Intrinsic and damage-induced JAK/STAT signaling regulate developmental timing by the Drosophila prothoracic gland.

Development involves tightly paced, reproducible sequences of events, yet it must adjust to conditions external to it, such as resource availability and organismal damage. A major mediator of damage-induced immune responses in vertebrates and insects is JAK/STAT signaling. At the same time, JAK/STAT activation by the Drosophila Upd cytokines is pleiotropically involved in normal development of multiple organs. Whether inflammatory and developmental JAK/STAT roles intersect is unknown. Here, we show that JAK/STAT is active during development of the prothoracic gland (PG), which controls metamorphosis onset through ecdysone production. Reducing JAK/STAT signaling decreased PG size and advanced metamorphosis. Conversely, JAK/STAT hyperactivation by overexpression of pathway components or SUMOylation loss caused PG hypertrophy and metamorphosis delay. Tissue damage and tumors, known to secrete Upd cytokines, also activated JAK/STAT in the PG and delayed metamorphosis, at least in part by inducing expression of the JAK/STAT target Apontic. JAK/STAT damage signaling, therefore, regulates metamorphosis onset by co-opting its developmental role in the PG. Our findings in Drosophila provide insights on how systemic effects of damage and cancer can interfere with hormonally controlled development and developmental transitions.

ER exit sites in Drosophila display abundant ER-Golgi vesicles and pearled tubes but no megacarriers.

Secretory cargos are collected at endoplasmic reticulum (ER) exit sites (ERES) before transport to the Golgi apparatus. Decades of research have provided many details of the molecular events underlying ER-Golgi exchanges. Essential questions, however, remain about the organization of the ER-Golgi interface in cells and the type of membrane structures mediating traffic from ERES. To investigate these, we use transgenic tagging in Drosophila flies, 3D-structured illumination microscopy (SIM), and focused ion beam scanning electron microscopy (FIB-SEM) to characterize ERES-Golgi units in collagen-producing fat body, imaginal discs, and imaginal discs overexpressing ERES determinant Tango1. Facing ERES, we find a pre-cis-Golgi region, equivalent to the vertebrate ER-Golgi intermediate compartment (ERGIC), involved in both anterograde and retrograde transport. This pre-cis-Golgi is continuous with the rest of the Golgi, not a separate compartment or collection of large carriers, for which we find no evidence. We observe, however, many vesicles, as well as pearled tubules connecting ERES and Golgi.

Um olhar interdisciplinar sobre o trabalho das merendeiras terceirizadas de escolas estaduais do município de Campinas, SP / An interdisciplinary look at the work of outsourced school cooks from state schools in the city of Campinas, state of São Paulo, Brazil

Resumo Introdução: o Programa Nacional de Alimentação Escolar (PNAE) do Brasil é um dos maiores do mundo, porém há poucos estudos que tenham por objeto os responsáveis por sua execução, em especial, as merendeiras. Objetivo: compreender a organização e as características do trabalho das merendeiras, assim como suas consequências, tanto para a implementação do programa de alimentação escolar quanto para as próprias trabalhadoras. Métodos: estudo qualitativo fundamentado na análise ergonômica do trabalho (AET). Os resultados foram discutidos à luz da ergonomia da atividade e da ciência política. Pesquisa realizada em 2017 com oito merendeiras terceirizadas alocadas em três escolas da rede pública estadual em Campinas (SP). Resultados: caracterizou-se o trabalho das merendeiras, seus desafios e desdobramentos. Desvelaram-se as dificuldades da realidade enfrentada nas cozinhas escolares, os principais mecanismos de enfrentamento desenvolvidos por elas para lidar com as demandas do trabalho prescrito pelas instâncias de controle e para viabilizar o trabalho nas condições que lhes são propiciadas. Discutiu-se o papel importante, embora não suficientemente reconhecido, desempenhado por essas profissionais na implementação do PNAE. Conclusão: o duplo olhar teórico possibilitou reconhecer a presença do coping no cotidiano dessas trabalhadoras e permitiu evidenciar os problemas gerados pela terceirização e pela desvalorização do saber prático.

