Identification of direct residue contacts in protein-protein interaction by message passing

Understanding the molecular determinants of specificity in protein-protein interaction is an outstanding challenge of postgenome biology. The availability of large protein databases generated from sequences of hundreds of bacterial genomes enables various statistical approaches to this problem. In this context covariance-based methods have been used to identify correlation between amino acid positions in interacting proteins. However, these methods have an important shortcoming, in that they cannot distinguish between directly and indirectly correlated residues. We developed a method that combines covariance analysis with global inference analysis, adopted from use in statistical physics. Applied to a set of >2,500 representatives of the bacterial two-component signal transduction system, the combination of covariance with global inference successfully and robustly identified residue pairs that are proximal in space without resorting to ad hoc tuning parameters, both for heterointeractions between sensor kinase (SK) and response regulator (RR) proteins and for homointeractions between RR proteins. The spectacular success of this approach illustrates the effectiveness of the global inference approach in identifying direct interaction based on sequence information alone. We expect this method to be applicable soon to interaction surfaces between proteins present in only 1 copy per genome as the number of sequenced genomes continues to expand. Use of this method could significantly increase the potential targets for therapeutic intervention, shed light on the mechanism of protein-protein interaction, and establish the foundation for the accurate prediction of interacting protein partners.Comment: Supplementary information available on http://www.pnas.org/content/106/1/67.abstrac

Adsorption and Quantum Chemical Studies on the Inhibition Potentials of Some Thiosemicarbazides for the Corrosion of Mild Steel in Acidic Medium

Three thiosemicarbazides, namely 2-(2-aminophenyl)-N phenylhydrazinecarbothioamide (AP4PT), N,2-diphenylhydrazinecarbothioamide (D4PT) and 2-(2-hydroxyphenyl)-N-phenyl hydrazinecarbothioamide (HP4PT), were investigated as corrosion inhibitors for mild steel in H2SO4 solution using gravimetric and gasometric methods. The results revealed that they all inhibit corrosion and their % inhibition efficiencies (%IE) follow the order: AP4PT > HP4PT > D4PT. The %IE obtained from the gravimetric and gasometric experiments were in good agreement. The thermodynamic parameters obtained support a physical adsorption mechanism and the adsorption followed the Langmuir adsorption isotherm. Some quantum chemical parameters were calculated using different methods and correlated with the experimental %IE. Quantitative structure activity relationship (QSAR) approach was used on a composite index of some quantum chemical parameters to characterize the inhibition performance of the studied molecules. The results showed that the %IE were closely related to some of the quantum chemical parameters, but with varying degrees. The calculated/theoretical %IE of the molecules were found to be close to their experimental %IE. The local reactivity has been studied through the Fukui and condensed softness indices in order to predict both the reactive centers and to know the possible sites of nucleophilic and electrophilic attacks

MVL-PLA2, a Snake Venom Phospholipase A2, Inhibits Angiogenesis through an Increase in Microtubule Dynamics and Disorganization of Focal Adhesions

Integrins are essential protagonists of the complex multi-step process of angiogenesis that has now become a major target for the development of anticancer therapies. We recently reported and characterized that MVL-PLA2, a novel phospholipase A2 from Macrovipera lebetina venom, exhibited anti-integrin activity. In this study, we show that MVL-PLA2 also displays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular-endothelial cells (HMEC-1) in a dose-dependent manner without being cytotoxic. Using Matrigel™ and chick chorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesis both in vitro and in vivo. We have also found that the actin cytoskeleton and the distribution of αvβ3 integrin, a critical regulator of angiogenesis and a major component of focal adhesions, were disturbed after MVL-PLA2 treatment. In order to further investigate the mechanism of action of this protein on endothelial cells, we analyzed the dynamic instability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubule dynamicity in HMEC-1 cells by 40%. We propose that the enhancement of microtubule dynamics may explain the alterations in the formation of focal adhesions, leading to inhibition of cell adhesion and migration

Moving from evidence-based medicine to evidence-based health.

While evidence-based medicine (EBM) has advanced medical practice, the health care system has been inconsistent in translating EBM into improvements in health. Disparities in health and health care play out through patients' limited ability to incorporate the advances of EBM into their daily lives. Assisting patients to self-manage their chronic conditions and paying attention to unhealthy community factors could be added to EBM to create a broader paradigm of evidence-based health. A perspective of evidence-based health may encourage physicians to consider their role in upstream efforts to combat socially patterned chronic disease

Cofilin determines the migration behavior and turning frequency of metastatic cancer cells

We have investigated the effects of inhibiting the expression of cofilin to understand its role in protrusion dynamics in metastatic tumor cells, in particular. We show that the suppression of cofilin expression in MTLn3 cells (an apolar randomly moving amoeboid metastatic tumor cell) caused them to extend protrusions from only one pole, elongate, and move rectilinearly. This remarkable transformation was correlated with slower extension of fewer, more stable lamellipodia leading to a reduced turning frequency. Hence, the loss of cofilin caused an amoeboid tumor cell to assume a mesenchymal-type mode of movement. These phenotypes were correlated with the loss of uniform chemotactic sensitivity of the cell surface to EGF stimulation, demonstrating that to chemotax efficiently, a cell must be able to respond to chemotactic stimulation at any region on its surface. The changes in cell shape, directional migration, and turning frequency were related to the re-localization of Arp2/3 complex to one pole of the cell upon suppression of cofilin expression

Inhibition effect of Vernonia amygdalina extract on the corrosion of mild steel reinforcement in concrete in 0.2 M H2SO4 Environment

Inhibition effect of Vernonia amygdalina (bitter leaf) extract on the corrosion behaviour of embedded mild steel rebar in concrete immersed in 0.2% H2SO4 solution was investigated by potential measurement, pH and gravimetric methods using the extracts concentrations of 25, 50, 75, and 100%. The results were further analysed using the two-factor ANOVA test. Potential measurement was performed using a digital voltmeter and a copper/copper sulphate reference electrode. Compressive strength of each block sample was determined after the experiments. Weight loss values were obtained from the gravimetric method, and the inhibitor efficiency was computed from the corrosion rate of each of the tested samples. Results showed that varied concentration of V. amygdalina and the test exposure time significantly affect both the corrosion potential of embedded steel rebar in concrete and the pH of the medium. The extracts gave appreciable corrosion inhibition performance of the embedded steel rebar at 25 and 50% concentrations with the weight loss of 500 (0.5 g) and 400 mg (0.4 g) and corrosion rates values of 0.000240 and 0.000180 mm/ yr, respectively. The highest inhibition efficiency (60.68%) was achieved at 50 and 39.94% at 25% concentrations, respectively. The 100 and 75% concentrations gave negative inhibitor values of �51.52 and �20.11%. The ANOVA test confirmed the results at 95% confidence, and further showed that concentration of V. amygdalina had greater effect on potential and pH measurement

Application of a conventional fishery model for assessment of entrainment and impingement impact

A conventional stock assessment model is applied to determine the impact of entrainment and impingement at the Monroe Power Plant on the yellow perch stock of the Western basin of Lake Erie. Parameters of the model are estimated using power plant data, biological data available in the literature, and commercial catch data. The model is applied to estimate the age structure and biomass of the perch stock and to estimate the impact of the power plant on abundance of the impingeable stock and abundance and biomass of the exploited stock. The level of impact was examined under a range of mortality conditions. Under the most extreme conditions examined of full pumping, high fishing mortality, and low natural mortality, the fishable biomass is reduced by 1.7%. This impact is not large, but there are several other power plants and many additional water intakes around the Western basin of Lake Erie.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42645/1/10641_2004_Article_BF00001790.pd