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The plant hormone gibberellin (GA) regulates multiple developmental processes. It accumulates in the root elongating endodermis, but how it moves into this cell file and the significance of this accumulation are unclear. Here we identify three NITRATE TRANSPORTER1/PEPTIDE TRANSPORTER (NPF) transporters required for GA and abscisic acid (ABA) translocation. We demonstrate that NPF2.14 is a subcellular GA/ABA transporter, presumably the first to be identified in plants, facilitating GA and ABA accumulation in the root endodermis to regulate suberization. Further, NPF2.12 and NPF2.13, closely related proteins, are plasma membrane-localized GA and ABA importers that facilitate shoot-to-root GA12 translocation, regulating endodermal hormone accumulation. This work reveals that GA is required for root suberization and that GA and ABA can act non-antagonistically. We demonstrate how the clade of transporters mediates hormone flow with cell-file-specific vacuolar storage at the phloem unloading zone, and slow release of hormone to induce suberin formation in the maturation zone.

The plant hormone gibberellin (GA) regulates multiple developmental processes. It accumulates in the root elongating endodermis, but how it moves into this cell file and the significance of this accumulation are unclear. Here we identify three NITRATE TRANSPORTER1/PEPTIDE TRANSPORTER (NPF) transporters required for GA and abscisic acid (ABA) translocation. We demonstrate that NPF2.14 is a subcellular GA/ABA transporter, presumably the first to be identified in plants, facilitating GA and ABA accumulation in the root endodermis to regulate suberization. Further, NPF2.12 and NPF2.13, closely related proteins, are plasma membrane-localized GA and ABA importers that facilitate shoot-to-root GA translocation, regulating endodermal hormone accumulation. This work reveals that GA is required for root suberization and that GA and ABA can act non-antagonistically. We demonstrate how the clade of transporters mediates hormone flow with cell-file-specific vacuolar storage at the phloem unloading zone, and slow release of hormone to induce suberin formation in the maturation zone.

The plant hormone gibberellin (GA) regulates multiple developmental processes. It accumulates in the root elongating endodermis, but how it moves into this cell file and the significance of this accumulation are unclear. Here we identify three NITRATE TRANSPORTER1/PEPTIDE TRANSPORTER (NPF) transporters required for GA and abscisic acid (ABA) translocation. We demonstrate that NPF2.14 is a subcellular GA/ABA transporter, presumably the first to be identified in plants, facilitating GA and ABA accumulation in the root endodermis to regulate suberization. Further, NPF2.12 and NPF2.13, closely related proteins, are plasma membrane-localized GA and ABA importers that facilitate shoot-to-root GA12 translocation, regulating endodermal hormone accumulation. This work reveals that GA is required for root suberization and that GA and ABA can act non-antagonistically. We demonstrate how the clade of transporters mediates hormone flow with cell-file-specific vacuolar storage at the phloem unloading zone, and slow release of hormone to induce suberin formation in the maturation zone., The plant hormone gibberellin (GA) regulates multiple developmental processes. It accumulates in the root elongating endodermis, but how it moves into this cell file and the significance of this accumulation are unclear. Here we identify three NITRATE TRANSPORTER1/PEPTIDE TRANSPORTER (NPF) transporters required for GA and abscisic acid (ABA) translocation. We demonstrate that NPF2.14 is a subcellular GA/ABA transporter, presumably the first to be identified in plants, facilitating GA and ABA accumulation in the root endodermis to regulate suberization. Further, NPF2.12 and NPF2.13, closely related proteins, are plasma membrane-localized GA and ABA importers that facilitate shoot-to-root GA12 translocation, regulating endodermal hormone accumulation. This work reveals that GA is required for root suberization and that GA and ABA can act non-antagonistically. We demonstrate how the clade of transporters mediates hormone flow with cell-file-specific vacuolar storage at the phloem unloading zone, and slow release of hormone to induce suberin formation in the maturation zone.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people fr