Abstract Introduction: the National School Feeding Program (PNAE), in Brazil, is one of the largest in the world. However, only few studies focus on those who are responsible for its execution, in particular, the school cooks. Objective: to understand the organization and the characteristics of the cooks' work and their consequences, both for the implementation of the school feeding program and for the workers themselves. Methods: qualitative study based on ergonomic work analysis (EWA). The results were discussed according to activity ergonomics and political science. This study, conducted in 2017, involved eight outsourced cooks allocated to three state schools of Campinas public network, in the state of São Paulo, Brazil. Results: the cooks' work was characterized, along with its challenges and developments. The study unveiled the reality faced in school kitchens. We identify the main coping mechanisms developed by the workers to deal with the work prescribed demands and to make it feasible according to the conditions offered to them. We discuss the important role, although not sufficiently recognized, played by these professionals in the implementation of the PNAE. Conclusion: the double theoretical view made it possible to recognize how coping is present in these workers' daily lives and made it possible to highlight the problems generated by outsourcing and the devaluation of practical knowledge.

Suplementação com probióticos e depressão: estratégia terapêutica? / Probiotics supplementation and depression: A therapeutic strategy?

Evidências crescentes de que a microbiota intestinal pode infl uenciar no funcionamento do sistema nervoso central levaram à hipótese de que a suplementação com microrganismos chave pode ter um efeito positivo no tratamento da depressão. O objetivo desta revisão foi compilar dados da literatura científi ca sobre o impacto do uso de probióticos como estratégia terapêutica nos desfechos depressão e sintomas depressivos em humanos. As evidências compiladas nesta revisão indicam que a suplementação com probióticos apresenta potencial promissor como terapia adjuvante no tratamento dos sintomas associados ao transtorno de Depressão Maior e, principalmente, como ação preventiva de quadros depressivos em indivíduos saudáveis ou com depressão leve. O estado da arte aponta para o potencial efeito psicobiótico de determinadas culturas, tais como as espécies Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus helveticus, Bifi dobacterium lactis, Bifidobacterium longum e Bifidobacterium bifidum recomendando-se para os próximos estudos a ênfase nas cepas específicas, dosagem e tempo de consumo para obtenção dos efeitos sobre o eixo intestino-cérebro.

Increasing evidence that the intestinal microbiota may influence central nervous system functioning has led to the hypothesis that supplementation with key microorganisms may have a positive effect on the treatment of depression. The objective of this review was to compile data from the scientific literature about the impact of probiotic use as a therapeutic strategy on depression outcomes and depressive symptoms in humans. The evidence compiled in this review indicates that probiotic supplementation presents promising potential as adjunctive therapy in the treatment of symptoms associated with Major Depressive Disorder and, mainly, as a preventive action of depressive disorders in healthy individuals or with mild depression. The state of the art points to the potential psychobiotic effect of certain cultures, such as the species Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus helveticus, Bifidobacterium lactis, Bifidobacterium longum and Bifidobacterium bifidum, but we recommend for the next studies an emphasis on the specific strains, dosage and time of consumption to obtain the effects on the intestine-brain axis.

Can the elite slalom kayaker's performance be correlated with anthropometric, nutritional, genetic, psychological as sleep traits?

