Lectin ligands: New insights into their conformations and their dynamic behavior and the discovery of conformer selection by lectins

The mysteries of the functions of complex glycoconjugates have enthralled scientists over decades. Theoretical considerations have ascribed an enormous capacity to store information to oligosaccharides, In the interplay with lectins sugar-code words of complex carbohydrate structures can be deciphered. To capitalize on knowledge about this type of molecular recognition for rational marker/drug design, the intimate details of the recognition process must be delineated, To this aim the required approach is garnered from several fields, profiting from advances primarily in X-ray crystallography, nuclear magnetic resonance spectroscopy and computational calculations encompassing molecular mechanics, molecular dynamics and homology modeling. Collectively considered, the results force us to jettison the preconception of a rigid ligand structure. On the contrary, a carbohydrate ligand may move rather freely between two or even more low-energy positions, affording the basis for conformer selection by a lectin. By an exemplary illustration of the interdisciplinary approach including up-to-date refinements in carbohydrate modeling it is underscored why this combination is considered to show promise of fostering innovative strategies in rational marker/drug design

Impact of human bladder cancer cell architecture on autologous T-lymphocyte activation

To investigate the influence of tumor cell architecture on T-cell activation, we used an autologous human model based on 2 bladder tumor cell lines as targets for cytotoxic tumor-infiltrating lymphocytes (TILs). These tumor cell lines were grown in vitro as either standard 2-dimensional (2D) monolayers or 3-dimensional (3D) spheroids. T-cell activation was determined by measuring the production of three major cytokines (tumor necrosis factor, granulocyte/macrophage colony-stimulating factor and interferon-gamma), known to be secreted by most activated TILs. Changes in the architecture of target cells from 2D to 3D induced a dramatic decrease in their capacity for stimulating TILs. Interestingly, neither TIL infiltration nor MHC class I, B7.1 costimulatory or lymphocyte function-associated factor-3 adhesion molecule downregulation played a major role in this decrease. These findings demonstrate that tumor architecture has a major impact on T-cell activation and might be implicated in the escape of tumor cells from the immune system

Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo

Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the "two-signal" model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2-like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid-binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid "missing self"-responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance

Neoglycolipids Micelle-like Structures as a Basis for Drug Delivery Systems

Targeted drug delivery is one of the most promising tasks of nanomedicine, as this is a real way to increase the effectiveness of therapeutic effects against many diseases. In this regard, the development of new inexpensive highly effective stimulating and non-immunogenic drug delivery systems (DDS) is of great importance. In this work new molecular candidates were proposed and studied for the creation of such systems based on the use of new compounds, neoglycolipids. It is shown that these compounds are capable of self-association in aqueous solutions and can serve as potential carriers of drug compounds with targeted delivery determined by their terminal groups (in particular, glycans). The processes of their associates formation and features of their structure are investigated. The results show that these selforganizing nanoscale systems can be used as a basis for developing new drug delivery systems. Keywords: neoglycolipids, micelle-like structures, small-angle X-ray scattering, molecular dynamics simulatio

Spontaneous alloying in binary metal microclusters - A molecular dynamics study -

Microcanonical molecular dynamics study of the spontaneous alloying(SA), which is a manifestation of fast atomic diffusion in a nano-sized metal cluster, is done in terms of a simple two dimensional binary Morse model. Important features observed by Yasuda and Mori are well reproduced in our simulation. The temperature dependence and size dependence of the SA phenomena are extensively explored by examining long time dynamics. The dominant role of negative heat of solution in completing the SA is also discussed. We point out that a presence of melting surface induces the diffusion of core atoms even if they are solid-like. In other words, the {\it surface melting} at substantially low temperature plays a key role in attaining the SA.Comment: 15 pages, 12 fgures, Submitted to Phys.Rev.

Gene expression profiles of bladder cancers: evidence for a striking effect of in vitro cell models on gene patterns.

In order to assess the effect of in vitro models on the expression of key genes known to be implicated in the development or progression of cancer, we quantified by real-time quantitative PCR the expression of 28 key genes in three bladder cancer tissue specimens and in their derived cell lines, studied either as one-dimensional single cell suspensions, two-dimensional monolayers or three-dimensional spheroids. Global analysis of gene expression profiles showed that in vitro models had a dramatic impact upon gene expression. Remarkably, quantitative differences in gene expression of 2-63-fold were observed in 24 out of 28 genes among the cell models. In addition, we observed that the in vitro model which most closely mimicked in vivo mRNA phenotype varied with both the gene and the patient. These results provide evidence that mRNA expression databases based on cancer cell lines, which are studied to provide a rationale for selection of therapy on the basis of molecular characteristics of a patient\u27s tumour, must be carefully interpreted