An automated framework for understanding structural variations in the binding grooves of MHC class II molecules

Background: MHC/HLA class II molecules are important components of the immune system and play a critical role in processes such as phagocytosis. Understanding peptide recognition properties of the hundreds of MHC class II alleles is essential to appreciate determinants of antigenicity and ultimately to predict epitopes. While there are several methods for epitope prediction, each differing in their success rates, there are no reports so far in the literature to systematically characterize the binding sites at the structural level and infer recognition profiles from them. Results: Here we report a new approach to compare the binding sites of MHC class II molecules using their three dimensional structures. We use a specifically tuned version of our recent algorithm, PocketMatch. We show that our methodology is useful for classification of MHC class II molecules based on similarities or differences among their binding sites. A new module has been used to define binding sites in MHC molecules. Comparison of binding sites of 103 MHC molecules, both at the whole groove and individual sub-pocket levels has been carried out, and their clustering patterns analyzed. While clusters largely agree with serotypic classification, deviations from it and several new insights are obtained from our study. We also present how differences in sub-pockets of molecules associated with a pair of autoimmune diseases, narcolepsy and rheumatoid arthritis, were captured by PocketMatch(13). Conclusion: The systematic framework for understanding structural variations in MHC class II molecules enables large scale comparison of binding grooves and sub-pockets, which is likely to have direct implications towards predicting epitopes and understanding peptide binding preferences.

A class of one-dimensional steady-state flows in radiation-gas-dynamics

The study of steady-state flows in radiation-gas-dynamics, when radiation pressure is negligible in comparison with gas pressure, can be reduced to the study of a single first-order ordinary differential equation in particle velocity and radiation pressure. The class of steady flows, determined by the fact that the velocities in two uniform states are real, i.e. the Rankine-Hugoniot points are real, has been discussed in detail in a previous paper by one of us, when the Mach number M of the flow in one of the uniform states (at x=+∞) is greater than one and the flow direction is in the negative direction of the x-axis. In this paper we have discussed the case when M is less than or equal to one and the flow direction is still in the negative direction of the x-axis. We have drawn the various phase planes and the integral curves in each phase plane give various steady flows. We have also discussed the appearance of discontinuities in these flows.

Transition metal complexes of 3-aryl-2-substituted 1,2-dihydroquinazolin-4(3H)-one derivatives: New class of analgesic and anti-inflammatory agents

Five-coordinate, neutral transition metal complexes of newly designed pyridine-2-ethyl-(3-carboxyhdeneamino)-3-(2-phenyl)-1,2-dihydroquinazoli n-4(3H)-one (L) were synthesized and characterized The structure of ligand is confirmed by single crystal X-ray diffraction studies The compounds were evaluated for the anti-inflammatory activity by carrageenan-induced rat paw edema model while their analgesic activity was determined by acetic acid-induced writhing test in mice wherein the transition metal complexes were found to be more active than the free ligand (C) 2010 Elsevier Masson SAS All rights reserved.

L2-Stability Of A Class Of Nonlinear-Systems

Sufficient conditions are given for the L2-stability of a class of feedback systems consisting of a linear operator G and a nonlinear gain function, either odd monotone or restricted by a power-law, in cascade, in a negative feedback loop. The criterion takes the form of a frequency-domain inequality, Re[1 + Z(jω)] G(jω) δ > 0 ω ε (−∞, +∞), where Z(jω) is given by, Z(jω) = β[Y1(jω) + Y2(jω)] + (1 − β)[Y3(jω) − Y3(−jω)], with 0 β 1 and the functions y1(·), y2(·) and y3(·) satisfying the time-domain inequalities, ∝−∞+∞¦y1(t) + y2(t)¦ dt 1 − ε, y1(·) = 0, t < 0, y2(·) = 0, t > 0 and ε > 0, and , c2 being a constant depending on the order of the power-law restricting the nonlinear function. The criterion is derived using Zames' passive operator theory and is shown to be more general than the existing criteria

Japanese Encephalitis Virus Utilizes the Canonical Pathway To Activate NF-kappa B but It Utilizes the Type I Interferon Pathway To Induce Major Histocompatibility Complex Class I Expression in Mouse Embryonic Fibroblasts

Flaviviruses have been shown to induce cell surface expression of major histocompatibility complex class I (MHC-I) through the activation of NF-kappa B. Using IKK1(-/-), IKK2(-/-), NEMO-/-, and IKK1-/- IKK2-/- double mutant as well as p50(-/-) RelA(-/-) cRel(-/-) triple mutant mouse embryonic fibroblasts infected with Japanese encephalitis virus (JEV), we show that this flavivirus utilizes the canonical pathway to activate NF-kappa B in an IKK2- and NEMO-, but not IKK1-, dependent manner. NF-kappa B DNA binding activity induced upon virus infection was shown to be composed of RelA: p50 dimers in these fibroblasts. Type I interferon (IFN) production was significantly decreased but not completely abolished upon virus infection in cells defective in NF-kappa B activation. In contrast, induction of classical MHC-I (class 1a) genes and their cell surface expression remained unaffected in these NF-kappa B-defective cells. However, MHC-I induction was impaired in IFNAR(-/-) cells that lack the alpha/beta IFN receptor, indicating a dominant role of type I IFNs but not NF-kappa B for the induction of MHC-I molecules by Japanese encephalitis virus. Our further analysis revealed that the residual type I IFN signaling in NF-kappa B-deficient cells is sufficient to drive MHC-I gene expression upon virus infection in mouse embryonic fibroblasts. However, NF-kappa B could indirectly regulate MHC-I expression, since JEV-induced type I IFN expression was found to be critically dependent on it.

Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a-i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by H-1 NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC50 value less than 60 mu M. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC50 similar to 15 mu M) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.

