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O presente artigo tem por finalidade, com foco no ensino medio, na faixa de fronteira do estado de Mato Grosso do Sul (MS), apresentar uma proposta de implementacao do Ensino a Distância (EAD), aos moldes do Sistema Colegio Militar do Brasil (SCMB), aos civis da area em questao . Nessas condicoes, o referencial no MS e o Colegio Militar de Campo Grande (CMCG), pois dentre as escolas 100 primeiras colocadas do MS, apenas 32 publicas foram destacadas pela media dos seus alunos no Exame Nacional do Ensino Medio (ENEM), ficando o CMCG em primeiro lugar. Tal fato atesta que o foco dos investimentos educacionais deve ser voltado para o interior (com destaque para os municipios fronteiricos), de forma que prosperem aos moldes da capital. Nao obstante, a pesquisa comprova, atraves da coleta de dados, a deficitaria qualidade do ensino publico do MS. Com isso, o resultado esperado, atraves do EAD, busca aproximar a qualidade do ensino da faixa de fronteira ao da capital, Campo Grande. Ademais, o estudo possibilita ratificar a condicao do SCMB como referencia positiva de ensino e a necessidade de melhorias na rede de ensino publico da Regiao Centro-Oeste do Brasil.

Ao longo da historia das relacoes internacionais, os conflitos armados continuam evoluindo paralelamente aos pensamentos e filosofias. Os Chefes de Estado na “corrida” por novos armamentos e tecnologias belicas negligenciam, por vezes, as bem feitorias relativas ao bem estar dos seus povos. Fez-se fundamental, ainda no seculo passado, como forma de conter os excessos cometidos pelas partes em situacoes de combate, tipificar a guerra em legislacao internacional. Este artigo aborda a intervencao do Direito Internacional Humanitario nos conflitos armados internacionais, ocorridos no Oriente Medio, por Israel contra a Faixa de Gaza. O seu objetivo geral e verificar os fatores historicos que motivaram os conflitos no Oriente Medio. Como objetivo especifico visa verificar a acao da Organizacao das Nacoes Unidas como orgao internacional que possui a missao de manter a paz mundial. O resultado da pesquisa esclarece se Israel, a luz do Direito Humanitario, pode bombardear areas civis, em Gaza, sob a alegacao de constituirem alvos militares. E, ainda, se Israel mantem o controle do abastecimento de agua, em Gaza, como tatica de combate.

SummaryUDP-glucose:glycoprotein glucosyltransferase (UGGT) is the only known glycoprotein folding quality control checkpoint in the eukaryotic glycoprotein secretory pathway. When the enzyme detects a misfolded glycoprotein in the Endoplasmic Reticulum (ER), it dispatches it for ER retention by re-glucosylating it on one of its N-linked glycans. Recent crystal structures of a fungal UGGT have suggested the enzyme is conformationally mobile. Here, a negative stain electron microscopy reconstruction of UGGT in complex with a monoclonal antibody confirms that the misfold-sensing N-terminal portion of UGGT and its C-terminal catalytic domain are tightly associated. Molecular Dynamics (MD) simulations capture UGGT in so far unobserved conformational states, giving new insights into the molecule’s flexibility. Principal component analysis of the MD trajectories affords a description of UGGT’s overall inter-domain motions, highlighting three types of inter-domain movements: bending, twisting and clamping. These inter-domain motions modify the accessible surface area of the enzyme’s central saddle, likely enabling the protein to recognize and re-glucosylate substrates of different sizes and shapes, and/or re-glucosylate N-linked glycans situated at variable distances from the site of misfold. We propose to name “Parodi limit” the maximum distance between a site of misfolding on a UGGT glycoprotein substrate and an N-linked glycan that monomeric UGGT can re-glucosylate on the same glycoprotein. MD simulations estimate the Parodi limit to be around 60-70 Å. Re-glucosylation assays using UGGT deletion mutants suggest that the TRXL2 domain is necessary for activity against urea-misfolded bovine thyroglobulin. Taken together, our findings support a “one-size-fits-all adjustable spanner” substrate recognition model, with a crucial role for the TRXL2 domain in the recruitment of misfolded substrates to the enzyme’s active site.

Endoplasmic reticulum glycoprotein folding quality control (ERQC) and ER-associated degradation (ERAD) preside over cellular glycoprotein secretion and maintain steady glycoproteostasis. When cells turn malignant, cancer cell plasticity is affected and supported either by point mutations, preferential isoform selection, altered expression levels, or shifts to conformational equilibria of a secreted glycoprotein. Such changes are crucial in mediating altered extracellular signalling, metabolic behavior, and adhesion properties of cancer cells. It is therefore conceivable that interference with ERQC and/or ERAD can be used to selectively damage cancers. Indeed, inhibitors of the late stages of ERAD are already in the clinic against cancers such as multiple myeloma. Here, we review recent advances in our understanding of the complex relationship between glycoproteostasis and cancer biology and discuss the potential of ERQC and ERAD modulators for the selective targeting of cancer cell plasticity.

