Protein pocket and ligand shape comparison and its application in virtual screening.

Understanding molecular recognition is one major requirement for drug discovery and design. Physicochemical and shape complementarity between two binding partners is the driving force during complex formation. In this study, the impact of shape within this process is analyzed. Protein binding pockets and co-crystallized ligands are represented by normalized principal moments of inertia ratios (NPRs). The corresponding descriptor space is triangular, with its corners occupied by spherical, discoid, and elongated shapes. An analysis of a selected set of sc-PDB complexes suggests that pockets and bound ligands avoid spherical shapes, which are, however, prevalent in small unoccupied pockets. Furthermore, a direct shape comparison confirms previous studies that on average only one third of a pocket is filled by its bound ligand, supplemented by a 50 % subpocket coverage. In this study, we found that shape complementary is expressed by low pairwise shape distances in NPR space, short distances between the centers-of-mass, and small deviations in the angle between the first principal ellipsoid axes. Furthermore, it is assessed how different binding pocket parameters are related to bioactivity and binding efficiency of the co-crystallized ligand. In addition, the performance of different shape and size parameters of pockets and ligands is evaluated in a virtual screening scenario performed on four representative targets.

Cost-effectivness in a DRG system for two-step exchange of infected total joint arthroplasty

The costs related to the treatment of infected total joint arthroplasties represent an ever groving burden to the society. Different patient-adapted therapeutic options like débridement and retention, 1- or 2-step exchange can be used. If a 2-step exchange is used we have to consider short (2-4 weeks) or long (>4-6 weeks) interval treatment. The Swiss DRG (Diagnose related Groups) determines the reimboursement the hopsital receives for the treatment of an infected total arthroplasty. The review assesses the cost-effectiveness of hospitalisation practices linked to surgical treatment in the two-stage exchange of a prosthetic-joint infection. The aim of this retrospectiv study is to compare the economical impact between a short (2 to 4 weeks) versus a long (6 weeks and above) interval during a two-satge procedure to determine the financial impact. Retrospectiv study of the patients with a two-stage procedure for a hip or knee prosthetic joint infection at CHUV hospital Lausanne (Switzerland) between 2012 and 2013. The review analyses the correlation between the interval length and the length of the hospital stay as well as with the costs and revenues per hospital stay. In average there is a loss of 40′000 Euro per hospitalisation for the treatment of prosthetic joint infection. Revenues never cover all the costs, even with a short interval procedure. This economical loss increases with the length of the hospital stay if a long-term intervall is choosen. The review explores potential for improvement in reimbourement practices and hospitalisation practices in the current Swiss healthcare setting. There should be alternative setups to decrease the burden of medical costs by a) increase the reimboursment for the treatment of infected total joints or by b) splitting the hospital stay with partners (rapid transfer after first operation from center hospital to level 2 hospital and retransfer for second operation to center) in order to increase revenues.

Prosthetic joint infections : A retrospective study on the timing of reimplantation in a two-stage exchange

Different therapeutic options for prosthetic joint infections exist, but surgery remains the key. With a two-stage exchange procedure, a success rate above 90% can be expected. Currently, there is no consensus regarding the optimal duration between explantation and the reimplantation in a two-stage procedure. The aim of this study was to retrospectively compare treatment outcomes between short-interval and long-interval two-stage exchanges. Patients having a two-stage exchange of a hip or knee prosthetic joint infection at Lausanne University Hospital (Switzerland) between 1999 and 2013 were included. The satisfaction of the patient, the function of the articulation and the eradication of infection, were compared between patients having a short (2 to 4 weeks) versus a long (4 weeks and more) interval during a two-stage procedure. Patient satisfaction was defined as good if the patient did not have pain and bad if the patient had pain. Functional outcome was defined good if the patient had a prosthesis in place and could walk, medium if the prosthesis was in place but the patient could not walk, and bad if the prosthesis was no longer in place. Infection outcome was considered good if there had been no re-infection and bad if there had been a re-infection of the prosthesis 145 patients (100 hips, 45 knees) were identified with a median age of 68 years (range 19-103). The median hospital stay was 58 days (range 10-402). The median follow-up was 12.9 months (range 0.5-152). 28 % and 72 % of the patients had a short-interval and long-interval exchange of the prosthesis, respectively. Patient satisfaction, functional outcome and infection outcome for patients having a short versus a long interval are reported in the Table. The patient satisfaction was higher when a long interval was performed whereas the functional and infection outcomes were higher when a short interval was performed. According to this study a short-interval exchange appears preferable to a long interval, especially in the view of treatment effectiveness and functional outcome.

