Inhibition of the Nef regulatory protein of HIV-1 by a single-domain antibody

The Nef protein of HIV-1 is important for AIDS pathogenesis, but it is not targeted by current antiviral strategies. Here, we describe a single-domain antibody (sdAb) that binds to HIV-1 Nef with a high affinity (K(d) = 2 × 10(-9)M) and inhibited critical biologic activities of Nef both in vitro and in vivo. First, it interfered with the CD4 down-regulation activity of a broad panel of nef alleles through inhibition of the Nef effects on CD4 internalization from the cell surface. Second, it was able to interfere with the association of Nef with the cellular p21-activated kinase 2 as well as with the resulting inhibitory effect of Nef on actin remodeling. Third, it counteracted the Nef-dependent enhancement of virion infectivity and inhibited the positive effect of Nef on virus replication in peripheral blood mononuclear cells. Fourth, anti-Nef sdAb rescued Nef-mediated thymic CD4(+) T-cell maturation defects and peripheral CD4(+) T-cell activation in the CD4C/HIV-1(Nef) transgenic mouse model. Because all these Nef functions have been implicated in Nef effects on pathogenesis, this anti-Nef sdAb may represent an efficient tool to elucidate the molecular functions of Nef in the virus life cycle and could now help to develop new strategies for the control of AIDS.

A statistical mechanical model for β-hairpin kinetics

Understanding the mechanism of protein secondary structure formation is an essential part of the protein-folding puzzle. Here, we describe a simple statistical mechanical model for the formation of a β-hairpin, the minimal structural element of the antiparallel β-pleated sheet. The model accurately describes the thermodynamic and kinetic behavior of a 16-residue, β-hairpin-forming peptide, successfully explaining its two-state behavior and apparent negative activation energy for folding. The model classifies structures according to their backbone conformation, defined by 15 pairs of dihedral angles, and is further simplified by considering only the 120 structures with contiguous stretches of native pairs of backbone dihedral angles. This single sequence approximation is tested by comparison with a more complete model that includes the 215 possible conformations and 15 × 215 possible kinetic transitions. Finally, we use the model to predict the equilibrium unfolding curves and kinetics for several variants of the β-hairpin peptide.

A single-code software model for multiphysics analysis-engine on parallel and distributed computers with the PHYSICA toolkit

Abstract not available

Targeting Heme with Single Domain Antibodies

Heme, i.e. iron (Fe) protoporphyrin IX, functions as a prosthetic group in a variety of hemoproteins that participate in vital biologic functions essential to sustain life. Heme is a highly reactive molecule, participating in redox reactions, and presumably for this reason it must be sequestered within the heme pockets of hemoproteins, controlling its reactivity. However, under biological stress conditions, hemoproteins can release their prosthetic groups, generating “free heme”, which binds loosely to proteins or to other molecules and presumably acquires unfettered redox activity. Moreover, a growing body of evidence supports the notion that “free heme” can act in a vasoactive, pro-inflammatory and cytotoxic manner when released from a subset of these hemoproteins, such as extracellular hemoglobin, generated during hemolytic conditions. (...)

Kerr measurements on single-domain SrRuO3 thin films

We report on the magneto-optical measurements of an epitaxial SrRuO3 film grown on SrTiO3 (0 0 1), which previously was determined to be single domain orientated by x-ray diffraction and Raman spectroscopy techniques. Our experiments reveal a large Kerr rotation, which reaches a maximum value of about 0.5° at low temperature. By measuring magnetic hysteresis loops at different temperatures, we determined the temperature dependence of the Kerr rotation in the polar configuration. Values of the anisotropic magnetoresistance ~ 20% have been measured. These values are remarkably higher than those of other metallic oxides such as manganites. This striking difference can be attributed to the strong spin-orbit interaction of the Ru 4d ion in the SrRuO3 compound.

