The COP9 SIGNALOSOME is required for postembryonic meristem maintenance in Arabidopsis thaliana

Cullin-RING E3 ligases (CRLs) regulate different aspects of plant development, and are activated by modification of their cullin subunit with the ubiquitin-like protein NEDD8 (NEural precursor cell expressed Developmentally Down-regulated 8) (neddylation) and deactivated by NEDD8 removal (deneddylation). The CONSTITUTIVELY PHOTOMORPHOGENIC9 (COP9) signalosome (CSN) acts as a molecular switch of CRLs activity by reverting their neddylation status, but its contribution to embryonic and early seedling development remains poorly characterized. Here, we analyzed the phenotypic defects of csn mutants and monitored the cullin deneddylation/neddylation ratio during embryonic and early seedling development. We show that while csn mutants can complete embryogenesis (albeit at a slower pace than wild type) and are able to germinate (albeit at a reduced rate), they progressively loose meristem activity upon germination, until they become unable to sustain growth. We also show that the majority of cullin proteins is progressively neddylated during the late stages of seed maturation and becomes deneddylated upon seed germination. This developmentally regulated shift in the cullin neddylation status is absent in csn mutants. We conclude that the CSN and its cullin deneddylation activity are required to sustain postembryonic meristem function in Arabidopsis

Agentes antitumorais inibidores da angiogênese: modelos farmacofóricos para inibidores da integrina ;anb;3

Cancer is one of the leading causes of death. Angiogenesis, the growth of new blood vessels, is essential for tumor development and spreading. Integrins are a family of surface receptors that are involved in angiogenesis. The ;anb;3 integrin plays an important role in tumor angiogenesis. ;anb;3 inhibitors have direct effects to prevent tumor metastases, growth and angiogenesis. In vitro screening of cyclic peptide libraries led to highly active and ;anb;3-selective compounds. Non-peptidic ;anb;3 antagonists were also designed and synthesized. The crystal structure of the ;anb;3 integrin in complex with RGD ligant allowed structure-based rational design of ligands and validation of pharmacophore model to ;anb;3 antagonists.O câncer é, atualmente, uma das principais causas de morte no mundo. A angiogênese, formação de novos vasos capilares a partir de células endoteliais, é essencial para vários processos fisiopatológicos, tais como o desenvolvimento e a disseminação dos tumores. As integrinas são uma família de receptores de superfície que estão envolvidos na angiogênese, na qual a integrina ;anb;3 exerce papel importante. Os antagonistas da integrina ;anb;3 têm efeitos diretos na prevenção do crescimento, angiogênese e metástase tumorais. A avaliação in vitro frente à integrina ;anb;3 de coleções de ciclopeptídeos levou a compostos muito ativos e seletivos. Antagonistas não-peptídicos da integrina ;anb;3 também foram planejados e sintetizados. A partir da determinação da estrutura tridimensional da integrina ;anb;3 complexada com um inibidor, tornou-se possível o planejamento racional de ligantes com alta afinidade. Além disto, estes estudos permitiram a validação e o refinamento de modelo farmacofórico para os inibidores da integrina ;anb;3

Excellent Response to OnabotulinumtoxinA : Different Definitions, Different Predictors

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle

Methylated HBHA produced in <i>M. smegmatis</i> discriminates between active and non-active tuberculosis disease among RD1-responders

Background. A challenge in tuberculosis (TB) research is to develop a new immunological test that can help distinguish, among subjects responsive to QuantiFERON TB Gold In tube (QFT-IT), those who are able to control Mtb replication (remote LTBI, recent infection and past TB) from those who cannot (active TB disease). IFN-γ; response to the Heparin-binding-hemagglutinin (HBHA) of Mtb has been associated with LTBI, but the cumbersome procedures of purifying the methylated and immunological active form of the protein from Mtb or M. bovis Bacillus Calmette et Guerin (BCG) have prevented its implementation in a diagnostic test. Therefore, the aim of the present study was to evaluate the IFN-γ response to methylated HBHA of Mtb produced in M. smegmatis (rHBHAms) in individuals at different stages of TB who scored positive to QFT-IT. Methodology/Principal Findings. 87 individuals at different stages of TB who scored positive to QFT-IT were selected. IFN-γ response to in vitro whole blood stimulation with rHBHAms was evaluated by short-term and long-term tests and detected by ELISA or flow cytometry. We demonstrated that the IFN-γ response to rHBHAms is mediated by CD4+ T-cells with an effector-memory phenotype. This response, evaluated by short-term-tests, is significantly lower in active TB than in remote LTBI (p = 0.0010) and past TB (p = 0.0152). These results were confirmed by long-term tests. The qualitative data confirmed that IFN-γ responses higher than the cut-off point identified by ROC analysis are associated with the status of non-active disease. Conclusions. In this study we show that the T-cell response to a recombinant and methylated HBHA of Mtb produced in M. smegmatis is useful to discriminate between active and non-active TB disease among those responsive to QFT-IT in a whole blood system. Further studies are needed to improve the accuracy of the assay

Materialist and Post-Materialist Concerns and the Wish for a Strong Leader in 27 Countries