Abstract AIMS The aims of this study were to investigate and characterize the anthropometric, nutritional, genetic, psychological and sleep variables of slalom kayakers, and to verify the correlation of these variables with the slalom kayakers' performance. METHODS Ten elite Brazilian team slalom kayakers participated of this study. Nutritional analysis was made by the Food Record (three days), 24 Hour Dietary Recall and Food Frequency Questionnaire. The ACE I/D, AGTMet235Thr, ACTN3R577X and BDKRB2+9/-9 were genotyped for genetic profile. The Profile of Mood States (POMS) and Sports Competition Anxiety Test (SCAT) were applied to investigate the psychological variables. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleep Scale (ESS) and Morningness-eveningness questionnaire (MEQ) were used for sleep traits analysis. Performance trials were performed on a white-water course with 24 gates, and finish time was considered as the variable related to performance. RESULTS Significant correlations were obtained between Performance Time Trial and %Fat (r=0.77), Energy (r=-0.75), Protein (r=-0.76), Carbohydrate (r=-0.72), Vitamin B6 (r=-0.87), Vitamin A (r=-0.82), Thiamine (r=-0.77), Riboflavin (r=-0.71), Magnesium (r=-0.86) and Phosphorus (r=-0.74) intake, besides the Fatigue mood domain (r=0.73) and the SCAT score (r=0.67). Athletes genotyped with the I, T, R and +9 alelle also presented better performances. CONCLUSIONSIn summary, the novel results provided by this study reinforce the necessity of considering several aspects during athlete development in order to achieve better performance in competitions.

Significados e sentidos atribuídos ao Centro de Atenção Psicossocial Álcool e outras Drogas (CAPS AD) por seus usuários: um estudo de caso / Meanings attributed to Psychosocial Care Center - Alcohol and Other Drugs (CAPS AD) by its users: a case study / Significados y sentidos atribuidos al Centro de Atención Sicosocial Alcohol y otras Drogas (CAPS AD) por sus usuarios: un estudio de caso

Este artigo tem por objetivo apresentar os significados e sentidos de um Centro de Atenção Psicossocial Álcool e outras Drogas (CAPS AD) para seus usuários. Neste estudo de caráter qualitativo, foram realizadas entrevistas semiestruturadas com 11 usuários em acompanhamento no serviço. Os significados e sentidos mais presentes nos discursos indicaram uma relação positiva com o serviço, visto como um local de apoio e cuidado. Constatou-se, também, que o CAPS, ao se mostrar como um local acolhedor e que proporciona o acesso a direitos para além da saúde, precisa ponderar entre o acesso a direitos e benefícios e a construção de autonomia, de forma que o serviço não deixe de atuar no âmbito social, mas, também, possa promover a reinserção social e o empoderamento desses indivíduos.(AU)

This paper aims to present the meanings that a Psychosocial Care Center - Alcohol and Other Drugs (CAPS AD) has from the point of view of its users. This qualitative study made semi-structured interviews with 11 patients currently followed by the CAPS AD. The most present meanings and senses in the discourse indicated a positive relationship with the service, seen as a place of support and care. It was also found that the CAPS, considered as a welcoming place that provides access to rights beyond health, must decide between access to rights and the construction of autonomy, so that the service does not stop acting in the social sphere and it can also promote social integration and empowerment of these individuals.(AU)

El objetivo de este artículo es presentar los significados y sentidos que un Centro de Atención Sicosocial Alcohol y otras Drogas (CAPS AD) tiene para sus usuarios. En este estudio de carácter cualitativo se realizaron entrevistas semi-estructuradas con once usuarios que eran acompañados en el servicio. Los significados y sentidos más presentes en los discursos indicaron una relación positiva con el servicio, visto como un local de apoyo y cuidado. También se constató que el CAPS, al mostrarse como local acogedor y que proporciona el acceso a derechos que van más allá de la salud, precisa ponderar entre el acceso a derechos y beneficios y la construcción de autonomía para que el servicio no deje de actuar en el ámbito social, sino que también pueda promover la reinserción social y el empoderamiento de esas personas.(AU)

Agentes de limpeza terceirizados: entre o ressentimento e o reconhecimento / Outsourced cleaning workers: between resentment and the recognition