Quantum tunneling of magnetization in single domain particles

We present a study of the magnetic relaxation of several ferrofluids composed of particles of about 40 Å in diameter (Fe3O4FeC, CoFe2O4). Our key observation is a nonthermal character of the relaxation below 3 K for the CoFe2O4 ferrofluid and below 1 K for the FeC ferrofluid. The crossover temperature from thermal to nonthermal (quantum) regime is in accordance with theoretical suggestions of macroscopic quantum tunneling of magnetization in single doma in particles

Face Short-Term Memory-Related Electroencephalographic Patterns can Differentiate Multi- versus Single-Domain Amnestic Mild Cognitive Impairment.

Amnestic mild cognitive impairment (aMCI) is characterized by memory deficits alone (single-domain, sd-aMCI) or associated with other cognitive disabilities (multi-domain, md-aMCI). The present study assessed the patterns of electroencephalographic (EEG) activity during the encoding and retrieval phases of short-term memory in these two aMCI subtypes, to identify potential functional differences according to the neuropsychological profile. Continuous EEG was recorded in 43 aMCI patients, whose 16 sd-aMCI and 27 md-aMCI, and 36 age-matched controls (EC) during delayed match-to-sample tasks for face and letter stimuli. At encoding, attended stimuli elicited parietal alpha (8-12 Hz) power decrease (desynchronization), whereas distracting stimuli were associated with alpha power increase (synchronization) over right central sites. No difference was observed in parietal alpha desynchronization among the three groups. For attended faces, the alpha synchronization underlying suppression of distracting letters was reduced in both aMCI subgroups, but more severely in md-aMCI cases that differed significantly from EC. At retrieval, the early N250r recognition effect was significantly reduced for faces in md-aMCI as compared to both sd-aMCI and EC. The results suggest a differential alteration of working memory cerebral processes for faces in the two aMCI subtypes, face covert recognition processes being specifically altered in md-aMCI.

A Practical Micro Mechanical Model Based Local Approach Methodology for the Analysis of Ductile Fracture of Welded T-Joints

This thesis concentrates on developing a practical local approach methodology based on micro mechanical models for the analysis of ductile fracture of welded joints. Two major problems involved in the local approach, namely the dilational constitutive relation reflecting the softening behaviour of material, and the failure criterion associated with the constitutive equation, have been studied in detail. Firstly, considerable efforts were made on the numerical integration and computer implementation for the non trivial dilational Gurson Tvergaard model. Considering the weaknesses of the widely used Euler forward integration algorithms, a family of generalized mid point algorithms is proposed for the Gurson Tvergaard model. Correspondingly, based on the decomposition of stresses into hydrostatic and deviatoric parts, an explicit seven parameter expression for the consistent tangent moduli of the algorithms is presented. This explicit formula avoids any matrix inversion during numerical iteration and thus greatly facilitates the computer implementation of the algorithms and increase the efficiency of the code. The accuracy of the proposed algorithms and other conventional algorithms has been assessed in a systematic manner in order to highlight the best algorithm for this study. The accurate and efficient performance of present finite element implementation of the proposed algorithms has been demonstrated by various numerical examples. It has been found that the true mid point algorithm (a = 0.5) is the most accurate one when the deviatoric strain increment is radial to the yield surface and it is very important to use the consistent tangent moduli in the Newton iteration procedure. Secondly, an assessment of the consistency of current local failure criteria for ductile fracture, the critical void growth criterion, the constant critical void volume fraction criterion and Thomason's plastic limit load failure criterion, has been made. Significant differences in the predictions of ductility by the three criteria were found. By assuming the void grows spherically and using the void volume fraction from the Gurson Tvergaard model to calculate the current void matrix geometry, Thomason's failure criterion has been modified and a new failure criterion for the Gurson Tvergaard model is presented. Comparison with Koplik and Needleman's finite element results shows that the new failure criterion is fairly accurate indeed. A novel feature of the new failure criterion is that a mechanism for void coalescence is incorporated into the constitutive model. Hence the material failure is a natural result of the development of macroscopic plastic flow and the microscopic internal necking mechanism. By the new failure criterion, the critical void volume fraction is not a material constant and the initial void volume fraction and/or void nucleation parameters essentially control the material failure. This feature is very desirable and makes the numerical calibration of void nucleation parameters(s) possible and physically sound. Thirdly, a local approach methodology based on the above two major contributions has been built up in ABAQUS via the user material subroutine UMAT and applied to welded T joints. By using the void nucleation parameters calibrated from simple smooth and notched specimens, it was found that the fracture behaviour of the welded T joints can be well predicted using present methodology. This application has shown how the damage parameters of both base material and heat affected zone (HAZ) material can be obtained in a step by step manner and how useful and capable the local approach methodology is in the analysis of fracture behaviour and crack development as well as structural integrity assessment of practical problems where non homogeneous materials are involved. Finally, a procedure for the possible engineering application of the present methodology is suggested and discussed.

