Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic‐level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high‐resolution crystal structures of the Jack bean α‐mannosidase (JBα‐man) in apo and inhibited states. The three‐dimensional structure of JBα‐man in complex with the multimeric cyclopeptoid‐based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.Instituto de Física de Líquidos y Sistemas Biológico

Expanding the scope of the successive ring expansion strategy for macrocycle and medium-sized ring synthesis : unreactive and reactive lactams

New methods are described that expand the scope of the Successive Ring Expansion (SuRE) with respect to synthetically challenging lactams. A protocol has been developed for use with 'unreactive' lactams, enabling SuRE reactions to be performed on subsrates that fail under previously established conditions. Ring expansion is also demonstarted on 'reactive' lactams derived from iminosugars for the first time. The new SuRE methods were used to prepare a diverse array of medium-sized and macrocyclic lactams and lactones, which were evaluted in an anti-bacterial assay against E. coli BW25113WT

Discovery of Inhibitors of Leishmania β-1,2-Mannosyltransferases Using a Click-Chemistry-Derived Guanosine Monophosphate Library

Leishmania spp. are a medically important group of protozoan parasites that synthesize a novel intracellular carbohydrate reserve polymer termed mannogen. Mannogen is a soluble homopolymer of β-1,2-linked mannose residues that accumulates in the major pathogenic stages in the sandfly vector and mammalian host. While several steps in mannogen biosynthesis have been defined, none of the enzymes have been isolated or characterized. We report the development of a simple assay for the GDP-mannose–dependent β-1,2-mannosyltransferases involved in mannogen synthesis. This assay utilizes octyl α-d-mannopyranoside to prime the formation of short mannogen oligomers up to 5 mannose residues. This assay was used to screen a focussed library of 44 GMP-triazole adducts for inhibitors. Several compounds provided effective inhibition of mannogen β-1,2-mannosyltransferases in a cell-free membrane preparation. This assay and inhibitor compounds will be useful for dissecting the role of different mannosyltransferases in regulating de novo biosynthesis and elongation reactions in mannogen metabolism

Research into the efficacy and cost-effectiveness of brief, free of charge and anonymous sex counselling to improve (mental) health in youth: Design of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The capacity to form romantic relationships and sexual health of adolescents in the Netherlands are compromised by several factors, including young age of first intercourse and adolescent depression. Several thresholds like own expenses, trust and embarrassment prevent adolescents to seek help for their sexual problems. To overcome these thresholds, brief sex counselling has been developed. It has been used since 2006 within the Rotterdam-Rijnmond Public Health Service, but there is lack of information about the (cost-) effectiveness. In the current study we will evaluate the (cost-) effectiveness of brief sex counselling for sexual problems in adolescents and young adults between 18 and 25 years of age.</p> <p>Methods</p> <p>In a randomised controlled trial we will compare (1) brief sex counselling with (2) intensive sexological treatment, and (3) delayed treatment (waiting list). Embedded in this RCT will be a trial-based economic evaluation, looking at the cost-effectiveness and cost-utility of brief sex counselling versus the two other interventions. Four hundred fifty adolescents (aged 18-25) with sexual problems will be recruited among the persons who visit the Public Health Service (PHS) and through various websites. After a screening procedure, eligible participants will be randomly allocated to one of the three intervention groups. Primary outcome measure of the clinical evaluation is the severity of sexual problems. Other outcomes include psychological distress, especially depression. The economic evaluation will be performed from a societal perspective. Costs will be assessed continuously by a retrospective questionnaire covering the last 3 month. All outcome assessments (including those for the economic evaluation) will take place via the internet at baseline, and at 3, 6, 9, and 12 months after baseline.</p> <p>Discussion</p> <p>The proposed research project will be the first study to provide preliminary data about the effect and cost-effectiveness of brief sex counselling in youth in comparison with intensive sexological treatment and delayed treatment. It is anticipated that positive results in (cost-) effectiveness of the proposed intervention will contribute to the improvement of sexual health care for adolescents and young adults.</p> <p>Trial registration</p> <p>The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (NTR1952)</p

Perfil de competências do enfermeiro em funções na emergência pré-hospitalar

O conceito de competência é amplamente discutido e aplicado em áreas como a formação e o apoio à gestão, no entanto a opinião acerca deste conceito não reúne consenso entre os especialistas. No campo da Emergência Pré-Hospitalar além de muito escassos os estudos, não existe qualquer ferramenta específica para a sua avaliação. O objetivo deste trabalho foi definir um perfil de competências ideal do Enfermeiro de Emergência Pré-Hospitalar e perceber de que forma os Enfermeiros que desempenham (ou desempenharam) funções nesta área se identificam com esse perfil. Desenvolveu-se um estudo correlacional, em que os dados foram recolhidos através de um questionário de autopreenchimento numa amostra de Enfermeiros que desempenham, ou desempenharam, funções na Emergência Pré-Hospitalar, mais propriamente na Viatura Médica de Emergência e Reanimação (VMER). Nos resultados destacamos a construção e validação de três escalas, utilizando para isso o Perfil de Competências definido por Malta (2016): Avaliação, Monitorização e Execução de Técnicas ao Doente em Situação Crítica (AMETDSC); Interpretação de dados e tomada de decisão em situação de pessoa em situação crítica e/ou situação de exceção (IDTDSPSC/SE); Identificação e gestão de fatores de mal-estar (IGFME). Foi também realizado um cruzamento entre os dados obtidos pelas escalas com os dados sociodemográficos com vista a estabelecer um relacionamento entre a forma como os Enfermeiros se identificam com as Competências definidas e as suas características pessoais. Observámos que de uma forma geral os Enfermeiros identificam-se com as competências do estudo de Malta (2016) que foram selecionadas para este estudo, obtendo pontuações médias superiores a 3 valores numa escala de 1 a 4. Observámos também que enquanto as variáveis género, estado civil e habilitações literárias parecem ter pouca influência na identificação com as competências estudadas, o mesmo já não se pode dizer das variáveis idade, experiência profissional genérica e experiência profissional específica que parecem exercer maior influência na forma como os Enfermeiros se identificam com estas Competências

The diagnosis of dysplasia of the esophagus with vital staining using Lugol solution

Chez un homme de 70 ans, dysplasie disparaissant sous l'effet du traitement médicamenteux (métoclopramide et antiacides