Resumo Objetivo: analisar a percepção sobre a atividade de trabalho dos agentes de limpeza terceirizados de uma faculdade pública e determinar seu índice de capacidade para o trabalho. Métodos: foram utilizadas três ferramentas - Análise Coletiva do Trabalho (ACT); Questionário Sociodemográfico de trabalho e de estilo de vida (QSD) e o Índice de Capacidade para o Trabalho (ICT). Resultados/discussão: das 22 agentes de limpeza, seis apresentaram ICT Baixo e Mode­rado, o que as coloca em posição de vulnerabilidade. Para além das demandas físicas de trabalho, as queixas das agentes de limpeza se concentraram nos riscos psicossociais, especialmente relacionados ao estresse e ao assédio moral. As trabalhadoras acreditam no valor de suas atividades, mas manifestaram ressentimento pela falta de reconhecimento por parte dos gestores e usuários da instituição. Conclusão: Fica evidente a necessidade de intervir nesse contexto para a manutenção da capacidade de trabalho e das condições para viver bem destes agentes de limpeza terceirizados.

Abstract Objective: to analyze the perception of the outsourced cleaning workers from a public university on their work activity and to determine their work ability index. Method: three tools were used - Collective Work Analysis; a social-demographic, occupational and lifestyle questionnaire; and Work Ability Index (WAI). Results/discussion: from the 22 cleaning workers, six presented low and moderated WAI, which shows that they are in a vulnerable position. Besides the physical demands, the workers’ complaints were about psychosocial risks, specially related to stress and workplace bullying. Discussion: The cleaning workers believe in the quality value that their activities add to the university and expressed resentment by the lack of recognition from the managers and users of the institution. It is clear that the university needs to intervene in those work conditions so that workers can maintain their work capacity and well being.

Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region.

OBJECTIVE: To determine whether there is an increased risk of hip fracture associated with the use of proton pump inhibitors in a Mediterranean area after adjusting for other potential risk factors. METHODS: Retrospective multicenter case-control study carried out in 6 primary health care centers in Catalonia, Spain. Cases were patients aged 50years and over with a fragility hip fracture registered between January 2007 and December 2010, matched with 2 controls by sex and age. DATA COLLECTED: use of proton pump inhibitors (type, dosage) in the 5years previous to the hip fracture, socio-demographic data, body mass index, alcohol and tobacco consumption as well as health conditions and drugs associated with an increase risk of fragility hip fracture. RESULTS: 358 cases were matched with 698 controls. The mean age was 82years old in both groups. Women represented 77.1% in the case group and 76.9% in the control group. Crude association between proton pump inhibitors and hip fracture was 1.44 (95% CI, 1.09-1.89) and adjusted OR was 1.24 (95% CI, 0.93-1.65). No association was found with the continuous or discontinuous use of proton pump inhibitors, OR 1.17 (95% CI, 0.77-1.79), and OR of 1.16 (95% CI, 0.85-1.60) respectively. No association was found when restricting the analysis by sex, OR of 1.19 (95% CI, 0.27-5.14) or by age, younger or older than 80years, OR of 0.72 (95% CI, 0.24-2.15). CONCLUSION: The use of proton pump inhibitors was not associated with an increased risk of hip fracture after adjusting for other risk factors in a Mediterranean area. This result suggests the existence of protective environmental factors linked to this southern area of Europe that eventually could compensate for the potential harm produced by proton pump inhibitors.

Access to the nucleus and functional association with c-Myc is required for the full oncogenic potential of ΔEGFR/EGFRvIII.

ΔEGFR is a potent glioblastoma oncogene which has been studied primarily as a plasma membrane kinase. Using intracranial xenograft studies in mice, we show that blocking ΔEGFR access to the nucleus attenuates its tumorigenicity and, conversely, that promoting nuclear accumulation enhances this, providing the first in vivo evidence that the nuclear actions of ΔEGFR contribute strongly to its oncogenic function. Nuclear actions of ΔEGFR include regulation of gene expression by participation in chromatin-bound complexes, and genome-wide mapping of these sequences by chromatin immunoprecipitation and massively parallel sequencing identified 2294 peaks. Bioinformatic analysis showed enrichment of the E-box motif in the dataset, and c-Myc and ΔEGFR were corecruited to the promoters of and transcriptionally activated a subset of nuclear ΔEGFR chromatin targets. Knockdown of c-Myc decreased the expression of these targets and diminished ΔEGFR-stimulated anchorage-independent colony formation. We conclude that transcriptional regulation of target genes by association with gene regulatory chromatin in cooperation with c-Myc by nuclear ΔEGFR makes a unique contribution to its oncogenicity and propose that this venue provides new targets for therapeutic intervention.

