Synthesis of peptide-ligand conjugates and their applications

Three research areas pertaining to this dissertation, (i) synthesis strategies of peptide-ligand conjugates, (ii) their applications and (iii) chemistry of ferryls were surveyed in the introduction chapter. Next, the divergent and dual divergent strategies for the synthesis of non-heme ligand-peptide conjugates were developed. Using these strategies various peptide-ligand conjugates were synthesized via solution as well as solid phase synthesis. The scope and the functional group compatibility of these strategies were also established. The utility of the dual divergent strategy has been demonstrated by synthesizing a small library of metal-binding LHRH analogues. This work showcased the ability of the dual divergent strategy to rapidly construct the diverse array of ligand structures. In another application, the synthesis and characterization of the first ferryl-peptide conjugate was presented. In this work the reactivity and the mechanistic study for this ferryl-peptide conjugate were also described. From the mechanistic studies it has been proven that the remote benzyl group controls the stability of ferryl-peptide conjugate via an intramolecular hydrogen atom transfer mechanism

Colonization and Penetration of the Stratum Corneum by Dermatophyte Fungi

The colonization and penetration of stratum corneum by dermatophyte fungi were investigated employing arthrospores of three strains, two of Trichophyton mentagrophytes and one of Trichophyton interdigitale. The adherence of arthrospores to corneocytes from palm and sole and germination in suspensions of corneocytes from the same body areas were determined. The growth of arthrospores on stripped sheets of stratum corneum from different body areas, namely, sole, leg, groin, abdomen, back, cheek, forearm, and palm, was also studied. The ultrastructure of corneocyte and stratum corneum - dermatophyte relationship was investigated by scanning and transmission electronmicroscopy. Scale from cases of tinea pedis was also investigated ultrastructurally. The resistance of arthrospores to ordinary environmental and desiccated conditions in the presence and absence of corneocytes was studied and the type of dormancy expressed by arthrospores was investigated. The effect of exposing arthrospores to distilled water for 24 hr on their germination in corneocyte suspensions and on stratum corneum was studied. The possibility of using corneocytes as a model for assessing antifungal activity of drugs against dermatophytes was explored. Two phases of investigation were conducted; phase I consisted of arthrospore germination in corneocyte suspensions in the presence of antifungal drugs and phase II consisted of firstly inducing arthrospore germination in corneocyte suspensions then adding antifungal drugs. Arthrospore formation was studied under various cultural conditions; temperature of 3

Amino acid substitutions in σ1 and μ1 outer capsid proteins are selected during mammalian reovirus adaptation to Vero cells

Establishment of viral persistence in cell culture has previously led to the selection of mammalian reovirus mutants, although very few of those have been characterized in details. In the present study, reovirus was adapted to Vero cells that, in contrast to classically-used L929 cells, are inefficient in supporting the early steps of reovirus uncoating and are also unable to produce interferon as an antiviral response once infection occurs. The Vero cell-adapted reovirus exhibits amino acids substitutions in both the σ1 and μ1 proteins. This contrasts with uncoating mutants from persistently-infected L929 cells, and various other cell types, that generally harbor amino acids substitutions in the σ3 outer capsid protein. The Vero cell-adapted virus remained sensitive to an inhibitor of lysosomal proteases; furthermore, in the absence of selective pressure for its maintenance, t he virus has partially lost its ability to resist interferon. The positions of the amino acids substitutions on the known protein structures suggest an effect on binding of the viral σ1 protein to the cell surface and on μ1 disassembly from the outer capsid.L'établissement de la persistance virale en culture cellulaire a précédemment mené à la sélection de mutants de réovirus, bien que peu d'entre eux aient été caractérisés en détail. Dans la présence étude, le réovirus a été adapté aux cellules Vero qui, contrairement aux cellules L929 classiquement utilisées, sont peu efficaces pour les étapes précoces de décapsidation de réovirus et sont également incapables de produire de l'interféron comme réponse antivirale, lorsqu'infectées. Le réovirus adapté aux cellules Vero porte des substitutions d'acides aminés à la fois dans les protéines σ1 et μ1. Ceci contraste avec les mutants de décapsidation des cellules L929 infectées de manière persistante, aussi bien que chez divers autres types de cellules, qui présentent généralement des substitutions d'acides aminés au niveau de la protéine de capside externe σ3. Le virus adapté aux cellules Vero demeure sensible à un inhibiteur de protéases lysosomales; de plus, en absence de pression de sélection, le virus a perdu en partie sa capacité à résister à l'interféron. La position des différentes substitutions d'acides aminés sur la structure connue de la protéine suggère un effet sur la fixation de la protéine virale σ1 à la surface cellulaire et sur l'élimination de la protéine μ1 de la capside externe du virus.Conseil de recherches en sciences naturelles et en génie du Canad

