143 research outputs found
A fast surface-matching procedure for protein-ligand docking.
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Previous issue date: 2006-12-2
Comparative genomics allowed the identification of drug targets against human fungal pathogens
<p>Abstract</p> <p>Background</p> <p>The prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non-immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases.</p> <p>Results</p> <p><it>In silico </it>analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for <it>Candida albicans </it>or <it>Aspergillus fumigatus </it>and other 2 genes (<it>kre2 </it>and <it>erg6</it>) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (<it>C. albicans</it>, <it>A. fumigatus</it>, <it>Blastomyces dermatitidis</it>, <it>Paracoccidioides brasiliensis</it>, <it>Paracoccidioides lutzii, Coccidioides immitis</it>, <it>Cryptococcus neoformans </it>and <it>Histoplasma capsulatum</it>). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: <it>trr1 </it>that encodes for thioredoxin reductase, <it>rim8 </it>that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, <it>kre2 </it>that encodes for α-1,2-mannosyltransferase and <it>erg6 </it>that encodes for Δ(24)-sterol C-methyltransferase.</p> <p>Conclusions</p> <p>Our data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of four new potential drug targets. The preferred profile for fungal targets includes proteins conserved among fungi, but absent in the human genome. These characteristics potentially minimize toxic side effects exerted by pharmacological inhibition of the cellular targets. From this first step of post-genomic analysis, we obtained information relevant to future new drug development.</p
Limit theorems for von Mises statistics of a measure preserving transformation
For a measure preserving transformation of a probability space
we investigate almost sure and distributional convergence
of random variables of the form where (called the \emph{kernel})
is a function from to and are appropriate normalizing
constants. We observe that the above random variables are well defined and
belong to provided that the kernel is chosen from the projective
tensor product with We establish a form of the individual ergodic theorem for such
sequences. Next, we give a martingale approximation argument to derive a
central limit theorem in the non-degenerate case (in the sense of the classical
Hoeffding's decomposition). Furthermore, for and a wide class of
canonical kernels we also show that the convergence holds in distribution
towards a quadratic form in independent
standard Gaussian variables . Our results on the
distributional convergence use a --\,invariant filtration as a prerequisite
and are derived from uni- and multivariate martingale approximations
Molecular, functional and structural properties of the prolyl oligopeptidase of Trypanosoma cruzi (POP Tc80), which is required for parasite entry into mammalian cells.
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Previous issue date: 2007-01-0
A chemosensory GPCR as a potential target to control the Root-Knot Nematode Meloidogyne incognita parasitism in plants.
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Previous issue date: 2019bitstream/item/203619/1/molecules-24-03798.pd
Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008
Recent breakthroughs in the determination of the crystal structures of G protein-coupled receptors (GPCRs) have provided new opportunities for structure-based drug design strategies targeting this protein family. With the aim of evaluating the current status of GPCR structure prediction and ligand docking, a community-wide, blind prediction assessment - GPCR Dock 2008 - was conducted in coordination with the publication of the crystal structure of the human adenosine A2Areceptor bound to the ligand ZM241385. Twenty-nine groups submitted 206 structural models before the release of the experimental structure, which were evaluated for the accuracy of the ligand binding mode and the overall receptor model compared with the crystal structure. This analysis highlights important aspects for success and future development, such as accurate modelling of structurally divergent regions and use of additional biochemical insight such as disulphide bridges in the extracellular loops
Leadership and style in the French Fifth Republic:Nicolas Sarkozy’s presidency in historical and cultural perspective
This article contributes to the body of the developing theoretical research in leadership and presidential studies by adding analysis of what I have termed ‘comportmental style’ as a factor in leader/follower relations. Within institutionalism and the wider structure/agency debate in political science, one of the challenges as regards the study of leadership is to identify factors that offer scope to or else militate against leaders’ performance. The comportmental style of Nicolas Sarkozy (President of the French Republic 2007–2012), deployed in the context of the – changing – institution of the presidency, was a major factor in his extreme unpopularity, and contributed to his defeat in 2012. What this tells us about the nature of the changing French presidency and the role of style will be discussed in the conclusion
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