Yeast Gis2 and its human ortholog CNBP are novel components of stress-induced RNP granules.

Although a CCTG expansion in the gene encoding the zinc knuckle protein CNBP causes a common form of muscular dystrophy, the function of both human CNBP and its putative budding yeast ortholog Gis2 remain poorly understood. Here we report the protein interactions of Gis2 and the subcellular locations of both Gis2 and CNBP. We found that Gis2 exhibits RNA-dependent interactions with two proteins involved in mRNA recognition, the poly(A) binding protein and the translation initiation factor eIF4G. We show that Gis2 is a component of two large RNA-protein granules, processing bodies and stress granules, which contain translationally repressed mRNAs. Consistent with a functional ortholog, CNBP also associates with the poly(A) binding protein and accumulates in stress granules during arsenite treatment of human cells. These results implicate both Gis2 and CNBP in mRNA handling during stress.

Psicologia e saúde: a terapia comunitária como instrumento de sensibilização para o trabalho com comunidades na formação do Psicólogo / Psychology and health: community therapy as a tool of awareness for the work with communities in Psychology formation / Psicología y salud: la terapia comunitaria como instrumento de sensibilización para el trabajo con comunidades en la formación del Psicólogo

A participação do psicólogo na atenção primária implica uma preparação para esse campo de trabalho. A terapia comunitária vem de encontro a essa proposta oferecendo ao psicólogo um instrumento de trabalho de promoção e prevenção em saúde mental. Este trabalho corresponde ao relato de experiência da autora no curso de Psicologia, sendo que, na reformulação do currículo desse curso, foi possível incluir a terapia comunitária a partir do 2º semestre de 2005, com a finalidade de oferecer aos alunos(as) uma visão diferente em relação à promoção e à prevenção em saúde nas comunidades. Foi possível observar que os alunos(as) desenvolveram uma postura crítica em relação ao uso das técnicas e de sua contribuição para o desenvolvimento das comunidades, sensibilizaram-se com a sua dor e o seu sofrimento, ressignificando, assim, o próprio conceito de sofrimento. Do atendimento clínico/individual, avançaram na direção de um trabalho mais coletivo e comunitário.(AU)

The involvement of psychologists in primary attention includes a preparation for this field of work. The community therapy takes part in this proposal offering psychologists a tool for the promotion and prevention in mental health. This paper is the report of the author’s experience in a university course of psychology, and the redevelopment of the course curriculum included community therapy since the 2nd semester of 2005, aiming to offer students a different view of health promotion and prevention in communities. It was observed that the students began to present a critical posture in relation to the use of techniques and to their contribution to the development of communities, for they became aware of their pain and suffering, re-signifying their own concept of suffering. From the clinical/individual care, they moved on to a more collective and communitarian work.(AU)

La participación del psicólogo en la atención primaria implica una preparación para ese campo de trabajo. La terapia comunitaria viene de encuentro a esa propuesta ofreciendo al psicólogo un instrumento de trabajo de promoción y prevención en salud mental. Este trabajo corresponde al relato de experiencia de la autora en el curso de Psicología, siendo que, en la reformulación del currículo de ese curso, fue posible incluir la terapia comunitaria a partir del 2º semestre de 2005, con la finalidad de ofrecer a los alumnos(as) una visión diferente en relación a la promoción y a la prevención en salud en las comunidades. Fue posible observar que los alumnos(as) desarrollaron una postura crítica en relación al uso de las técnicas y de su contribución para el desarrollo de las comunidades, se sensibilizaron con su dolor y su sufrimiento, dando un nuevo significado entonces al propio concepto de sufrimiento. De la atención clínico/individual, avanzaron en dirección a un trabajo más colectivo y comunitario.(AU)