There is evidence that democracies are under threat around the world while the quest for strong leaders is increasing. Although the causes of these developments are complex and multifaceted, here we focus on one factor: the extent to which citizens express materialist and post-materialist concerns. We explore whether objective higher levels of democracy are differentially associated with materialist and post-materialist concerns and, in turn, whether this is related to the wish for a strong leader. Testing this hypothesis across 27 countries (N = 5,741) demonstrated a direct negative effect of democracies' development on the wish for a strong leader. Further, multi-level mediation analysis showed that the relation between the Democracy Index and the wish for a strong leader was mediated by materialist concerns. This pattern of results suggests that lower levels of democracy are associated with enhanced concerns about basic needs and this is linked to greater support for strong leaders.Peer reviewe

Materialist and Post-Materialist Concerns and the Wish for a Strong Leader in 27 Countries

There is evidence that democracies are under threat around the world while the quest for strong leaders is increasing. Although the causes of these developments are complex and multifaceted, here we focus on one factor: the extent to which citizens express materialist and post-materialist concerns. We explore whether objective higher levels of democracy are differentially associated with materialist and post-materialist concerns and, in turn, whether this is related to the wish for a strong leader. Testing this hypothesis across 27 countries (N = 5,741) demonstrated a direct negative effect of democracies' development on the wish for a strong leader. Further, multi-level mediation analysis showed that the relation between the Democracy Index and the wish for a strong leader was mediated by materialist concerns. This pattern of results suggests that lower levels of democracy are associated with enhanced concerns about basic needs and this is linked to greater support for strong leaders.Peer reviewe

Revisiting the Measurement of Anomie

Peer reviewe

Cultural Values Moderate the Impact of Relative Deprivation

Relative deprivation (RD) is the judgment that one or one’s ingroup is worse off compared with some relevant standard coupled with feelings of dissatisfaction, anger, and resentment. RD predicts a wide range of outcomes, but it is unclear whether this relationship is moderated by national cultural differences. Therefore, in the first study, we used national assessments of individual-collectivism and power distance to code 303 effect sizes from 31 different countries with 200,578 participants. RD predicted outcomes ranging from life satisfaction to collective action more strongly within individualistic nations. A second survey of 6,112 undergraduate university students from 28 different countries confirmed the predictive value of RD. Again, the relationship between individual RD and different outcomes was stronger for students who lived in more individualistic countries. Group-based RD also predicted political trust more strongly for students who lived in countries marked by lower power distance. RD effects, although consistent predictors, are culturally bounded. In particular, RD is more likely to motivate reactions within individualistic countries that emphasize individual agency and achievement as a source of self-worth

Síntese de derivados da lactose e investigação de sua interação com lectina de Erythrina cristagalli por ensaio de inibição de hemaglutinação

Exportado OPUSMade available in DSpace on 2019-08-12T11:22:33Z (GMT). No. of bitstreams: 1 tese_anna_paola_butera_.pdf: 26799901 bytes, checksum: ae87c9271086e8afd917d2f0ee0dae0e (MD5) Previous issue date: 23Lectinas vegetais são especialmente utilizadas como sistema modelo para o estudo das bases moleculares do reconhecimento lectina-carboidrato. As lectinas são proteínas, desprovidas de atividade enzimática, que se ligam de maneira reversível e específica a mono- e oligossacarídeos. Distinguem-se das imunoglobulinas, que eventualmente reconhecem especificamente antígenos sacarídicos, seja estruturalmente, seja porque estas últimas dependem de estímulo antigênico para serem sintetizadas. Reconhecidamente, as interações entre lectinas e carboidratos desempenham importante papel em diversos processos biológicos. No presente trabalho, descreve-se a síntese vinte e um derivados da lactose, obtidos a partir de modificações na posição anomérica livre, dentre os quais, quatro são lactosilamidas e sulfomidas e oito são lactosídeos aromáticos. Duas outras séries de derivados foram resultantes das modificações nas posições 6 e 6' do lactosideo de 4-metoxicarbonilfenila. A afinidade relativa dos derivados sintetizados foi avaliada por ensaio de inibição da hemaglutinação mediada por lectina isolada das sementes de Erythrina cristagalli. Nenhuma das modificações realizadas na estrutura da lactose resultaram em aumento da afinidade destes compostos pela lectina, sendo que para os lactosídeos 6'-desoxi foi observada diminuição da afinidade.Plant lectins are especially well suited as a model system to study the molecular basis of protein-carbohydrate recognition. Lectins are carbohydrate binding proteins other than immunoglobulins that display no enzymatic activity towards the recognized sugars. Lectincarbohydrate interactions play an important role on a miriad of biological processes. In this work, it is reported the synthesis of twenty one lactose derivatives. Four of them are lactosyl amides (acetamide and benzamide) and sulfonamides (methanesulfonamide and benzenesulfonamide) and eight are aromatic lactosides (benzyl, 2-phenylethyl, phenyl, 4-methoxycarbonylphenyl, 4-carboxylphenyl, 4-methoxycarbonylphenyl-2-nitrophenyl, 2-amino-4-methoxycarbonylphenylphenyl, 2-acetylamino-4-methoxycarbonylphenylphenyl lactosides). Two other series were obtained by modification of 6 and 6 positions of 4-methoxycarbonylphenyl lactoside (6-deoxy-6-iodo, -6-azido, -6-amino, -6-acetylamino, 6-deoxy-6-azido, -6-amino, -6-acetylamino, 6- e 6-deoxy). The relative affinity of the synthesized derivatives towards the lectin from seeds of Erythrina cristagalli was evaluated by hemagglutination inhibition assay. None of the synthetic derivatives were better inhibitors than lactose