Mutations that silence constitutive signaling activity in the allosteric ligand-binding site of the thyrotropin receptor

The thyrotropin receptor (TSHR) exhibits elevated cAMP signaling in the basal state and becomes fully activated by thyrotropin. Previously we presented evidence that small-molecule ligands act allosterically within the transmembrane region in contrast to the orthosteric extracellular hormone-binding sites. Our goal in this study was to identify positions that surround the allosteric pocket and that are sensitive for inactivation of TSHR. Homology modeling combined with site-directed mutagenesis and functional characterization revealed seven mutants located in the allosteric binding site that led to a decrease of basal cAMP signaling activity. The majority of these silencing mutations, which constrain the TSHR in an inactive conformation, are found in two clusters when mapped onto the 3D structural model. We suggest that the amino acid positions identified herein are indicating locations where small-molecule antagonists, both neutral antagonists and inverse agonists, might interfere with active TSHR conformations.     

Protecting the boundary: the sentinel role of host defense peptides in the skin

The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production, cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient’s susceptibility to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders.     

Bacterial resistance mechanisms against host defense peptides

Host defense peptides and proteins are important components of the innate host defense against pathogenic microorganisms. They target negatively charged bacterial surfaces and disrupt microbial cytoplasmic membranes, which ultimately leads to bacterial destruction. Throughout evolution, pathogens devised several mechanisms to protect themselves from deleterious damage of host defense peptides. These strategies include (a) inactivation and cleavage of host defense peptides by production of host defense binding proteins and proteases, (b) repulsion of the peptides by alteration of pathogen’s surface charge employing modifications by amino acids or amino sugars of anionic molecules (e.g., teichoic acids, lipid A and phospholipids), (c) alteration of bacterial membrane fluidity, and (d) expulsion of the peptides using multi drug pumps. Together with bacterial regulatory network(s) that regulate expression and activity of these mechanisms, they represent attractive targets for development of novel antibacterials.     

Faithful chaperones

This review describes the properties of some rare eukaryotic chaperones that each assist in the folding of only one target protein. In particular, we describe (1) the tubulin cofactors, (2) p47, which assists in the folding of collagen, (3) α-hemoglobin stabilizing protein (AHSP), (4) the adenovirus L4-100 K protein, which is a chaperone of the major structural viral protein, hexon, and (5) HYPK, the huntingtin-interacting protein. These various-sized proteins (102–1,190 amino acids long) are all involved in the folding of oligomeric polypeptides but are otherwise functionally unique, as they each assist only one particular client. This raises a question regarding the biosynthetic cost of the high-level production of such chaperones. As the clients of faithful chaperones are all abundant proteins that are essential cellular or viral components, it is conceivable that this necessary metabolic expenditure withstood evolutionary pressure to minimize biosynthetic costs. Nevertheless, the complexity of the folding pathways in which these chaperones are involved results in error-prone processes. Several human disorders associated with these chaperones are discussed.     

Immune biology of Ag-specific γδ T cells in infections

Accumulating evidence suggests that human γδ T cells act as non-classical T cells and contribute to both innate and adaptive immune responses in infections. Vγ2 Vδ2 T (also termed Vγ9 Vδ2 T) cells exist only in primates, and in humans represent a dominant circulating γδ T-cell subset. Primate Vγ2 Vδ2 T cells are the only γδ T cell subset capable of recognizing microbial phosphoantigen. Since nonhuman primate Vγ2 Vδ2 T cells resemble their human counterparts, in-depth studies have been undertaken in macaques to understand the biology and function of human Vγ2 Vδ2 T cells. This article reviews the recent progress for immune biology of Vγ2 Vδ2 T cells in infections.     

Effects of Hydrophilic Monomer Types and Level on Polystyrene-Acrylate/montmorillonite Nanocomposite Made by Emulsion Polymerization

1 Results Nanocomposite has attracted more and more interest all over the world.Polystyrene (PS) is a commercialized and mass-productive polymer,continuous research efforts have been devoted to the development of polystyrene/montmorillonite (PS/MMT) nanocomposites[1-2].But the polarity of styrene (St) is too small to intercalate the space between the clay layers.The polarity of hydrophilic monomer is so strong that it can intercalate the MMT easily,the intercalated smectic clays maybe exfoliated by usin...     

Connecting informal networks to management of tacit knowledge

The relationship between tacit knowledge and informal networks has not been fully explored.Tacit knowledge cannot be well managed directly,because it is deeply embedded in individual actions and experiences.This study proposes an approach to managing informal networks as a new middle way to facilitate the sharing and transferring of tacit knowledge,owing to the fact that tacit knowledge is mostly shared and transferred through informal networks.To support the idea of the approach,an empirical case study of applying the approach to management of a large scientific project is also included.Our findings suggest that informal networks play essential roles for management of tacit knowledge,and thus good management of informal networks can lead to efficient sharing and transferring of tacit knowledge.     

Optimal control of multisolution ordinary differential equations in the absence of convexity

<正> In this paper,the authors study an optimal control problem governed by a class of multistateordinary differential equations in the absence of convexity.To overcome the difficulty that thecorresponding approximate optimal control problem may have no solution,relaxed controls are introduced.With the help of relaxation theory,Pontryagin's maximum principle for the optimal pairs ofthe original control problem is obtained.In the end of this paper,the authors discuss the applicationof the maximum principle by an example.     

Solving the perspective-three-point problem using comprehensive Gröbner systems

A complete solution classification of the perspective-three-point (P3P) problem is given by using the Gröbner basis method. The structure of the solution space of the polynomial system deduced by the P3P problem can be obtained by computing a comprehensive Gröbner system. Combining with properties of the generalized discriminant sequences, the authors give the explicit conditions to determine the number of distinct real positive solutions of the P3P problem. Several examples are provided to illustrate the effectiveness of the proposed conditions.     

Effect of Ni addition on the glass-forming ability and soft-magnetic properties of FeNiBPNb metallic glasses

The effect of Ni addition on the glass-forming ability (GFA) and soft-magnetic properties of an (Fe1-xNix)75.5B14.5P7Nb3 (x=0-0.6) alloy system were investigated. We found that the addition of Ni was effective in allowing the alloy to approach a eutectic point as well as increasing the thermal stability of the supercooled liquid. By increasing the amount of Ni,the supercooled liquid region (ΔTx),the reduced glass transition temperature Trg (Tg/Tl) and the Y parameter [Tx/(Tg+Tl)] increased from 49 to 75 K,0...