Psicologia e saúde: a terapia comunitária como instrumento de sensibilização para o trabalho com comunidades na formação do Psicólogo / Psychology and health: community therapy as a tool of awareness for the work with communities in Psychology formation / Psicología y salud: la terapia comunitaria como instrumento de sensibilización para el trabajo con comunidades en la formación del Psicólogo

A participação do psicólogo na atenção primária implica uma preparação para esse campo de trabalho. A terapia comunitária vem de encontro a essa proposta oferecendo ao psicólogo um instrumento de trabalho de promoção e prevenção em saúde mental. Este trabalho corresponde ao relato de experiência da autora no curso de Psicologia, sendo que, na reformulação do currículo desse curso, foi possível incluir a terapia comunitária a partir do 2º semestre de 2005, com a finalidade de oferecer aos alunos(as) uma visão diferente em relação à promoção e à prevenção em saúde nas comunidades. Foi possível observar que os alunos(as) desenvolveram uma postura crítica em relação ao uso das técnicas e de sua contribuição para o desenvolvimento das comunidades, sensibilizaram-se com a sua dor e o seu sofrimento, ressignificando, assim, o próprio conceito de sofrimento. Do atendimento clínico/individual, avançaram na direção de um trabalho mais coletivo e comunitário....(AU)

The involvement of psychologists in primary attention includes a preparation for this field of work. The community therapy takes part in this proposal offering psychologists a tool for the promotion and prevention in mental health. This paper is the report of the author’s experience in a university course of psychology, and the redevelopment of the course curriculum included community therapy since the 2nd semester of 2005, aiming to offer students a different view of health promotion and prevention in communities. It was observed that the students began to present a critical posture in relation to the use of techniques and to their contribution to the development of communities, for they became aware of their pain and suffering, re-signifying their own concept of suffering. From the clinical/individual care, they moved on to a more collective and communitarian work....(AU)

La participación del psicólogo en la atención primaria implica una preparación para ese campo de trabajo. La terapia comunitaria viene de encuentro a esa propuesta ofreciendo al psicólogo un instrumento de trabajo de promoción y prevención en salud mental. Este trabajo corresponde al relato de experiencia de la autora en el curso de Psicología, siendo que, en la reformulación del currículo de ese curso, fue posible incluir la terapia comunitaria a partir del 2º semestre de 2005, con la finalidad de ofrecer a los alumnos(as) una visión diferente en relación a la promoción y a la prevención en salud en las comunidades. Fue posible observar que los alumnos(as) desarrollaron una postura crítica en relación al uso de las técnicas y de su contribución para el desarrollo de las comunidades, se sensibilizaron con su dolor y su sufrimiento, dando un nuevo significado entonces al propio concepto de sufrimiento. De la atención clínico/individual, avanzaron en dirección a un trabajo más colectivo y comunitario....(AU)

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.

Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty-three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III-IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant-related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11-110), the event free survival and OS were 0.49 (95% CI: 0.31-0.67) and 0.53 (CI: 0.44-0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.

Genomewide expression profiling of cryptolepine-induced toxicity in Saccharomyces cerevisiae.

We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by either increasing cell permeability (Deltaerg6 or ISE2 strains) or disrupting DNA damage repair (Deltarad52 strains). These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC(20) and IC(40)]) were analyzed by comparing the gene expression profiles of treated and untreated Deltaerg6 yeast cells. Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated). General stress-related genes constituted the only recognizable functional cluster whose expression was increased upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this finding supports the utility of S. cerevisiae in drug-developing schemes.

Selective inhibition of yeast regulons by daunorubicin: a transcriptome-wide analysis.

