New Interaction Partners For Nek4.1 And Nek4.2 Isoforms: From The Dna Damage Response To Rna Splicing.

Neks are serine-threonine kinases that are similar to NIMA, a protein found in Aspergillus nidulans which is essential for cell division. In humans there are eleven Neks which are involved in different biological functions besides the cell cycle control. Nek4 is one of the largest members of the Nek family and has been related to the primary cilia formation and in DNA damage response. However, its substrates and interaction partners are still unknown. In an attempt to better understand the role of Nek4, we performed an interactomics study to find new biological processes in which Nek4 is involved. We also described a novel Nek4 isoform which lacks a region of 46 amino acids derived from an insertion of an Alu sequence and showed the interactomics profile of these two Nek4 proteins. Isoform 1 and isoform 2 of Nek4 were expressed in human cells and after an immunoprecipitation followed by mass spectrometry, 474 interacting proteins were identified for isoform 1 and 149 for isoform 2 of Nek4. About 68% of isoform 2 potential interactors (102 proteins) are common between the two Nek4 isoforms. Our results reinforce Nek4 involvement in the DNA damage response, cilia maintenance and microtubule stabilization, and raise the possibility of new functional contexts, including apoptosis signaling, stress response, translation, protein quality control and, most intriguingly, RNA splicing. We show for the first time an unexpected difference between both Nek4 isoforms in RNA splicing control. Among the interacting partners, we found important proteins such as ANT3, Whirlin, PCNA, 14-3-3ε, SRSF1, SRSF2, SRPK1 and hNRNPs proteins. This study provides new insights into Nek4 functions, identifying new interaction partners and further suggests an interesting difference between isoform 1 and isoform 2 of this kinase. Nek4 isoform 1 may have similar roles compared to other Neks and these roles are not all preserved in isoform 2. Besides, in some processes, both isoforms showed opposite effects, indicating a possible fine controlled regulation.

Epilepsia e atividade fisica : um estudo em crianças e adolescentes epileticos

Universidade Estadual de Campinas . Faculdade de Educação Física

A novel missense mutation p.L76P in the GJB2 gene causing nonsyndromic recessive deafness in a Brazilian family

Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of nonsyndromic recessive hearing loss in many countries. We report here on a novel point mutation in GJB2, p.L76P (c.227C>T), in compound heterozygosity with a c.35delG mutation, in two Brazilian sibs, one presenting mild and the other profound nonsyndromic neurosensorial hearing impairment. Their father, who carried a wild-type allele and a p.L76P mutation, had normal hearing. The mutation leads to the substitution of leucine (L) by proline (P) at residue 76, an evolutionarily conserved position in Cx26 as well as in other connexins. This mutation is predicted to affect the first extracellular domain (EC1) or the second transmembrane domain (TM2). EC1 is important for connexon-connexon interaction and for the control of channel voltage gating. The segregation of the c.227C>T (p.L76P) mutation together with c.35delG in this family indicates a recessive mode of inheritance. The association between the p.L76P mutation and hearing impairment is further supported by its absence in a normal hearing control group of 100 individuals, 50 European-Brazilians and 50 African-Brazilians.

Environmental Risk Factors for Parkinson's Disease

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

The efficacy of a universal school-based program to prevent adolescent depression

Evaluated whether a universal school-based program, designed to prevent depression in adolescents, could be effectively implemented within the constraints of the school environment. Participants were 260 Year 9 secondary school students. Students completed measures of depressive symptoms and hopelessness and were then assigned to 1 of 3 groups: (a) Resourceful Adolescent Program Adolescents (RAP A), an 11-session school-based resilience building program, as part of the school curriculum; (b) Resourceful Adolescent Program-Family (RAP-F), the same program as in RAP A, but in which each student's parents were also invited to participate in a 3-session parent program; and (c) Adolescent Watch, a comparison group in which adolescents simply completed the measures. The program was implemented with a high recruitment (88%), low attrition rate (5.8%), and satisfactory adherence to program protocol. Adolescents in either of the RAP programs reported significantly lower levels of depressive symptomatology and hopelessness at post-intervention and 10-month follow-up, compared with those in the comparison group. Adolescents also reported high satisfaction with the program. The study provides evidence for the efficacy of a school-based universal program designed to prevent depression in adolescence.