Comparing assays for the measurement of AhR ligand activity

In this thesis (TFG) the results of the comparison of three assays for the measurement of AhR ligand activity are exposed. This study was part of a collaborative project aiming at the characterization of the AhR signaling activities of known naturally occurring compounds to explore the potential of using non-toxic compounds to treat inflammatory diseases via oral administration. The first goal of this project was to find an assay able to measure AhR-activity, so the comparison of different assays has been done in order to find the most convenient one according to the efficiency, sensitivity and precision. Moreover, other elements with operational nature such as price, toxicity of components or ease of use has been considered. From the use of compounds known from the literature to be AhR ligands, three assays have been tested: (1) P450-GloTM CYP1A2 Induction/Inhibition assay, (2) quantitative Polymerase Chain Reaction (qPCR) and (3) DR. CALUX® Bioassay. Moreover, a different experiment using the last assay was performed for the study in vivo of the transport of the compounds tested. The results of the TFG suggested the DR. CALUX® Bioassay as the most promising assay to be used for the screening of samples as AhR-ligands because it is quicker, easier to handle and less expensive than qPCR and more reproducible than the CYP1A2 Induction/Inhibition assay. Moreover, the use of this assay allowed having a first idea of which compounds are uptaken by the epithelial barrier and in with direction the transport happens.

Stabilization of the ionic form of weak acid cation exchange resins

Weak acid cation exchange (WAC) resins are used in the chromatographic separation of betaine from vinasse, a by-product of sugar industry. The ionic form of the resin determines the elution time of betaine. When a WAC-resin is in hydrogen form, the retention time of betaine is the longest and betaine elutes as the last component of vi-nasse from the chromatographic column. If the feed solution contains salts and its pH is not acidic enough to keep the resin undissociated, the ionic form of the hydrogen form resin starts to alter. Vinasse contains salts and its pH is around 5, it also contains weak acids. To keep the metal ion content (Na/H ratio) of the resin low enough to ensure successful separation of betaine, acid has to be added to either eluent (water) or vinasse. The aim of the present work was to examine by laboratory experiments which option requires less acid. Also the retention mechanism of betaine was investigated by measuring retention volumes of acetic acid and choline in different Na/H ratios of the resin. It was found that the resulting ionic form of the resin is the same regardless of whether the regeneration acid is added to the eluent or the feed solution (vinasse). Be-sides the salt concentration and the pH of vinasse, also the concentration of weak acids in the feed affects the resulting ionic form of the resin. The more buffering capacity vinasse has, the more acid is required to keep the ionic form of the resin desired. Vinasse was found to be quite strong buffer solution, which means relatively high amounts of acid are required to prevent the Na/H ratio from increasing too much. It is known that the retention volume of betaine decreases significantly, when the Na/H ratio increases. This is assumed to occur, because the amount of hydrogen bonds between the carboxylic groups of betaine and the resin decreases. Same behavior was not found with acetic acid. Choline has the same molecular structure as betaine, but instead of carboxylic group it has hydroxide group. The retention volume of choline increased as the Na/H ratio of the resin increased, because of the ion exchange reaction between choline cation and dissociated carboxylic group of the resin. Since the retention behavior of choline on the resin is opposite to the behavior of be-taine, the strong affinity of betaine towards hydrogen form WAC-resin has to be based on its carboxylic group. It is probable that the quaternary ammonium groups also affect the behavior of the carboxylic groups of betaine, causing them to form hydrogen bonds with the carboxylic groups of the resin.