The effects of abscisic acid (ABA) on plant growth, development, and response to the environment depend on local ABA concentrations. Here, we show that in Arabidopsis, ABA homeostasis is regulated by two previously unknown ABA transporters. Adenosine triphosphate-binding cassette subfamily G member 17 (ABCG17) and ABCG18 are localized to the plasma membranes of leaf mesophyll and cortex cells to redundantly promote ABA import, leading to conjugated inactive ABA sinks, thus restricting stomatal closure. ABCG17 and ABCG18 double knockdown revealed that the transporters encoded by these genes not only limit stomatal aperture size, conductance, and transpiration while increasing water use efficiency but also control ABA translocation from the shoot to the root to regulate lateral root emergence. Under abiotic stress conditions, ABCG17 and ABCG18 are transcriptionally repressed, promoting active ABA movement and response. The transport mechanism mediated by ABCG17 and ABCG18 allows plants to maintain ABA homeostasis under normal growth conditions.

The effects of abscisic acid (ABA) on plant growth, development, and response to the environment depend on local ABA concentrations. Here, we show that in Arabidopsis, ABA homeostasis is regulated by two previously unknown ABA transporters. Adenosine triphosphate-binding cassette subfamily G member 17 (ABCG17) and ABCG18 are localized to the plasma membranes of leaf mesophyll and cortex cells to redundantly promote ABA import, leading to conjugated inactive ABA sinks, thus restricting stomatal closure. ABCG17 and ABCG18 double knockdown revealed that the transporters encoded by these genes not only limit stomatal aperture size, conductance, and transpiration while increasing water use efficiency but also control ABA translocation from the shoot to the root to regulate lateral root emergence. Under abiotic stress conditions, ABCG17 and ABCG18 are transcriptionally repressed, promoting active ABA movement and response. The transport mechanism mediated by ABCG17 and ABCG18 allows plants to maintain ABA homeostasis under normal growth conditions.

In recent years, both homing endonucleases (HEases) and zinc-finger nucleases (ZFNs) have been engineered and selected for the targeting of desired human loci for gene therapy. However, enzyme engineering is lengthy and expensive and the off-target effect of the manufactured endonucleases is difficult to predict. Moreover, enzymes selected to cleave a human DNA locus may not cleave the homologous locus in the genome of animal models because of sequence divergence, thus hampering attempts to assess the in vivo efficacy and safety of any engineered enzyme prior to its application in human trials. Here, we show that naturally occurring HEases can be found, that cleave desirable human targets. Some of these enzymes are also shown to cleave the homologous sequence in the genome of animal models. In addition, the distribution of off-target effects may be more predictable for native HEases. Based on our experimental observations, we present the HomeBase algorithm, database and web server that allow a high-throughput computational search and assignment of HEases for the targeting of specific loci in the human and other genomes. We validate experimentally the predicted target specificity of candidate fungal, bacterial and archaeal HEases using cell free, yeast and archaeal assays

Este trabalho é fruto das discussões realizadas em uma das sessões de Cineclube organizadas pelo Grupo de pesquisa “Turismo e Cultura” (UFF) no ano de 2010, dos debates ocorridos em 2011 na disciplina “Turismos, Migrações, Exílios e as Teorias Contemporâneas da Mobilidade” do curso de Doutorado em História, Política e Bens Culturais (Cpdoc/FGV) e das trocas sobrevindas da disciplina optativa que ministrei no curso de graduação em Turismo da UFF em 2011 e em 2012, intitulada “Mobilidades, Lazer e Turismo”. A partir do filme Up in the Air, este artigo pretende discutir os significados que as mobilidades, em seus mais diferentes e interdependentes modos, fornecem às relações sociais construídas nos (inter) espaços e nas redes de sociabilidade contemporâneas, This work is the result of discussions in a Film session organized by the research group "tourism and culture" (UFF) in year 2010, of the debates occurred in 2011 in course “Tourism’s, Migrations, Exiles and the Contemporary Theories of Mobility” of the Doctorate in History, Politics and Cultural Goods (Cpdoc/FGV) and of the exchanges of optional course that I gave in the graduation in Tourism of the UFF in 2011 and 2012, untitled “Mobilities, Leisure and Tourism”. From the movie “Up in the Air”, this article aims to discuss the meanings that mobilities, in his more different and Interdependent modes, provides to social relations built in (inter) spaces and in networks of contemporary sociability