BACKGROUND: The antitumor drug daunorubicin exerts some of its cytotoxic effects by binding to DNA and inhibiting the transcription of different genes. We analysed this effect in vivo at the transcriptome level using the budding yeast Saccharomyces cerevisiae as a model and sublethal (IC40) concentrations of the drug to minimise general toxic effects. RESULTS: Daunorubicin affected a minor proportion (14%) of the yeast transcriptome, increasing the expression of 195 genes and reducing expression of 280 genes. Daunorubicin down-regulated genes included essentially all genes involved in the glycolytic pathway, the tricarboxylic acid cycle and alcohol metabolism, whereas transcription of ribosomal protein genes was not affected or even slightly increased. This pattern is consistent with a specific inhibition of glucose usage in treated cells, with only minor effects on proliferation or other basic cell functions. Analysis of promoters of down-regulated genes showed that they belong to a limited number of transcriptional regulatory units (regulons). Consistently, data mining showed that daunorubicin-induced changes in expression patterns were similar to those observed in yeast strains deleted for some transcription factors functionally related to the glycolysis and/or the cAMP regulatory pathway, which appeared to be particularly sensitive to daunorubicin. CONCLUSION: The effects of daunorubicin treatment on the yeast transcriptome are consistent with a model in which this drug impairs binding of different transcription factors by competing for their DNA binding sequences, therefore limiting their effectiveness and affecting the corresponding regulatory networks. This proposed mechanism might have broad therapeutic implications against cancer cells growing under hypoxic conditions.

Circumvention of the multidrug-resistance protein (MRP-1) by an antitumor drug through specific inhibition of gene transcription in breast tumor cells.

Multidrug-resistance protein 1 (MRP-1) confers resistance to a number of clinically important chemotherapeutic agents. The promoter of the mrp-1 gene contains an Sp1-binding site, which we targeted using the antitumor bis-anthracycline WP631. When MCF-7/VP breast cancer cells, which overexpress MRP-1 protein, were incubated with WP631 the expression of the multidrug-resistance protein gene decreased. Conversely, doxorubicin did not alter mrp-1 gene expression. The inhibition of gene expression was followed by a decrease in the activity of the MRP-1 protein. The IC(75) for WP631 (drug concentration required to inhibit cell growth by 75%) circumvented the drug-efflux pump, without addition of resistant modifiers. After treatment with WP631, MCF-7/VP cells were committed to die after entering mitosis (mitotic catastrophe), while treatment with doxorubicin did not affect cell growth. This is the first report on an antitumor drug molecule inhibiting the mrp-1 gene directly, rather than being simply a poor substrate for the transporter-mediated efflux. However, both situations appeared to coexist, thereby a superior cytotoxic effect was attained. Ours results suggest that WP631 offers great potential for the clinical treatment of tumors displaying a multidrug-resistance phenotype.

Cryopreserved morulae can be used to efficiently generate germline-transmitting chimeras by blastocyst injection.

The production of chimeric mice is a complex process, requiring the careful coordination of tissue culture cell growth, production of a large number (30-75) of competent blastocysts and the availability of appropriately timed pseudo pregnant female mice. Failure at any of these steps can impinge upon the rapid production of chimeras. One potential improvement for the efficient generation of chimeric mice would be the utilization of cryopreserved embryos suitable for injection. C57Bl/6 morulae were frozen using a standard 2-step protocol with ethylene glycol as the cryopreservation agent. We determined that cryopreserved morulae could thaw, culture to blastocyst stage in KSOM media and survive injection at rates equivalent to control embryos. Cryopreserved morulae were also equivalent to controls at all later stages in the process of production of chimeric mice, including birth rate, percentage chimerism of resulting animals and ability to produce germline progeny. Hence, cryopreservation of morulae for blastocyst injection is a suitable option to enhance the efficiency of chimeric mouse generation.