Non-linear analysis of laminated metal matrix composites by an integrated micro/macro-mechanical model

The present paper describes an integrated micro/macro mechanical study of the elastic-viscoplastic behavior of unidirectional metal matrix composites (MMC). The micromechanical analysis of the elastic moduli is based on the Composites Cylinder Assemblage model (CCA) with comparisons also draw with a Representative Unit Cell (RUC) technique. These "homogenization" techniques are later incorporated into the Vanishing Fiber Diameter (VFD) model and a new formulation is proposed. The concept of a smeared element procedure is employed in conjunction with two different versions of the Bodner and Partom elastic-viscoplastic constitutive model for the associated macroscopic analysis. The formulations developed are also compared against experimental and analytical results available in the literature.

The role of local atmospheric forcing on the modulation of the ocean mixed layer depth in reanalysis and a coupled single column ocean model

The role of the local atmospheric forcing on the ocean mixed layer depth (MLD) over the global oceans is studied using ocean reanalysis data products and a single-column ocean model coupled to an atmospheric general circulation model. The focus of this study is on how the annual mean and the seasonal cycle of the MLD relate to various forcing characteristics in different parts of the world's ocean, and how anomalous variations in the monthly mean MLD relate to anomalous atmospheric forcings. By analysing both ocean reanalysis data and the single-column ocean model, regions with different dominant forcings and different mean and variability characteristics of the MLD can be identified. Many of the global oceans' MLD characteristics appear to be directly linked to different atmospheric forcing characteristics at different locations. Here, heating and wind-stress are identified as the main drivers; in some, mostly coastal, regions the atmospheric salinity forcing also contributes. The annual mean MLD is more closely related to the annual mean wind-stress and the MLD seasonality is more closely to the seasonality in heating. The single-column ocean model, however, also points out that the MLD characteristics over most global ocean regions, and in particular the tropics and subtropics, cannot be maintained by local atmospheric forcings only, but are also a result of ocean dynamics that are not simulated in a single-column ocean model. Thus, lateral ocean dynamics are essentially in correctly simulating observed MLD.

On local analysis of oscillations of a non-ideal and non-linear mechanical model

It is of major importance to consider non-ideal energy sources in engineering problems. They act on an oscillating system and at the same time experience a reciprocal action from the system. Here, a non-ideal system is studied. In this system, the interaction between source energy and motion is accomplished through a special kind of friction. Results about the stability and instability of the equilibrium point of this system are obtained. Moreover, its bifurcation curves are determined. Hopf bifurcations are found in the set of parameters of the oscillating system.

Influence of the magnetization damping on dynamic hysteresis loops in single domain particles

This article reports on the influence of the magnetization damping on dynamic hysteresis loops in single-domain particles with uniaxial anisotropy. The approach is based on the Neel-Brown theory and the hierarchy of differential recurrence relations, which follow from averaging over the realizations of the stochastic Landau-Lifshitz equation. A new method of solution is proposed, where the resulting system of differential equations is solved directly using optimized algorithms to explore its sparsity. All parameters involved in uniaxial systems are treated in detail, with particular attention given to the frequency dependence. It is shown that in the ferromagnetic resonance region, novel phenomena are observed for even moderately low values of the damping. The hysteresis loops assume remarkably unusual shapes, which are also followed by a pronounced reduction of their heights. Also demonstrated is that these features remain for randomly oriented ensembles and, moreover, are approximately independent of temperature and particle size. (C) 2012 American Institute of Physics. [doi:10.1063/1.3684629]