Estimating the value of the metal-ligand bond dissociation enthalpy<D> (M-L) for adducts using empirical equations supported by TG data

In this work is presented and tested (for 106 adducts, mainly of the zinc group halides) two empirical equations supported in TG data to estimate the value of the metal-ligand bond dissociation enthalpy for adducts: <D> (M-O) = t i / g if t i < 420 K and <D> (M-O) = (t i / g ) - 7,75 . 10-2 . t i if t i > 420 K. In this empirical equations, t i is the thermodynamic temperature of the beginning of the thermal decomposition of the adduct, as determined by thermogravimetry, andg is a constant factor that is function of the metal halide considered and of the number of ligands, but is not dependant of the ligand itself. To half of the tested adducts the difference between experimental and calculated values was less than 5%. To about 80% of the tested adducts, the difference between the experimental (calorimetric) and the calculated (using the proposed equations) values are less than 15%.

Context exchange between devices in mobile environment

Context awareness is emerging on mobile devices. Context awareness can be used to improve usability of a mobile device. Context awareness is particularly important on mobile devices due the limitations they have. At first in this work, a literature review on context awareness and mobile environment is made. For aiding context awareness there exist an implementation of a Context Framework for Symbian S60 devices. It provides a possibility for exchanging the contexts inside the device between the client applications of the local Context Framework. The main contribution of this thesis is to design and implement an enhancement to the S60 Context Framework for providing possibility to exchange context over device boundaries. Using the implemented Context Exchange System, the context exchange is neither depending on the type of the context nor the type of the client. In addition, the clients and the contexts can reside on any interconnected device. The usage of the system is independent of the programming language since in addition to using only Symbian C++ function interfaces it can also be utilized using XML scripts. The Meeting Sniffer application, which uses the Context Exchange System, was also developed in this work. Using this application, it is possible to recognize a meeting situation and suggest device profile change to a user.

Azolium-based systems: application of an anion exchange resin (A- form) method and 1H NMR analysis of the charged-assisted (CH)+·anion hydrogen bonds

The counteranion exchange of quaternary 1,2,3-triazolium salts was examined using a simple method that permitted halide ions to be swap for a variety of anions using an anion exchange resin (A¯ form). The method was applied to 1,2,3-triazolium-based ionic liquids and the iodideto- anion exchange proceeded in excellent to quantitative yields, concomitantly removing halide impurities. Additionally, an anion exchange resin (N3¯ form) was used to obtain the benzyl azide from benzyl halide under mild reaction. Likewise, following a similar protocol, bis(azidomethyl)arenes were also synthesized in excellent yields. The results of a proton NMR spectroscopic study of simple azolium-based ion pairs are discussed, with attention focused on the significance of the charged-assisted (CH)+···anion hydrogen bonds of simple azolium systems such as 1-butyl-3-methylimidazolium and 1-benzyl-3-methyl-1,2,3-triazolium salts.

Azolium-based systems: application of an anion exchange resin (A- form) method and 1H NMR analysis of the charged-assisted (CH)+·anion hydrogen bonds

The counteranion exchange of quaternary 1,2,3-triazolium salts was examined using a simple method that permitted halide ions to be swap for a variety of anions using an anion exchange resin (A¯ form). The method was applied to 1,2,3-triazolium-based ionic liquids and the iodideto- anion exchange proceeded in excellent to quantitative yields, concomitantly removing halide impurities. Additionally, an anion exchange resin (N3¯ form) was used to obtain the benzyl azide from benzyl halide under mild reaction. Likewise, following a similar protocol, bis(azidomethyl)arenes were also synthesized in excellent yields. The results of a proton NMR spectroscopic study of simple azolium-based ion pairs are discussed, with attention focused on the significance of the charged-assisted (CH)+···anion hydrogen bonds of simple azolium systems such as 1-butyl-3-methylimidazolium and 1-benzyl-3-methyl-1,2,3-triazolium salts.