Valores, família e autodeterminação: questões complexas para pessoas com deficiência mental que envelhecem / Values, family and self determination: complex questions for mental disable people who is getting older

Apresenta questões complexas sobre conceitos de valores, família e autodeterminação que estão intimamente relacionados para pessoas com deficiência mental que estão envelhecendo e para todos que tentam compreendê-las

Promoter-specific inhibition of transcription by daunorubicin in Saccharomyces cerevisiae.

Several anti-tumour drugs exert some of their cytotoxic effects by direct binding to DNA, thus inhibiting the transcription of certain genes. We analysed the influence of the anti-tumour antibiotic daunorubicin on the transcription of different genes in vivo using the budding yeast Saccharomyces cerevisiae. Daunorubicin only affected wild-type yeast strains at very high concentrations; however, erg6 mutant strains (but not pdr1, pdr3 or pdr5 strains) were sensitive to daunorubicin at low micromolar concentrations. In Delta erg6 strains, daunorubicin inhibited the galactose-induced transcription by Gal4p in a specific manner, since the transcription of identical reporters driven by other activators (either constitutive or inducible) was not inhibited. The drug concentrations at which Gal4p function was inhibited did not affect cell growth or viability. Furthermore, daunorubicin inhibited the growth in galactose and the transcriptional induction of resident Gal4p-driven genes upon galactose addition, two processes absolutely dependent on Gal4p function. We propose that daunorubicin and some transcription factors compete for DNA sequences encompassing CpG steps, and that this is the main determinant of the effects of the drug on transcription in vivo. Our approach may foster the development of anti-tumour drugs with more specific mechanisms of action.

Família e deficiência: o significado de conviver e crescer junto a uma pessoa portadora de deficiência mental na idade adulta / Family and mental retardation: the meaning of living and growing up close to a mentally disabled person in adult age

Esta pesquisa levanta alguns elementos que permitem criar subsídios para auxiliar o profissional que trabalha com a deficiência mental e para melhorar o atendimento a estas famílias. Os elementos foram identificados das experiências cotidianas de seis famílias, cada uma com um membro portador de deficiência mental na idade adulta, levantando dados sobre: a construção do conceito de deficiência mental; as formas de agir e de reagir do portador de deficiência e dos demais membros do grupo familiar; a construção das relações familiares; e a compreensão da condição de adulto no portador de deficiência mental. Entendendo a interação entre os diferentes membros do grupo familiar, como um fator determinante na construção das relações da pessoa portadora de deficiência mental, considera-se necessário compreender a forma destes membros lidarem e se relacionarem, durante vinte ou mais anos com esta pessoa. Para tanto, foram entrevistadas mães, pais e irmãos(as), num total de 18 pessoas (seis grupos familiares), cujos filhos e filhas participaram de um programa de adaptação física para portadores de deficiência mental na idade adulta, na FEF-UNICAMP. Abordamos nosso objeto de conhecimento, utilizando para a coleta de informações a entrevista semi-estruturada, realizada durante visitas de observação do cotidiano, no próprio lar de cada entrevistado. Uma vez transcritas as entrevistas, estas foram apresentadas para serem discutidas, corrigidas, completadas por cada pessoa entrevistada. Encontrou-se que: a construção do conceito de deficiência mental depende mais da própria convivência do grupo que de concepções externas; as relações entre os diferentes membros do grupo familiar e a pessoa portadora de deficiência mental são marcadas por uma infinidade de sentimentos positivos ou negativos, gerados, na maioria das vezes, pelos comportamentos do portador de deficiência; o grupo familiar, como intermediário do social, determina e conduz a entrada da pessoa portadora de deficiência na sociedade de acordo com padrões sociais aceitos. Esta tese poderá contribuir para: problematizar o conceito de deficiência; questionar a visão de que a pessoa portadora de deficiência mental é uma eterna criança; esclarecer que o seu desenvolvimento como ser adulto tem a ver sobretudo com aspectos da sua sexualidade, independência e produtividade.