Optimization of minimum set of protein–DNA interactions: a quasi exact solution with minimum over-fitting

Motivation: A major limitation in modeling protein interactions is the difficulty of assessing the over-fitting of the training set. Recently, an experimentally based approach that integrates crystallographic information of C2H2 zinc finger–DNA complexes with binding data from 11 mutants, 7 from EGR finger I, was used to define an improved interaction code (no optimization). Here, we present a novel mixed integer programming (MIP)-based method that transforms this type of data into an optimized code, demonstrating both the advantages of the mathematical formulation to minimize over- and under-fitting and the robustness of the underlying physical parameters mapped by the code

Identifying allosteric fluctuation transitions between different protein conformational states as applied to Cyclin Dependent Kinase 2

BACKGROUND: The mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues. Transitional Dynamic Analysis (TDA) is a new method to detect these changes in local protein flexibility between different conformations arising from, for example, ligand binding. Additionally, Positional Impact Vertex for Entropy Transfer (PIVET) uses TDA to identify important residue contact changes that have a large impact on global fluctuation. We demonstrate the utility of these methods for Cyclin-dependent kinase 2 (CDK2), a system with crystal structures of this protein in multiple functionally relevant conformations and experimental data revealing the importance of local fluctuation changes for protein function. RESULTS: TDA and PIVET successfully identified select residues that are responsible for conformation specific regional fluctuation in the activation cycle of Cyclin Dependent Kinase 2 (CDK2). The detected local changes in protein flexibility have been experimentally confirmed to be essential for the regulation and function of the kinase. The methodologies also highlighted possible errors in previous molecular dynamic simulations that need to be resolved in order to understand this key player in cell cycle regulation. Finally, the use of entropy compensation as a possible allosteric mechanism for protein function is reported for CDK2. CONCLUSION: The methodologies embodied in TDA and PIVET provide a quick approach to identify local fluctuation change important for protein function and residue contacts that contributes to these changes. Further, these approaches can be used to check for possible errors in protein dynamic simulations and have the potential to facilitate a better understanding of the contribution of entropy to protein allostery and function

7th Drug hypersensitivity meeting: part two

No abstract availabl

Piperonyl butoxide increases oxidative toxicity of fenthion in the brain of oreochromis niloticus

PubMedID: 24497177The present study was designed to understand the effects of piperonyl butoxide (PBO), modulator of cytochrome P450 (CYP 450), on the neurotoxicity of organophosphate pesticide fenthion in the brain of Oreochromis niloticus used as a model organism. Fish were exposed to one-fourth of the LC50 value of fenthion (0.567 mg/L) and 0.5 mg/L PBO concentration for 24 h, 96 h, and 15 days. Glutathione (GSH)-related antioxidant system, lipid peroxidation, stress proteins, and acetylcholinesterase (AchE) activity were investigated. Our results showed that PBO induced the neurotoxic effect of fenthion with increasing oxidative stress in long-term exposure. GSH-related antioxidant system might take a role in protecting the brain from these oxidative effects. PBO possibly inhibited the biotransformation of fenthion by inhibiting CYP 450; thereby preventing the brain from AChE inhibition in short-term exposure. Changes in parameters indicated that PBO caused biphasic response by affecting CYP 450 in the brain of O. niloticus. © 2014 Wiley Periodicals, Inc

Geochemical characteristics of ophiolitic rocks from the southern margin of the sivas basin and their implications for the inner tauride ocean, central-eastern Turkey

Number of dismembered ophiolite bodies crop out between Sivas and Malatya on the top of the Eastern Tauride platform in the central-eastern Turkey. One of which at the southern margin of the Sivas basin in the Tecer Mountain area comprises melange and the lower part of an oceanic lithospheric section on top of the Tauride platform. The mantle tectonites are characterized by variably serpentinized harzburgites and dunites, and are intruded by numerous isolated dykes. The gabbroic cumulates consist of olivine gabbro, gabbro and gabbronorite. The major and trace element geochemistry of the mafic cumulate rocks suggests that the primary magma was compositionally similar to those observed in modern island-arc tholeiitic sequences. The isolated dykes are exclusively basaltic in composition and display geochemically two distinct subgroups: Group I is represented by high TiO2 (.87–1.47 wt.%) and other incompatible elements, whereas Group II is characterized by low TiO (.36–.66 wt.%) and other incompatible elements. The Group I isolated diabase dykes have flat to2 slightly LREE-depleted profiles (La/YbN =.32–.79), whereas the Group II isolated diabase dykes are more depleted in general and have a LREE-depleted character (La/YbN =.19–.49). This suggests that the isolated dykes were derived from an island arc tholeiitic magma (Nb/Y =.02–.05) with different degrees of partial melting (Group II > Group I) and relatively high oxygen fugacity in intra-oceanic subduction zone. The ophiolitic rocks in the study area may well be compared with the Divriği ophiolite to the southeast. All the evidence suggests that the isolated dykes in the Tecer Mountain area differ from the alkaline isolated dykes cutting the Divriği ophiolite. Since the late stage dykes (~76 Ma) in the Divriği area are alkaline, the tholeiitic isolated dykes in the present study should have been emplaced prior to the alkaline dykes during Late Cretaceous SSZ-spreading (~90 Ma) within the Inner Tauride Ocean. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.107Y146This study was supported by the Scientific and Technological Research Council of Turkey [grant number TÜBİTAK-ÇAYDAG: 107Y146]

Erythrocyte deformability in high-tension and normal tension glaucoma

WOS: 000078775700002PubMed ID: 10090442The exact cause of primary open angle glaucoma is still unknown. Intraocular pressure is a major factor but it is impossible to explain the whole mechanism of glaucomatous optic nerve damage with only increased intraocular pressure. Other factors play important roles in the development of glaucoma. With this point of view, vascular factors have been implicated in the pathogenesis of glaucoma. We tried to determine the etiopathogenetic role of decreased erythrocyte deformability in normal tension glaucoma and high-tension glaucoma. The study group consisted of 16 patients with the diagnosis of normal tension glaucoma, 17 patients with the diagnosis of high-tension glaucoma, and 24 patients as controls. Independent t-tests were used to compare the three groups two by two for age, hematocrit, mean cell volume, plasma protein level, cardiovascular risk factors, and erythrocyte deformability. There was no statistically significant relationship (p > 0.05) between the groups concerning the erythrocyte deformability. When we consider all of 57 patients, we found that both increasing age (> 60 years) and greater mean cell volume (> 84 fl) had a statistically significant relationship with decreased erythrocyte deformability (p < 0.05). When we performed Pearson correlation analysis, we found that only mean cell volume and erythrocyte deformability had a statistically significant relationship (r = 0.31, p = 0.02). We conclude that decreased erythrocyte deformability is not a major factor in the ethiopathogenesis of normal tension glaucoma and high-tension glaucoma