T1D progression is associated with loss of CD3+CD56+regulatory cells

Peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56, is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. We demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in T1D children. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D

Antiplasmodial activity of p-substituted benzyl thiazinoquinone derivatives and their potential against parasitic infections

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold

Alkaloids from marine ascidians

About 300 alkaloid structures isolated from marine ascidians are discussed in term of their occurrence, structural type and reported pharmacol. activity. Some major groups (e.g., the lamellarins and the ecteinascidins) are discussed in detail, highlighting their potential as therapeutic agents for the treatment of cancer or viral infections

Nonlocal Singular Problems and Applications to MEMS

We consider fourth order nonlinear problems which describe electrostatic actuation in MicroElectroMechanicalSystems (MEMS) both in the stationary case and in the evolution case; we prove existence, uniqueness and regularity theorems by exploiting the Near Operators Theory

Aurantoside J: a New Tetramic Acid Glycoside from Theonella swinhoei. Insights into the Antifungal Potential of Aurantosides

The chemical investigation of an Indonesian specimen of Theonella swinhoei afforded four aurantosides, one of which, aurantoside J (5), is a new compound. The structure of this metabolite, exhibiting the unprecedented N-α-glycosidic linkage between the pentose and the tetramate units, has been determined through detailed spectroscopic analysis. The four obtained aurantosides have been tested against five fungal strains (four Candida and one Fusarium) responsible of invasive infections in immuno-compromised patients. The non-cytotoxic aurantoside I (4) was the single compound to show an excellent potency against all the tested strains, thus providing valuable insights about the antifungal potential of this class of compounds and the structure-activity relationships

Marine Antimalarials

Malaria is an infectious disease causing at least 1 million deaths per year, and, unfortunately, the chemical entities available to treat malaria are still too limited. In this review we highlight the contribution of marine chemistry in the field of antimalarial research by reporting the most important results obtained until the beginning of 2009, with particular emphasis on recent discoveries. About 60 secondary metabolites produced by marine organisms have been grouped into three structural types and discussed in terms of their reported antimalarial activities. The major groups of metabolites include isonitrile derivatives, alkaloids and endoperoxide derivatives. The following discussion evidences that antimalarial marine molecules can efficiently integrate the panel of lead compounds isolated from terrestrial sources with new chemical backbones and, sometimes, with unique functional groups

Structural and biochemical insights of CypA and AIF interaction

The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370-394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed. We show that AIF(370-394) interacts with CypA on the same surface recognized by AIF(Δ1-121) protein and that the region is very close to the CypA catalytic pocket. Such region partially overlaps with the binding site of cyclosporin A (CsA), the strongest catalytic inhibitor of CypA. Our data point toward distinct CypA structural determinants governing the inhibitor selectivity and the differential biological effects of AIF and CsA, and provide new structural insights for designing CypA/AIF selective inhibitors with therapeutic relevance in neurodegenerative diseases

Mapping Functional Interaction Sites of Human Prune C-Terminal Domain by NMR Spectroscopy in Human Cell Lysates

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UK executive pay: the special case of executive bonuses

Executive pay research has traditionally focused on salary, severance payments and longterm incentives. A systematic rigorous empirical examination of short-term annual bonuses is lacking. To address this omission, this research empirically examines the relationship between short-term bonuses and firm performance (TSR and EPS), in the UK. It also considers the association between form of bonus payment (i.e. cash/shares), and type of performance target (i.e. hard/soft and simple/complex) with bonus and performance. Furthermore, firm size and particular corporate governance factors are included (i.e. NED ratio on remuneration committee, CEO presence on nominations committee, CEO/Chair duality, tenure, and power) to examine their relationship with bonus value. From a sample of 299 firms listed in the FTSE-350 (1,542 executives including 300 CEOs), this study uses two competing theories (i.e. agency and power theory) to provide a fuller explanation of the subtleties of the pay-performance relation. The main findings support the agency view, since bonus is positively and significantly associated with financial performance. As with previous studies on executive bonus pay this association remains weak. By implication, power theory is not supported. However, other findings indicate: (1) although firm size may change, the proportion of bonus pay relative to salary does not vary. This suggests that large and small firms pay out proportionally similar bonuses; (2) cash bonuses are not positively related with the total value of bonus pay, suggesting that they are not any more open to abuse than other methods of compensation, as agency theory would predict; (3) cash bonuses encourage short-term achievement, as predicted by power theory; (4) consistent with agency theory, share-based bonuses are positively related to bonus pay and performance (weak association), suggesting that share-based bonuses (rather than cash bonuses) may be more effective at aligning pay with performance; (5) in line with agency theory, transparency (i.e. hard (external/published) and simple bonus conditions) is positively associated with performance, providing support for the alignment between principals' and agents' interests; (6) detailed bonus scheme characteristics are generally insensitive to performance and are becoming increasingly softer (i.e. more internal/unspecified targets) and complex (i.e. multiple targets). On the power view, these may create opportunities for executives to mask weak performance and extract greater rents; (7) governance factors are insignificant, suggesting that efforts to improve this area may be wasted, since they mainly leave pay-performance sensitivities unaffected. However, based on power theory, weak governance may foster the rise of powerful executives and widen the pay-performance gap. Therefore, it is suggested that close monitoring of executive pay must continue and shareholders should remain vigilant.EThOS - Electronic Theses Online ServiceGBUnited Kingdo