013. The nurses were requested to return their completed questionnaires within two weeks. We ensured the effectiveness of the interview process to obtain accurate answers.The sample comprised 240 head nurses and assistant head nurses who were asked to respond anonymously to 57 questions about non-acute (stable) psychiatric or physical nurse-patient scenarios. Qualitative data analysis was conducted using these responses. RESULTS: We received 41 completed responses (response rate = 17.1%). The expectations of patients and their families were reflected in five categories, namely, inference, empathic understanding, listening attitude, individual treatment, and reliable skills and explanations. Inference was independently categorized as a particularly strong characteristic of Japanese patients' expectations. CONCLUSIONS: Nursing care in situations where conflicts or misunderstandings may arise can be improved by encouraging nurses to be attentive to the moods, feelings, and expectations of patients and their families. The findings from this study can improve the quality of Japanese nursing care with regard to sensing (inferring) and reacting to the expectations of patients.
RESUMO
Using longitudinal data from the Youth Development Study (analytic sample N = 712), we investigate how age, adult role acquisition and attainments, family resources, parent-child relationship quality, school attendance, and life events influence support received from parents in young adulthood. Parental assistance was found to be less forthcoming for those who had made greater progress on the road to adulthood, signified by socioeconomic attainment and union formation. The quality of mother-child and father-child relationships affected parental support in different ways, positively for mothers, negatively for fathers. School enrollment, negative life events, and employment problems were associated with a greater likelihood of receiving support. The findings suggest that parents act as "scaffolding" and "safety nets" to aid their children's successful transition to adulthood.
RESUMO
In general, the enzymes of thermophilic organisms are more resistant to thermal denaturation than are those of mesophilic or psychrophilic organisms. Further, as is true for their mesophilic and psychrophilic counterparts, the activities of thermophilic enzymes are smaller at temperatures that are less than the optimal temperature. In an effort to characterize the properties that would improve its activity at temperatures less than the optimal, we subjected the thermostable Sulfolobus tokodaii (S. tokodaii) 3-isopropylmalate dehydrogenase to two rounds of random mutagenesis and selected for improved low-temperature activity using an in vivo recombinant Escherichia coli system. Five dehydrogenase mutants were purified and their catalytic properties and thermostabilities characterized. The mutations favorably affect the K(m) values for NAD (nicotinamide adenine dinucleotide) and/or the k(cat) values. The results of thermal stability measurements show that, although the mutations somewhat decrease the stability of the enzyme, the mutants are still very resistant to heat. The locations and properties of the mutations found for the S. tokodaii enzyme are compared with those found for the previously isolated low-temperature adapted mutants of the homologous Thermus thermophilus enzyme. However, there are few, if any, common properties that enhance the low-temperature activities of both enzymes; therefore, there may be many ways to improve the low-temperature catalytic activity of a thermostable enzyme.