Childhood absence epilepsy and febrile seizures: A family with a GABAA receptor mutation

Although several genes for idiopathic epilepsies from families with simple Mendelian inheritance have been found, genes for the common idiopathic generalized epilepsies, where inheritance is complex, presently are elusive. We studied a large family with epilepsy where the two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), which offered a special opportunity to identify epilepsy genes. A total of 35 family members had seizures over four generations. The phenotypes comprised typical CAE (eight individuals); FS alone (15), febrile seizures plus (FS+) (three); myoclonic astatic epilepsy (two); generalized epilepsy with tonic-clonic seizures alone (one); partial epilepsy (one); and unclassified epilepsy despite evaluation (two). In three remaining individuals, no information was available. FS were inherited in an autosomal dominant fashion with 75% penetrance. The inheritance of CAE in this family was not simple Mendelian, but suggestive of complex inheritance with the involvement of at least two genes. A GABA(A) receptor gamma2 subunit gene mutation on chromosome 5 segregated with FS, FS+ and CAE, and also occurred in individuals with the other phenotypes. The clinical and molecular data suggest that the GABA(A) receptor subunit mutation alone can account for the FS phenotype. An interaction of this gene with another gene or genes is required for the CAE phenotype in this family. Linkage analysis for a putative second gene contributing to the CAE phenotype suggested possible loci on chromosomes 10, 13, 14 and 15. Examination of these loci in other absence pedigrees is warranted.

Impact of undergraduate and postgraduate rural training, and medical school entry criteria on rural practice among Australian general practitioners: national study of 2414 doctors

Objective To determine the association between rural undergraduate training, rural postgraduate training and medical school entry criteria favouring rural students, on likelihood of working in rural Australian general practice. Methods National case - control study of 2414 rural and urban general practitioners (GPs) sampled from the Health Insurance Commission database. Participants completed a questionnaire providing information on demographics, current practice location and rural undergraduate and postgraduate experience. Results Rural GPs were more likely to report having had any rural undergraduate training [ odds ratio ( OR) 1.61, 95% confidence interval (CI) 1.32 - 1.95] than were urban GPs. Rural GPs were much more likely to report having had rural postgraduate training ( OR 3.14, 95% CI 2.57 - 3.83). As the duration of rural postgraduate training increased so did the likelihood of working as a rural GP: those reporting that more than half their postgraduate training was rural were most likely to be rural GPs ( OR 10.52, 95% CI 5.39 - 20.51). South Australians whose final high school year was rural were more likely to be rural GPs ( OR 3.18, 95% CI 0.99 - 10.22). Conclusions Undergraduate rural training, postgraduate training and medical school entry criteria favouring rural students, all are associated with an increased likelihood of being a rural GP. Longer rural postgraduate training is more strongly associated with rural practice. These findings argue for continuation of rural undergraduate training opportunities and rural entry schemes, and an expansion in postgraduate training opportunities for GPs.

Characterization of temperature dependent and substrate-binding cleft movements in Bacillus circulans family 11 xylanase: A molecular dynamics investigation

Background: Xylanases (EC 3.2.1.8) hydrolyze xylan, one of the most abundant plant polysaccharides found in nature, and have many potential applications in biotechnology. Methods: Molecular dynamics simulations were used to investigate the effects of temperature between 298 to 338 K and xylobiose binding on residues located in the substrate-binding cleft of the family 11 xylanase from Bacillus circulans (BcX). Results: In the absence of xylobiose the BcX exhibits temperature dependent movement of the thumb region which adopts an open conformation exposing the active site at the optimum catalytic temperature (328 K). In the presence of substrate, the thumb region restricts access to the active site at all temperatures, and this conformation is maintained by substrate/protein hydrogen bonds involving active site residues, including hydrogen bonds between Tyr69 and the 2` hydroxyl group of the substrate. Substrate access to the active site is regulated by temperature dependent motions that are restricted to the thumb region, and the BcX/substrate complex is stabilized by extensive intermolecular hydrogen bonding with residues in the active site. General significance: These results call for a revision of both the ""hinge-bending"" model for the activity of group 11 xylanases, and the role of Tyr69 in the catalytic mechanism. (C) 2009 Elsevier B.V. All rights reserved.

Interaction of adrenocorticotropin peptides with microheterogeneous systems - A fluorescence study

