113 research outputs found
A Dangerous Liaison between Two Major Killers: Mycobacterium tuberculosis and HIV Target Dendritic Cells through DC-SIGN
Simulated Annealing with Tsallis Weights - A Numerical Comparison
We discuss the use of Tsallis generalized mechanics in simulated annealing
algorithms. For a small peptide it is shown that older implementations are not
more effective than regular simulated annealing in finding ground state
configurations. We propose a new implementation which leads to an improvement
over regular simulated annealing.Comment: Late
Correction of the Iron Overload Defect in β-2-Microglobulin Knockout Mice by Lactoferrin Abolishes Their Increased Susceptibility to Tuberculosis
As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. β-2-microglobulin (β2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)–restricted CD8 T cells in protection against M. tuberculosis. However, β2m associates with a number of MHC-I–like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, β2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in β2m–KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I–KO mice. In parallel, the generation of nitric oxide impaired in β2m–KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of β2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis
Stochastic dynamics simulations in a new generalized ensemble
We develop a formulation for molecular dynamics, Langevin, and hybrid Monte
Carlo algorithms in the recently proposed generalized ensemble that is based on
a physically motivated realisation of Tsallis weights. The effectiveness of the
methods are tested with an energy function for a protein system. Simulations in
this generalized ensemble by the three methods are performed for a penta
peptide, Met-enkephalin. For each algorithm, it is shown that from only one
simulation run one can not only find the global-minimum-energy conformation but
also obtain probability distributions in canonical ensemble at any temperature,
which allows the calculation of any thermodynamic quantity as a function of
temperature.Comment: to appear in Chem. Phy. Let
Large Fatty Acid-Derived Aβ42 Oligomers Form Ring-Like Assemblies
As the primary toxic species in the etiology of Alzheimer disease (AD) are low molecular weight oligomers of Aβ, it is crucial to understand the structure of Aβ oligomers for gaining molecular insights into AD pathology. We have earlier demonstrated that in the presence of fatty acids, Aβ42 peptides assemble as 12-24mer oligomers. These Large Fatty Acid-derived Oligomers (LFAOs) exist predominantly as 12mers at low and as 24mers at high concentrations. The 12mers are more neurotoxic than the 24mers and undergo self-replication, while the latter propagate to morphologically distinct fibrils with succinct pathological consequences. In order to glean into their functional differences and similarities, we have determined their structures in greater detail by combining molecular dynamic simulations with biophysical measurements. We conjecture that the LFAO are made of Aβ units in an S-shaped conformation, with the 12mers forming a double-layered hexamer ring (6 × 2) while the structure of 24mers is a double-layered dodecamer ring (12 × 2). A closer inspection of the (6 × 2) and (12 × 2) structures reveals a concentration and pH dependent molecular reorganization in the assembly of 12 to 24mers, which seems to be the underlying mechanism for the observed biophysical and cellular properties of LFAOs
Solvation model dependency of helix-coil transition in polyalanine
Helix-coil transitions in poly-alanine molecules of length 10 are studied by
multicanonical Monte Carlo simulations. The solvation effects are included by
either a distance-dependent dielectric permittivity or by a term that is
proportional to the solvent-accessible surface area of the peptide. We found a
strong dependence of the characteristics of the helix-coil transition from the
details of the solvation model.Comment: to appear in Biophysical Journa
Comparative Study of Multicanonical and Simulated Annealing Algorithms in the Protein Folding Problem
We compare a few variants of the recently proposed multicanonical method with
the well known simulated annealing for the effectiveness in search of the
energy global minimum of a biomolecular system. For this we study in detail
Met-enkephalin, one of the simplest peptides. We show that the new method not
only outperforms simulated annealing in the search of the energy groundstate
but also provides more statistical-mechanical information about the system.Comment: to be published in Physica A, LATEX 32 pages, figures available on
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Link between Organ-specific Antigen Processing by 20S Proteasomes and CD8+ T Cell–mediated Autoimmunity
Adoptive transfer of cross-reactive HSP60-specific CD8+ T cells into immunodeficient mice causes autoimmune intestinal pathology restricted to the small intestine. We wondered whether local immunopathology induced by CD8+ T cells can be explained by tissue-specific differences in proteasome-mediated processing of major histocompatibility complex class I T cell epitopes. Our experiments demonstrate that 20S proteasomes of different organs display a characteristic composition of α and β chain subunits and produce distinct peptide fragments with respect to both quality and quantity. Digests of HSP60 polypeptides by 20S proteasomes show most efficient generation of the pathology related CD8+ T cell epitope in the small intestine. Further, we demonstrate that the organ-specific potential to produce defined T cell epitopes reflects quantities that are relevant for cytotoxic T lymphocyte recognition. We propose tissue-specific antigen processing by 20S proteasomes as a potential mechanism to control organ-specific immune responses
Active Galactic Nuclei at the Crossroads of Astrophysics
Over the last five decades, AGN studies have produced a number of spectacular
examples of synergies and multifaceted approaches in astrophysics. The field of
AGN research now spans the entire spectral range and covers more than twelve
orders of magnitude in the spatial and temporal domains. The next generation of
astrophysical facilities will open up new possibilities for AGN studies,
especially in the areas of high-resolution and high-fidelity imaging and
spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These
studies will address in detail a number of critical issues in AGN research such
as processes in the immediate vicinity of supermassive black holes, physical
conditions of broad-line and narrow-line regions, formation and evolution of
accretion disks and relativistic outflows, and the connection between nuclear
activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic
Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical
Symposia Serie
Bioavaliação de estado nutricional do arroz (Oryza sativa L. var. IAC-165) e do feijoeiro (Phaseolus vulgaris L. Var. carioca) utilizando 15N e 32P
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