Este trabalho é fruto das discussões realizadas em uma das sessões de Cineclube organizadas pelo Grupo de pesquisa “Turismo e Cultura” (UFF) no ano de 2010, dos debates ocorridos em 2011 na disciplina “Turismos, Migrações, Exílios e as Teorias Contemporâneas da Mobilidade” do curso de Doutorado em História, Política e Bens Culturais (Cpdoc/FGV) e das trocas sobrevindas da disciplina optativa que ministrei no curso de graduação em Turismo da UFF em 2011 e em 2012, intitulada “Mobilidades, Lazer e Turismo”. A partir do filme Up in the Air, este artigo pretende discutir os significados que as mobilidades, em seus mais diferentes e interdependentes modos, fornecem às relações sociais construídas nos (inter) espaços e nas redes de sociabilidade contemporâneas, This work is the result of discussions in a Film session organized by the research group "tourism and culture" (UFF) in year 2010, of the debates occurred in 2011 in course “Tourism’s, Migrations, Exiles and the Contemporary Theories of Mobility” of the Doctorate in History, Politics and Cultural Goods (Cpdoc/FGV) and of the exchanges of optional course that I gave in the graduation in Tourism of the UFF in 2011 and 2012, untitled “Mobilities, Leisure and Tourism”. From the movie “Up in the Air”, this article aims to discuss the meanings that mobilities, in his more different and Interdependent modes, provides to social relations built in (inter) spaces and in networks of contemporary sociability

Background: Prior research suggests that the Big Five personality dimensions might be associated with coping strategies as well as acute psychopathology. The aim of the present study was to investigate direct and indirect associations between the Big Five personality traits, coping styles, and psychopathological variables. Subjects and methods: Subjects were 1140 adults from various institutions and regions in Hungary. A comprehensive test battery was administered including the Big Five Inventory (BFI), Psychological Immune System Inventory (PISI), and some subscales of the Brief Symptom Inventory (BSI). Several moderation-mediation analyses were conducted using the PROCESS tool in SPSS to test for influence paths. Results: Coping and personality variables jointly accounted for 40% to 50% of variance in psychopathology outcome. Personality dimensions of Extraversion, Conscientiousness and Emotional Stability had strongest predictive values. Emotional Stability had a more direct and unmediated effect, whereas Extraversion and Conscientiousness effects were mediated by the Approach and Self-regulation coping systems. In comparison to personality, coping style was generally a stronger predictor. Conclusions: The findings of this study might add to better understanding of complex pathways leading from broad personality dimensions to coping strategies and psychological (mal)adjustment.

BACKGROUND: Aging and degeneration of human intervertebral disc (IVD) are associated with biochemical changes, including racemization and glycation. These changes can only be counteracted by protein turnover. Little is known about the longevity of IVD elastin in health or disease. Yet, such knowledge is important for a quantitative understanding of tissue synthesis and degradation.METHODS: We have measured the accumulation of d-Asp and pentosidine in IVD elastin. Samples representing a broad range of ages (28-82years) and degeneration grades (1-5) were analyzed.RESULTS: d/l-Asp for elastin increased linearly with age from 3.2% (early 30s) to 14.8% (early 80s) for normal tissue (grades 1-2) and from 1.7% (late 20s) to 6.0% (until the mid 50s) for degenerate tissue (grades 3-5) with accumulation rates of 16.2±3.1×10(-4) and 11.7±3.8×10(-4)year(-1), respectively; no significant difference was found between these values (p<0.05). Above the mid 50s, a decrease in d-Asp accumulation was recorded in the degenerate tissue. d-Asp accumulation correlated well with pentosidine content for elastin from healthy and degenerate tissues combined. We conclude that IVD elastin is metabolically-stable and long-lived in both healthy and degenerate human IVDs, with signs of new synthesis in the latter. The correlation of d-Asp with pentosidine content suggests that both these agents may be used as markers in the overall aging process of IVD.GENERAL SIGNIFICANCE: Accumulation of modified IVD elastin argues for its longevity and may have a negative impact on its role in disc function. Weak signs of newly synthesized molecules may act to counteract this effect in degenerate tissue.