A new class of separators and planarity of chordal graphs

We introduce a new class of clique separators, called base sets, for chordal graphs. Base sets of a chordal graph closely reflect its structure. We show that the notion of base sets leads to structural characterizations of planar k-trees and planar chordal graphs. Using these characterizations, we develop linear time algorithms for recognizing planar k-trees and planar chordal graphs. These algorithms are extensions of the Lexicographic_Breadth_First_Search algorithm for recognizing chordal graphs and are much simpler than the general planarity checking algorithm. Further, we use the notion of base sets to prove the equivalence of hamiltonian 2-trees and maximal outerplanar graphs.

Optimal infinite-horizon feedback laws for a general class of constrained discrete-time systems: stability and moving-horizon approximations

Stability results are given for a class of feedback systems arising from the regulation of time-varying discrete-time systems using optimal infinite-horizon and moving-horizon feedback laws. The class is characterized by joint constraints on the state and the control, a general nonlinear cost function and nonlinear equations of motion possessing two special properties. It is shown that weak conditions on the cost function and the constraints are sufficient to guarantee uniform asymptotic stability of both the optimal infinite-horizon and movinghorizon feedback systems. The infinite-horizon cost associated with the moving-horizon feedback law approaches the optimal infinite-horizon cost as the moving horizon is extended.

The hardness of approximating the boxicity, cubicity and threshold dimension of a graph

A k-dimensional box is the Cartesian product R-1 X R-2 X ... X R-k where each R-i is a closed interval on the real line. The boxicity of a graph G, denoted as box(G), is the minimum integer k such that G can be represented as the intersection graph of a collection of k-dimensional boxes. A unit cube in k-dimensional space or a k-cube is defined as the Cartesian product R-1 X R-2 X ... X R-k where each R-i is a closed interval oil the real line of the form a(i), a(i) + 1]. The cubicity of G, denoted as cub(G), is the minimum integer k such that G can be represented as the intersection graph of a collection of k-cubes. The threshold dimension of a graph G(V, E) is the smallest integer k such that E can be covered by k threshold spanning subgraphs of G. In this paper we will show that there exists no polynomial-time algorithm for approximating the threshold dimension of a graph on n vertices with a factor of O(n(0.5-epsilon)) for any epsilon > 0 unless NP = ZPP. From this result we will show that there exists no polynomial-time algorithm for approximating the boxicity and the cubicity of a graph on n vertices with factor O(n(0.5-epsilon)) for any epsilon > 0 unless NP = ZPP. In fact all these hardness results hold even for a highly structured class of graphs, namely the split graphs. We will also show that it is NP-complete to determine whether a given split graph has boxicity at most 3. (C) 2010 Elsevier B.V. All rights reserved.

Cubicity of Interval Graphs and the Claw Number

Let G(V, E) be a simple, undirected graph where V is the set of vertices and E is the set of edges. A b-dimensional cube is a Cartesian product l(1) x l(2) x ... x l(b), where each l(i) is a closed interval of unit length on the real line. The cub/city of G, denoted by cub(G), is the minimum positive integer b such that the vertices in G can be mapped to axis parallel b-dimensional cubes in such a way that two vertices are adjacent in G if and only if their assigned cubes intersect. An interval graph is a graph that can be represented as the intersection of intervals on the real line-i.e. the vertices of an interval graph can be mapped to intervals on the real line such that two vertices are adjacent if and only if their corresponding intervals overlap. Suppose S(m) denotes a star graph on m+1 nodes. We define claw number psi(G) of the graph to be the largest positive integer m such that S(m) is an induced subgraph of G. It can be easily shown that the cubicity of any graph is at least log(2) psi(G)]. In this article, we show that for an interval graph G log(2) psi(G)-]<= cub(G)<=log(2) psi(G)]+2. It is not clear whether the upper bound of log(2) psi(G)]+2 is tight: till now we are unable to find any interval graph with cub(G)> (log(2)psi(G)]. We also show that for an interval graph G, cub(G) <= log(2) alpha], where alpha is the independence number of G. Therefore, in the special case of psi(G)=alpha, cub(G) is exactly log(2) alpha(2)]. The concept of cubicity can be generalized by considering boxes instead of cubes. A b-dimensional box is a Cartesian product l(1) x l(2) x ... x l(b), where each I is a closed interval on the real line. The boxicity of a graph, denoted box(G), is the minimum k such that G is the intersection graph of k-dimensional boxes. It is clear that box(G)<= cub(G). From the above result, it follows that for any graph G, cub(G) <= box(G)log(2) alpha]. (C) 2010 Wiley Periodicals, Inc. J Graph Theory 65: 323-333, 2010

Synthesis and Identification of a new class of antileukemic agents containing 2-(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzod]thiazole

Recently we have reported the effect of (S)-6-aryl urea/thiourea substituted-2-amino-4,5,6,7-tetrahydrobenzod]thiazole derivatives as potent anti-leukemic agents. To elucidate further the Structure Activity Relationship (SAR) studies on the anti-leukemic activity of (S)-2,6-diamino-4,5,6,7 tetrahydrobenzod]thiazole moiety, a series of 2-arlycarboxamide substituted-(S)-6-amino-4,5,6,7-tetrahydrobenzod]thiazole were designed, synthesized and evaluated for their anti-leukemic activity by trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays and cell cycle analysis. Results suggest that the position, number and bulkiness of the substituent on the phenyl ring of aryl carboxamide moiety at 2nd position of 6-amino-4,5,6,7-tetrhydrobenzod]thiazole play a key role in inhibiting the proliferation of leukemia cells. Compounds with ortho substitution showed poor activity and with meta and para substitution showed good activity. (C) 2010 Elsevier Masson SAS. All rights reserved.