Role of PheE15 gate in ligand entry and nitric oxide detoxification function of Mycobacterium tuberculosis truncated hemoglobin N

The truncated hemoglobin N, HbN, of Mycobacterium tuberculosis is endowed with a potent nitric oxide dioxygenase (NOD) activity that allows it to relieve nitrosative stress and enhance in vivo survival of its host. Despite its small size, the protein matrix of HbN hosts a two-branched tunnel, consisting of orthogonal short and long channels, that connects the heme active site to the protein surface. A novel dual-path mechanism has been suggested to drive migration of O(2) and NO to the distal heme cavity. While oxygen migrates mainly by the short path, a ligand-induced conformational change regulates opening of the long tunnel branch for NO, via a phenylalanine (PheE15) residue that acts as a gate. Site-directed mutagenesis and molecular simulations have been used to examine the gating role played by PheE15 in modulating the NOD function of HbN. Mutants carrying replacement of PheE15 with alanine, isoleucine, tyrosine and tryptophan have similar O(2)/CO association kinetics, but display significant reduction in their NOD function. Molecular simulations substantiated that mutation at the PheE15 gate confers significant changes in the long tunnel, and therefore may affect the migration of ligands. These results support the pivotal role of PheE15 gate in modulating the diffusion of NO via the long tunnel branch in the oxygenated protein, and hence the NOD function of HbN.

Azolium-based systems: application of an anion exchange resin (A- form) method and 1H NMR analysis of the charged-assisted (CH)+·anion hydrogen bonds

The counteranion exchange of quaternary 1,2,3-triazolium salts was examined using a simple method that permitted halide ions to be swap for a variety of anions using an anion exchange resin (A¯ form). The method was applied to 1,2,3-triazolium-based ionic liquids and the iodideto- anion exchange proceeded in excellent to quantitative yields, concomitantly removing halide impurities. Additionally, an anion exchange resin (N3¯ form) was used to obtain the benzyl azide from benzyl halide under mild reaction. Likewise, following a similar protocol, bis(azidomethyl)arenes were also synthesized in excellent yields. The results of a proton NMR spectroscopic study of simple azolium-based ion pairs are discussed, with attention focused on the significance of the charged-assisted (CH)+···anion hydrogen bonds of simple azolium systems such as 1-butyl-3-methylimidazolium and 1-benzyl-3-methyl-1,2,3-triazolium salts.

Another Look at the Null of Stationary Real Exchange Rates: Panel Data with Structural Breaks and Cross-section Dependence

This paper re-examines the null of stationary of real exchange rate for a panel of seventeen OECD developed countries during the post-Bretton Woods era. Our analysis simultaneously considers both the presence of cross-section dependence and multiple structural breaks that have not received much attention in previous panel methods of long-run PPP. Empirical results indicate that there is little evidence in favor of PPP hypothesis when the analysis does not account for structural breaks. This conclusion is reversed when structural breaks are considered in computation of the panel statistics. We also compute point estimates of half-life separately for idiosyncratic and common factor components and find that it is always below one year.

Guidelines for CERIF-XML Data Exchange with CSUC’s Catalan Research Portal (PRC) (Version 2.2)

The Catalan Research Portal (Portal de la Recerca de Catalunya or PRC) is an initiative carried out by the Consortium for University Services in Catalonia (CSUC) in coordination with nearly all universities in Catalonia. The Portal will provide an online CERIF-compliant collection of all research outputs produced by Catalan HEIs together with an appropriate contextual information describing the specific environment where the output was generated (such as researchers, research group, research project, etc). The initial emphasis of the Catalan Research Portal approach to research outputs will be made on publications, but other outputs such as patents and eventually research data will eventually be addressed as well. These guidelines provide information for PRC data providers to expose and exchange their research information metadata in CERIFXML compatible structure, thus allowing them not just to exchange validated CERIF XML data with the PRC platform, but to improve their general interoperability by being able to deliver CERIFcompatible outputs.