Adrenocorticotropin (ACM) and alpha-melanocyte stimulating hormone (alpha-MSH) are peptides which present many physiological effects related to pigmentation, motor and sexual behavior, learning and memory, analgesia, anti-inflammatory and antipyretic processes. The 13 amino acid residues of alpha-MSH are the same initial sequence of ACM and due to the presence of a tryptophan residue in position 9 of the peptide chain, fluorescence techniques could be used to investigate the conformational properties of the hormones in different environments and the mechanisms of interaction with biomimetic systems like sodium dodecyl sulphate (SDS) micelles, sodium dodecyl sulphate-poly(ethylene oxide) (SDS-PEO) aggregates and neutral polymeric micelles. In buffer solution, fluorescence parameters were typical of peptides containing tryptophan exposed to the aqueous medium and upon addition of surfactant and polymer molecules, the gradual change of those parameters demonstrated the interaction of the peptides with the microheterogeneous systems. From time-resolved experiments it was shown that the interaction proceeded with conformational changes in both peptides, and further information was obtained from quenching of Trp fluorescence by a family of N-alkylpyridinium ions, which possess affinity to the microheterogeneous systems dependent on the length of the alkyl chain. The quenching of Trp fluorescence was enhanced in the presence of charged micelles, compared to the buffer solution and the accessibility of the fluorophore to the quencher was dependent on the peptide and the alkylpyridinium: in ACTH(1-21) highest collisional constants were obtained using ethylpyridinium as quencher, indicating a location of the residue in the surface of the micelle, while in alpha-MSH the best quencher was hexylpyridinium, indicating insertion of the residue into the non-polar region of the micelles. The results had shown that the interaction between the peptides and the biomimetic systems where driven by combined electrostatic and hydrophobic effects: in ACTH(1-24) the electrostatic interaction between highly positively charged C-terminal and negatively charged surface of micelles; and aggregates predominates over hydrophobic interactions involving residues in the central region of the peptide; in alpha-MSH, which presents one residual positive charge, the hydrophobic interactions are relevant to position the Trp residue in the non-polar region of the microheterogeneous systems. (C) 2008 Elsevier B.V. All rights reserved.

Family Environment and Pediatric Major Depressive Disorder

Background: The risks for depression broadly include biological and environmental factors. Furthermore, having a family member suffering from major depression is also likely to have consequences for the family environment. Further research aimed at understanding the effects of having a child with major depression on family interaction patterns is warranted. Methods: We studied 31 families with an 8- to 17-year-old child (mean age +/- SD = 12.9 +/- 2.7 years) who met the DSM-IV criteria for major depressive disorder (MDD) and 34 families with no mentally ill children (mean age 8 SD = 12.6 +/- 2.9 years) or parents. Children and their parents were assessed with the K-SADS-PL (Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version) interview. Parents completed the Moos Family Environment Scale (FES) to assess their perceptions of current family functioning. Data were analyzed using the nonparametric Wilcoxon-Mann-Whitney test. Results: Families of MDD children showed significantly different patterns of family functioning on FES subscales representing relationships and personal growth dimensions. The families with MDD children showed higher levels of conflict (p < 0.001) and lower levels of cohesion (p < 0.001), expressiveness (p = 0.003) and active-recreational orientation (p = 0.02) compared to the families without mentally ill children. Conclusion: Families with MDD children show a lower degree of commitment, provide less support to one another, provide less encouragement to express feelings and have more conflicts compared to families with no mentally ill children or parents. Interventions aimed at improving family dynamics may be beneficial to MDD children and their families. Copyright (C) 2010 S. Karger AG, Basel

Cultural Consonance, a 5HT2A Receptor Polymorphism, and Depressive Symptoms: A Longitudinal Study of Gene x Culture Interaction in Urban Brazil

In this study in urban Brazil we examine, as a predictor of depressive symptoms, the interaction between a single nucleotide polymorphism in the 2A receptor in the serotonin system (-1438G/A) and cultural consonance in family life, a measure of the degree to which an individual perceives her family as corresponding to a widely shared cultural model of the prototypical family. A community sample of 144 adults was followed over a 2-year-period. Cultural consonance in family life was assessed by linking individuals` perceptions of their own families with a shared cultural model of the family derived from cultural consensus analysis. The -1438G/A polymorphism in the 2A serotonin receptor was genotyped using a standard protocol for DNA extracted from leukocytes. Covariates included age, sex, socioeconomic status, and stressful life events. Cultural consonance in family life was prospectively associated with depressive symptoms. In addition, the interaction between genotype and cultural consonance in family life was significant. For individuals with the A/A variant of the -1438G/A polymorphism of the 2A receptor gene, the effect of cultural consonance in family life on depressive symptoms over a 2-year-period was larger (beta = -0.533, P < 0.01) than those effects for individuals with either the G/A (beta = -0.280, P < 0.10) or G/G (beta = -0.272, P < 0.05) variants. These results are consistent with a process in which genotype moderates the effects of culturally meaningful social experience on depressive symptoms. Am. J. Hum. Biol. 21:91-97, 2009. (C) 2008 Wiley-Liss, Inc.