BACKGROUND: Aging and degeneration of human intervertebral disc (IVD) are associated with biochemical changes, including racemization and glycation. These changes can only be counteracted by protein turnover. Little is known about the longevity of IVD elastin in health or disease. Yet, such knowledge is important for a quantitative understanding of tissue synthesis and degradation.METHODS: We have measured the accumulation of d-Asp and pentosidine in IVD elastin. Samples representing a broad range of ages (28-82years) and degeneration grades (1-5) were analyzed.RESULTS: d/l-Asp for elastin increased linearly with age from 3.2% (early 30s) to 14.8% (early 80s) for normal tissue (grades 1-2) and from 1.7% (late 20s) to 6.0% (until the mid 50s) for degenerate tissue (grades 3-5) with accumulation rates of 16.2±3.1×10(-4) and 11.7±3.8×10(-4)year(-1), respectively; no significant difference was found between these values (p<0.05). Above the mid 50s, a decrease in d-Asp accumulation was recorded in the degenerate tissue. d-Asp accumulation correlated well with pentosidine content for elastin from healthy and degenerate tissues combined. We conclude that IVD elastin is metabolically-stable and long-lived in both healthy and degenerate human IVDs, with signs of new synthesis in the latter. The correlation of d-Asp with pentosidine content suggests that both these agents may be used as markers in the overall aging process of IVD.GENERAL SIGNIFICANCE: Accumulation of modified IVD elastin argues for its longevity and may have a negative impact on its role in disc function. Weak signs of newly synthesized molecules may act to counteract this effect in degenerate tissue.

We present an embryonic investigation - on the Doctorate in History, Politics and Cultural Goods of Cpdoc/FGV - regarding the origin, constitution and implementation of the idea of social tourism at Sesc, examining the circumstances in which leisure and tourism become relevant to its policies and actions, contextualized by the social and political history of Brazil. In this broad view, we try to comprehend the changes and readjustments that guided the institution?s actions, and how the modifications in the concept of social tourism have been interacting with Sesc?s guidelines, postures and intentions during the last decade. Besides that, we have mapped and analyzed the Brazilian academic production, which, in different manners, has addressed the theme mentioned above. So far, two interviews were performed with the professionals responsible for the sectors of research and documents of the regional administration at the Sesc of Rio de Janeiro and São Paulo – the two regional offices that are most actively and "attentively" involved with the ideas and changes related to the social tourism in the world and present in the history of the Institution and of the social tourism in the country. The main motivation for the development of this investigation is the consideration of the importance to discuss the social tourism, especially in a society that is so infected with social differences, such as the Brazilian society., Apresentamos uma investigação embrionária - no Doutorado em História, Política e Bens Culturais do Cpdoc/FGV - acerca da origem, constituição e implementação da ideia de turismo social no Sesc, examinando as circunstâncias em que o lazer e o turismo tornam-se relevantes nas suas políticas e ações, contextualizadas pela história político-social do Brasil. Neste panorama, procuramos entender as metamorfoses e readequações que nortearam as ações da instituição, e como as modificações no conceito de turismo social vêm dialogando com as diretrizes, posturas e intenções do Sesc nas últimas décadas. Além disso, mapeamos e analisamos a produção acadêmica brasileira, que de forma central ou tangencial, abordou a temática supracitada. Até o momento, foram realizadas duas entrevistas com profissionais responsáveis pelos setores de pesquisa e documentação das administrações regionais do Sesc do Rio de Janeiro e de São Paulo – as duas regionais mais atuantes e "atentas" às idéias e mudanças envolvendo o turismo social no mundo e representativas na história da Instituição e na história do turismo social no país. A motivação central para o desenvolvimento dessa investigação é a consideração da importância de discutir o turismo social, especialmente em uma sociedade tão eivada de desigualdades sociais, como é o caso da brasileira.