Plants offer a simpler and cheaper alternative to mammalian animal models for the study of endoplasmic reticulum glycoprotein folding quality control (ERQC). In particular, the Arabidopsis thaliana (At) innate immune response to bacterial peptides provides an easy means of assaying ERQC function in vivo. A number of mutants that are useful to study ERQC in planta have been described in the literature, but only for a subset of these mutants the innate immune response to bacterial elicitors has been measured beyond monitoring plant weight and some physio-pathological parameters related to the plant immune response. In order to probe deeper into the role of ERQC in the plant immune response, we monitored expression levels of the Phosphate-induced 1 (PHI-1) and reticulin-oxidase homologue (RET-OX) genes in the At ER &alpha, Glu II rsw3 and the At UGGT uggt1-1 mutant plants, in response to bacterial peptides elf18 and flg22. The elf18 response was impaired in the rsw3 but not completely abrogated in the uggt1-1 mutant plants, raising the possibility that the latter enzyme is partly dispensable for EF-Tu receptor (EFR) signaling. In the rsw3 mutant, seedling growth was impaired only by concomitant application of the At ER &alpha, Glu II NB-DNJ inhibitor at concentrations above 500 nM, compatibly with residual activity in this mutant. The study highlights the need for extending plant innate immune response studies to assays sampling EFR signaling at the molecular level.

Plants offer a simpler and cheaper alternative to mammalian animal models for the study of Endoplasmic Reticulum glycoprotein folding Quality Control (ERQC). In particular, the Arabidopsis thaliana (At) innate immune response to bacterial peptides provides an easy means of assaying ERQC function in vivo. A number of mutants that are useful to study ERQC in planta have been described in the literature, but only for a subset of these mutants the innate immune response to bacterial elicitors has been measured beyond monitoring plant weight and some physio-pathological parameters related to the plant immune response. In order to probe deeper into the role of ERQC in the plant immune response, we monitored expression levels of the PHI-1 and RET-OX genes in the At ER α-Glu II rsw3 and the At UGGT uggt1-1 mutant plants, in response to bacterial peptides elf18 and flg22. The elf18 response was impaired in the rsw3 but not completely abrogated in the uggt1-1 mutant plants, raising the possibility that the latter enzyme is partly dispensable for ERF signalling. In the rsw3 mutant, seedling growth was impaired only by concomitant application of the At ER α-Glu II NB-DNJ inhibitor at concentrations above 500 nM, suggesting residual activity in this mutant. The study highlights the need for extending plant innate immune response studies to assays sampling EFR signalling at the molecular level.

Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER &alpha, glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER &alpha, glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.

One major challenge in human behavior and brain sciences is to understand how we can rewire already existing perceptual, motor, cognitive, and social skills or habits. Here we aimed to characterize one aspect of rewiring, namely, how we can update our knowledge of sequential/statistical regularities when they change. The dynamics of rewiring was explored from learning to consolidation using a unique experimental design which is suitable to capture the effect of implicit and explicit processing and the proactive and retroactive interference. Our results indicate that humans can rewire their knowledge of such regularities incidentally, and consolidation has a critical role in this process. Moreover, old and new knowledge can coexist, leading to effective adaptivity of the human mind in the changing environment, although the execution of the recently acquired knowledge may be more fluent than the execution of the previously learned one. These findings can contribute to a better understanding of the cognitive processes underlying behavior change, and can provide insights into how we can boost behavior change in various contexts, such as sports, educational settings or psychotherapy.

Endoplasmic reticulum (ER) retention of mis-folded glycoproteins is mediated by the ERlocalised eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognises a mis-folded glycoprotein and flags it for ER retention by reglucosylating one of its N-linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT-mediated ER retention can cause rare disease even if the mutant glycoprotein retains activity ("responsive mutant"). Here, we investigated the subcellular localisation of the human Trop-2 Q118E variant, which causes gelatinous droplike corneal dystrophy (GDLD). Compared with the wild type Trop-2, which is correctly localised at the plasma membrane, the Trop-2-Q118E variant is found to be heavily retained in the ER. Using Trop-2-Q118E, we tested UGGT modulation as a rescue-of-secretion therapeutic strategy for congenital rare disease caused by responsive mutations in genes encoding secreted glycoproteins. We investigated secretion of a EYFP-fusion of Trop-2-Q118E by confocal laser scanning microscopy. As a limiting case of UGGT inhibition, mammalian cells harbouring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 gene expressions were used. The membrane localisation of the Trop-2-Q118E-EYFP mutant was successfully rescued in UGGT1 -/- and UGGT1/2 -/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula . The study supports the hypothesis that UGGT1 modulation constitutes a novel therapeutic strategy for the treatment of Trop-2-Q118E associated GDLD, and it encourages the testing of modulators of ER glycoprotein folding Quality Control (ERQC) as broad-spectrum rescueof-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.