A new integrable model of strongly correlated electrons with Hubbard-like interaction

A new completely integrable model of strongly correlated electrons is proposed which describes two competitive interactions: one is the correlated one-particle hopping, the other is the Hubbard-like interaction. The integrability follows from the fact that the Hamiltonian is derivable from a one-parameter family of commuting transfer matrices. The Bethe ansatz equations are derived by algebraic Bethe ansatz method.

Social competence and peer interactions of students with intellectual disability in an inclusive high school

This paper reports descriptive information on the relationship between social competence and the amount and type of peer interaction for nine adolescents with intellectual disability attending a regular high school. Each adolescent's social competence was assessed using the AAMR Adaptive Behavior Scale-School (2nd edn) (ABS-S:2). Naturalistic observations were conducted to obtain information on the amount and type of peer interaction. Data were analysed to determine the relationship between social competence and peer interactions. Social competence was not consistently correlated with the amount of peer interaction. Results from the naturalistic observations showed individual differences in patterns of peer interaction with a tendency towards more frequent interactions with peers who also had intellectual disabilities. These data suggest that social competence did not significantly influence the amount and type of peer interaction. Implications for facilitating peer interactions between adolescents with and without intellectual disability are discussed.

Matching SOX: partner proteins and co-factors of the SOX family of transcriptional regulators

SOX transcription factors perform a remarkable variety of important roles in vertebrate development, either activating or repressing specific target genes through interaction with different partner proteins. Surprisingly, these interactions are often mediated by the conserved, DNA-binding HMG domain, raising questions as to how each factor's specificity is generated. We propose a model whereby non-HMG domains may influence partner protein selection and/or binding stability.

Experiência sensível na educação : um encontro com a arte

A pesquisa tem como sujeito a criança pequena em uma instituição de educação infantil e investiga processos de formação mediados pela experiência sensível com as artes visuais. A educação infantil é lugar das interações, das brincadeiras e da educação estética, sensível. Problematiza o espaço da alfabetização na escola, restrito à apropriação da linguagem verbal, escrita. Por meio de intervenção, propõe um elo entre a criança, sua cultura e seu meio, sugerindo um contato mais próximo com as múltiplas linguagens e com a educação estética. Investiga a educação infantil como o lugar da experiência, da brincadeira e da formação do ser humano em sua totalidade, que não se limita à alfabetização pautada na linguagem verbal e na fragmentação do saber. Este trabalho foi realizado em uma Creche-Escola do município de Vitória/ES, situada no bairro Jardim da Penha. Tem como público crianças de seis meses a cinco anos, divididas em grupos conforme a faixa etária. A participação ativa da pesquisadora na rotina da instituição pesquisada direcionou a um diálogo com a pesquisa-ação, um tipo de pesquisa de natureza qualitativa que se revela na ação e no discurso, segundo Barbier (2007). Busca analisar os possíveis efeitos dessa experiência estética no cotidiano das crianças, observando como afetam e geram interlocuções com a comunidade escolar e com a família. Fundamenta-se nos conceitos de experiência, sentidos como uma experiência estética e a linguagem visual como uma forma de comunicação nas discussões de Vigotski (2010), Duarte Júnior (2001) e Bakhtin (2010). Procura reconhecer a criança como sujeito ativo, em consonância com as contribuições da Sociologia da Infância, expressa no pensamento de Sarmento (2008). Focaliza a criança como ser social, lúdico, pleno de direitos, apto a viver e ressignificar experiências individuais e sociais. O estudo dialoga com o pensamento de Benjamin (1987) que, em seus escritos filosóficos, revela o conceito de uma infância universal, e de Giorgio Agamben (2005) sobre infância e experiência. Com Angel Pino (2005) analisa a constituição do ser humano como um ser cultural. Apoia-se também em autores que realizam uma reflexão sobre a criança e a infância, como Ribes (2012). Apresenta a Arte como área de conhecimento capaz de formar e inserir a criança em seu meio cultural, proporcionando um conhecimento mais amplo do mundo e da sociedade em que está inserida. Acompanhou quatro momentos que promoveram a aproximação das crianças às expressões artísticas, por meio de visitas a espaços expositivos com a presença da artista plástica, ceramista, a professora Drª. Regina Rodrigues, no espaço educacional. Analisa os processos de interação e a expressão das crianças em face à experiência com a Arte. A chegada ao museu e a interação lúdica das crianças com os espaços, com as obras, com os diversos ambientes e com os mediadores despontou como material potente de conhecimento. A pesquisa mostrou a importância de a instituição de ensino estar aberta à cidade, provocando nas crianças a percepção do pertencimento aos espaços de cultura, lazer e demais lugares que a compõem.