We present an embryonic investigation - on the Doctorate in History, Politics and Cultural Goods of Cpdoc/FGV - regarding the origin, constitution and implementation of the idea of social tourism at Sesc, examining the circumstances in which leisure and tourism become relevant to its policies and actions, contextualized by the social and political history of Brazil. In this broad view, we try to comprehend the changes and readjustments that guided the institution?s actions, and how the modifications in the concept of social tourism have been interacting with Sesc?s guidelines, postures and intentions during the last decade. Besides that, we have mapped and analyzed the Brazilian academic production, which, in different manners, has addressed the theme mentioned above. So far, two interviews were performed with the professionals responsible for the sectors of research and documents of the regional administration at the Sesc of Rio de Janeiro and São Paulo – the two regional offices that are most actively and "attentively" involved with the ideas and changes related to the social tourism in the world and present in the history of the Institution and of the social tourism in the country. The main motivation for the development of this investigation is the consideration of the importance to discuss the social tourism, especially in a society that is so infected with social differences, such as the Brazilian society., Apresentamos uma investigação embrionária - no Doutorado em História, Política e Bens Culturais do Cpdoc/FGV - acerca da origem, constituição e implementação da ideia de turismo social no Sesc, examinando as circunstâncias em que o lazer e o turismo tornam-se relevantes nas suas políticas e ações, contextualizadas pela história político-social do Brasil. Neste panorama, procuramos entender as metamorfoses e readequações que nortearam as ações da instituição, e como as modificações no conceito de turismo social vêm dialogando com as diretrizes, posturas e intenções do Sesc nas últimas décadas. Além disso, mapeamos e analisamos a produção acadêmica brasileira, que de forma central ou tangencial, abordou a temática supracitada. Até o momento, foram realizadas duas entrevistas com profissionais responsáveis pelos setores de pesquisa e documentação das administrações regionais do Sesc do Rio de Janeiro e de São Paulo – as duas regionais mais atuantes e "atentas" às idéias e mudanças envolvendo o turismo social no mundo e representativas na história da Instituição e na história do turismo social no país. A motivação central para o desenvolvimento dessa investigação é a consideração da importância de discutir o turismo social, especialmente em uma sociedade tão eivada de desigualdades sociais, como é o caso da brasileira.

In recent years, both homing endonucleases (HEases) and zinc-finger nucleases (ZFNs) have been engineered and selected for the targeting of desired human loci for gene therapy. However, enzyme engineering is lengthy and expensive and the off-target effect of the manufactured endonucleases is difficult to predict. Moreover, enzymes selected to cleave a human DNA locus may not cleave the homologous locus in the genome of animal models because of sequence divergence, thus hampering attempts to assess the in vivo efficacy and safety of any engineered enzyme prior to its application in human trials. Here, we show that naturally occurring HEases can be found, that cleave desirable human targets. Some of these enzymes are also shown to cleave the homologous sequence in the genome of animal models. In addition, the distribution of off-target effects may be more predictable for native HEases. Based on our experimental observations, we present the HomeBase algorithm, database and web server that allow a high-throughput computational search and assignment of HEases for the targeting of specific loci in the human and other genomes. We validate experimentally the predicted target specificity of candidate fungal, bacterial and archaeal HEases using cell free, yeast and archaeal assays