Fibrillation atriale et infarctus du myocarde : un risque accru de mortalité

RésuméLa fibrillation atriale coexiste souvent avec l’infarctus du myocarde, et son incidence au décours de l’infarctus du myocarde varie entre 4% et 25%. La présence d’une fibrillation atriale chez les patients présentant un infarctus du myocarde est associée à un risque accru de mortalité, malgré l’ajustement sur des facteurs de confusion connus et indépendamment du moment de survenue de la fibrillation atriale. Cette augmentation de 40% du risque de mortalité conduit à porter une attention particulière à la fibrillation atriale chez les patients présentant un infarctus du myocarde. Des études sont nécessaires pour identifier les moyens de prévenir la survenue de la fibrillation atriale au cours de l’infarctus du myocarde et déterminer les thérapeutiques optimales de la fibrillation atriale chez les patients présentant un infarctus du myocarde afin de réduire la mortalité.SummaryAtrial fibrillation is a common finding in patients with myocardial infarction, its incidence vanes between 4% and 25% in the acute phase of myocardial infarction. The présence of atrial fibrillation is associated with an increased risk of mortality in patients with a myocardial infarction, even after adjustment for several important atrial fibrillation risk factors and regardless of the timing of onset of atrial fibrillation. This subsequent 40% increase in mortality associated with atrial fibrillation during myocardial infarction suggests that closer attention should be paid to these patients. Further research is needed to identify ways to prevent the occurrence of atrial fibrillation during myocardial infarction and to determine the optimal atrial fibrillation therapeutics strategies to reduce mortality in patients with myocardial infarction

Associação das estratégias de coping com a ocorrência de lesões desportivas: revisão bibliográfica

Projeto de Graduação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciado em FisioterapiaIntrodução: todos os atletas em geral, independentemente da modalidade e nível desportivo, experienciam vários tipos de stress, podendo influenciar o seu rendimento, e/ou ser causador do aparecimento de lesões. Objetivo: analisar a existência de estratégias de Coping que possam interferir com a ocorrência de lesões desportivas. Metodologia: a pesquisa foi realizada nas bases de dados Pubmed, Cohrane e PEDro. A análise da qualidade metodológica foi efetuada com o checklist Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). Resultados: foram selecionados 5 artigos observacionais, respeitando os critérios de elegibilidade. Da totalidade da amostra de 934 atletas, 843 integraram os estudos. Estes atletas, de ambos os géneros eram praticantes de dança, Rugby e futebol, com idades compreendidas entre 12 e 28 anos. As estratégias de coping, avaliadas pelo Athletic Coping Skills Inventory–28 (ACSI-28), reduziram significativamente a probabilidade de ocorrer lesões desportivas quando ajustadas a outras variáveis. Diversos constructos do inventário Brief- COPE têm influência no risco ou na proteção de ocorrência de lesões. E, os scores de stress, avaliados com a Escala Visual analógica (EVA), são distintos aquando da presença de lesões. Conclusão: a utilização de estratégias de coping poderá ser uma mais-valia nos momentos lesivos.Background: all athletes in general, regardless of the modality and sport level, experience various types of stress, which can influence their performance, and/or cause the appearance of injuries.Objective: to analyze the existence of Coping strategies that may interfere with the occurrence of sports injuries Methodology: the search was carried out in Pubmed, Cohrane and PEDro databases. Methodological quality analysis was performed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.Results: 5 observational articles were selected, respecting the eligibility criteria. Of the total sample of 934 athletes, 843 participated in the studies. These athletes, of both genders, practiced dance, rugby, and football, aged between 12 and 28 years. Coping strategies, evaluated by the Athletic Coping Skills Inventory–28 (ACSI-28), significantly reduced the likelihood of sports injuries occurring when adjusted for other variables. Several constructs of the Brief-COPE inventory have an influence on the risk or protection of the occurrence of injuries. And, the stress scores, evaluated with the Visual Analog Scale (VAS), are different in the presence of injuries Conclusion: the use of coping strategies can be an asset in harmful moments.N/

Molecular underpinnings and biogeochemical consequences of enhanced diatom growth in a warming Southern Ocean

Phytoplankton contribute to the Southern Ocean’s (SO) ability to absorb atmospheric CO2 and shape the stoichiometry of northward macronutrient delivery. Climate change is altering the SO environment, yet we know little about how resident phytoplankton will react to these changes. Here, we studied a natural SO community and compared responses of two prevalent, bloom-forming diatom groups to changes in temperature and iron that are projected to occur by 2100 to 2300. We found that one group, Pseudo-nitzschia, grows better under warmer low-iron conditions by managing cellular iron demand and efficiently increasing photosynthetic capacity. This ability to grow and draw down nutrients in the face of warming, regardless of iron availability, has major implications for ocean ecosystems and global nutrient cycles

Primary stroke prevention and hypertension treatment: which is the first-line strategy?

Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed