Towards accurate solvation free energies of large biological systems

Continuum solvation models like PCM or COSMO are the standard tool to calculate solvation free energies in a quantum level, but have been typically limited to small biological molecules due to its large computational cost. Recently, a new implementation of COSMO based on a domain decomposition strategy (ddCOSMO) [1] has been presented, which speeds up calculations by several orders of magnitude, thus paving the way for its application to very large systems. Here, we report the parameterization of ddCOSMO to the prediction of hydration free energies based on the MST solvation model developed in Barcelona, [2][3]. The parameterization is based on the PM6 semi-empirical Hamiltonian, on a set of over 200 experimental hydration free energies. The new model opens the way to the accurate prediction of hydration free energies of very large biomolecules, thus going beyond the usual classical MM-PBSA or MM-GBSA approaches

rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids

Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrodinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net

Miniatures from domestic contexts in Iron age Iberia

This article reviews a set of miniatures from domestic contexts in Iron Age eastern Iberia, and interprets them in terms of their role in forging social personae. After an introduction to the historical case under consideration, the miniatures are described in terms of their typology and their contexts of provenance are outlined. Though not abundant, they tend to occur in central places in the landscape; specifically, they are often found in houses of the powerful. The vast majority are miniatures of pottery and tools, though some miniature weapons are recorded. We contend that these objects were used as a means of enculturation and for the learning of values and norms. It is no coincidence that they emerge in the archaeological record of Iron Age Iberia at the same time as the rise of a social structure based on hereditary power

Spatiotemporal changes in the accumulation of sugar and potassium within individual 'Sauvignon Blanc' (Vitis vinifera L.) berries

It has been speculated that there may be a link between the transport of sugar and potassium into grape berries during ripening as they exhibit similar accumulation patterns. It is unclear if this proposed link is apparent in individual grape berries and in the grape berry compartments. Single grape berries were therefore analysed for sugar and potassium content and concentration within the skin, seeds and the pulp from pre-véraison until harvest. Sugar and potassium had similar accumulation patterns and positive relationships were confirmed between the sugar and potassium content within individual berries and compartments. The sugar content in the grape berry, however, increased 5-fold during ripening whereas the potassium content only doubled. Both sugar and potassium increased with berry size, suggesting a ternary relationship with berry water. The high variability in sugar and potassium contents between berries however affirms plasticity in their accumulation within individual berries

Wear and corrosion interactions on titanium in oral environment : literature review

The oral cavity is a complex environment where corrosive substances from dietary, human saliva, and oral biofilms may accumulate in retentive areas of dental implant systems and prostheses promoting corrosion at their surfaces. Additionally, during mastication, micromovements may occur between prosthetic joints causing a relative motion between contacting surfaces, leading to wear. Both processes (wear and corrosion) result in a bio-tribocorrosion system once that occurs in contact with biological tissues and fluids. This review paper is focused on the aspects related to the corrosion and wear behavior of titanium-based structures in the oral environment. Furthermore, the clinical relevance of the oral environment is focused on the harmful effect that acidic substances and biofilms, formed in human saliva, may have on titanium surfaces. In fact, a progressive degradation of titanium by wear and corrosion (tribocorrosion) mechanisms can take place affecting the performance of titanium-based implant and prostheses. Also, the formation of wear debris and metallic ions due to the tribocorrosion phenomena can become toxic for human tissues. This review gathers knowledge from areas like materials sciences, microbiology, and dentistry contributing to a better understanding of bio-tribocorrosion processes in the oral environment.(undefined

Adaptation of O157:H7 and non-O157 Escherichia coli strains in orange juice and subsequent resistance to UV-C radiation

This study assessed the acid-adaptation of pathogenic and non-pathogenic strains of Escherichia coli in orange juice and the microbial resistance to the subsequent UV-C radiation treatment. Nine Shiga toxin-producing E. coli (STEC) and one strain of a non-pathogenic surrogate E. coli were used in this study. Each E. coli strain was inoculated in orange juice, following pre-exposure during 0, 1, 2, and 3 h at 10 °C. Then, the inoculated juices with the ten different strains separately were exposed to 0 and 2 J/cm2 of UV-C radiation. The D value (i.e., the UV-C dose in J/cm2 required to cause a one-log reduction in the target microorganism) was calculated. Further, the resistance coefficient [RC; i.e., the ratio between the D-values for the control condition (D0h) and each pre-exposure tested time (D1h, D2h, D3h)] were determined. The results indicated that the resistance of E. coli was influenced by the pre-exposure period in the orange juice, with increased resistance to UV-C observed for periods >2 h. Furthermore, the sensitivity of cells to subsequent UV-C treatment was found to be strain-dependent. The results may allow the development of more reliable UV-C radiation processes for orange juice processing aiming the inactivation of pathogenic E. coli.Fil: Oteiza, Juan Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial. Centro de Investigación y Asistencia Técnica a la Industria; ArgentinaFil: Caturla, Magdevis Y. R.. Universidade Estadual de Campinas; BrasilFil: do Prado Silva, Leonardo. Universidade Estadual de Campinas; BrasilFil: Câmara, Antonio A.. Universidade Estadual de Campinas; BrasilFil: Barril, Patricia Angelica. Instituto Nacional de Tecnología Industrial. Centro de Investigación y Asistencia Técnica a la Industria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sant'Ana, Anderson S.. Universidade Estadual de Campinas; BrasilFil: Giannuzzi, Leda. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; ArgentinaFil: Zaritzky, Noemi Elisabet. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; Argentin

A bottom-up approach to find lead compounds in expansive chemical spaces

Drug discovery starts with the identification of a “hit” compound that, following a long and expensive optimization process, evolves into a drug candidate. Bigger screening collections increase the odds of finding more and better hits. For this reason, large pharmaceutical companies have invested heavily in high-throughput screening (HTS) collections that can contain several million compounds. However, this figure pales in comparison with the emergent on-demand chemical collections, which have recently reached the trillion scale. These chemical collections are potentially transformative for drug discovery, as they could deliver many diverse and high-quality hits, even reaching lead-like starting points. But first, it will be necessary to develop computational tools capable of efficiently navigating such massive virtual collections. To address this challenge, we have conceived an innovative strategy that explores the chemical universe from the bottom up, performing a systematic search on the fragment space (exploration phase), to then mine the most promising areas of on-demand collections (exploitation phase). Using a hierarchy of increasingly sophisticated computational methods to remove false positives, we maximize the success probability and minimize the overall computational cost. A basic implementation of the concept has enabled us to validate the strategy prospectively, allowing the identification of new BRD4 (BD1) binders with potencies comparable to stablished drug candidates

Acute hepatitis C virus infection assessment among chronic hemodialysis patients in the Southwest Parana State, Brazil

BACKGROUND: Chronic hemodialysis patients are at higher risk for acquiring hepatitis C virus (HCV). The prevalence varies among different countries and hemodialysis centers. Although guidelines for a comprehensive infection control program exist, the nosocomial transmission still accounts for the new cases of infection. The aim of this study was analyze the follow up of newly acquired acute hepatitis C cases, during the period from January 2002 to May 2005, in the Hemodialysis Center, located in the Southwest region of Parana State, Brazil and to analyze the effectiveness of the measures to restrain the appearance of new cases of acute hepatitis C. METHODS: Patients were analyzed monthly with anti-HCV tests and ALT measurements. Patients with ALT elevations were monitored for possible acute hepatitis C. RESULTS: During this period, 32 new cases were identified with acute hepatitis C virus infection. Blood screening showed variable ALT levels preceding the anti-HCV seroconversion. HCV RNA viremia by PCR analysis was intermittently and even negative in some cases. Ten out of 32 patients received 1 mcg/kg dose of pegylated interferon alfa-2b treatment for 24 weeks. All dialysis personnel were re-trained to strictly follow the regulations and recommendations regarding infection control, proper methods to clean and disinfect equipment were reviewed and HCV-positive patients were isolated. CONCLUSION: Laboratory tests results showed variable ALT preceding anti-HCV seroconversion and intermittent viremia. The applied recommendations contributed importantly to restrain the appearance of new cases of acute hepatitis C in this center and the last case was diagnosed in May 2004

Emergence of unusual human rotavirus strains in Salento, Italy, during 2006–2007

<p>Abstract</p> <p>Background</p> <p>In recent years, rotavirus genotyping by RT-PCR has provided valuable information about the diversity of rotaviruses (RV) circulating throughout the world.</p> <p>The purpose of the present study was to monitor the prevalence of the different G and P genotypes of rotaviruses circulating in Salento and detect any uncommon or novel types.</p> <p>Methods</p> <p>During the period from January 2006 to December 2007, a total of 243 rotavirus positive stool samples were collected from children with diarrhoea admitted to four Hospitals in the province of Lecce (Copertino, Galatina, Gallipoli and Tricase).</p> <p>All the specimens were tested for RV by real time PCR and genotyped for VP7 (G-type) and VP4 (P-type) gene by reverse transcription (RT) and multiplex PCR using different type specific primers.</p> <p>Results</p> <p>In course of this study we identified 4 common G&P combinations viz. G2P[8], G1P[8], G2P[4] and G9P[8] amongst 59.8% of the typeable rotavirus positives.</p> <p>Rotavirus G2P[8] was recognized as the most widespread genotype during the sentinel-based survey in Salento.</p> <p>The detection of other novel and unusual strains, such as G2P[10], G4P[10], G8P[4], G9P[11] and G10P[8] is noteworthy.</p> <p>Furthermore, a significant number of mixed infections were observed during the survey period but G3P[8] rotaviruses were not detected.</p> <p>Conclusion</p> <p>This study highlights the genetic diversity among rotaviruses isolated from children in Salento and the emergence of some novel strains. Therefore, it is highly essential to continuously monitor for these strains so as to assess the impact of vaccines on RV strains circulating in Salento and understand the effect of strain variation on efficacy of presently available vaccines.</p