A Molecular-Modeling Toolbox Aimed at Bridging the Gap between Medicinal Chemistry and Computational Sciences

In the current era of high-throughput drug discovery and development, molecular modeling has become an indispensable tool for identifying, optimizing and prioritizing small-molecule drug candidates. The required background in computational chemistry and the knowledge of how to handle the complex underlying protocols, however, might keep medicinal chemists from routinely using in silico technologies. Our objective is to encourage those researchers to exploit existing modeling technologies more frequently through easy-to-use graphical user interfaces. In this account, we present two innovative tools (which we are prepared to share with academic institutions) facilitating computational tasks commonly utilized in drug discovery and development: (1) the VirtualDesignLab estimates the binding affinity of small molecules by simulating and quantifying their binding to the three-dimensional structure of a target protein; and (2) the MD Client launches molecular dynamics simulations aimed at exploring the time-dependent stability of ligand–protein complexes and provides residue-based interaction energies. This allows medicinal chemists to identify sites of potential improvement in their candidate molecule. As a case study, we present the application of our tools towards the design of novel antagonists for the FimH adhesin.     

A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate

ABSTRACT: BACKGROUND: Creatine monohydrate (CrM) has been consistently reported to increase muscle creatine content and improve high-intensity exercise capacity. However, a number of different forms of creatine have been purported to be more efficacious than CrM. The purpose of this study was to determine if a buffered creatine monohydrate (KA) that has been purported to promote greater creatine retention and training adaptations with fewer side effects at lower doses is more efficacious than CrM supplementation in resistance-trained individuals. METHODS: In a double-blind manner, 36 resistance-trained participants (20.2 +/- 2 years, 181 +/- 7 cm, 82.1 +/- 12 kg, and 14.7 +/- 5% body fat) were randomly assigned to supplement their diet with CrM (Creapure(R) AlzChem AG, Trostberg, Germany) at normal loading (4 x 5 g/d for 7-days) and maintenance (5 g/d for 21-days) doses; KA (Kre-Alkalyn(R), All American Pharmaceutical, Billings, MT, USA) at manufacturer's recommended doses (KA-L, 1.5 g/d for 28-days); or, KA with equivalent loading (4 x 5 g/d for 7-days) and maintenance (5 g/d) doses of CrM (KA-H). Participants were asked to maintain their current training programs and record all workouts. Muscle biopsies from the vastus lateralis, fasting blood samples, body weight, DEXA determined body composition, and Wingate Anaerobic Capacity (WAC) tests were performed at 0, 7, and 28-days while 1RM strength tests were performed at 0 and 28-days. Data were analyzed by a repeated measures multivariate analysis of variance (MANOVA) and are presented as mean +/- SD changes from baseline after 7 and 28-days, respectively. RESULTS: Muscle free creatine content obtained in a subgroup of 25 participants increased in all groups over time (1.4 +/- 20.7 and 11.9 +/- 24.0 mmol/kg DW, p = 0.03) after 7 and 28-days, respectively, with no significant differences among groups (KA-L -7.9 +/- 22.3, 4.7 +/- 27.0; KA-H 1.0 +/- 12.8, 9.1 +/- 23.2; CrM 11.3 +/- 23.9, 22.3 +/- 21.0 mmol/kg DW, p = 0.46). However, while no overall group differences were observed (p = 0.14), pairwise comparison between the KA-L and CrM groups revealed that changes in muscle creatine content tended to be greater in the CrM group (KA-L -1.1 +/- 4.3, CrM 11.2 +/- 4.3 mmol/kg DW, p = 0.053 [mean +/- SEM]). Although some significant time effects were observed, no significant group x time interactions (p > 0.05) were observed in changes in body mass, fat free mass, fat mass, percent body fat, or total body water; bench press and leg press 1RM strength; WAC mean power, peak power, or total work; serum blood lipids, markers of catabolism and bone status, and serum electrolyte status; or, whole blood makers of lymphocytes and red cells. Serum creatinine levels increased in all groups (p < 0.001) with higher doses of creatine promoting greater increases in serum creatinine (p = 0.03) but the increases observed (0.1 -- 0.2 mg/dl) were well within normal values for active individuals (i.e., <1.28 +/- 0.2 mg/dl). Serum LDL was decreased to a greater degree following ingesting loading doses in the CrM group but returned to baseline during the maintenance phase. No side effects were reported. CONCLUSIONS: Neither manufacturers recommended doses of KA (1.5 g/d) or KA with equivalent loading (20 g/d for 7-days) and maintenance doses (5 g/d for 21-days) of CrM promoted greater changes in muscle creatine content, body composition, strength, or anaerobic capacity than CrM (20 g/d for 7-days, 5 g/d for 21-days). There was no evidence that supplementing the diet with a buffered form of creatine resulted in fewer side effects than CrM. These findings do not support claims that consuming a buffered form of creatine is a more efficacious and/or safer form of creatine to consume than creatine monohydrate.     

An economic evaluation of photovoltaic grid connected systems (PVGCS) in Flanders for companies: A generic model

In this paper an economic evaluation of photovoltaic grid connected systems (PVGCS) for companies situated in Flanders (Belgium) is conducted by using a generic Excel model. The model is unique in that it includes the dimension of taxation. This inclusion is required, otherwise the fiscal benefit of using solar panels is not accounted for. The model uses the cash flow projection method. This technique allows the calculation of the following classical evaluation criteria: net present value, internal rate of return, payback period, discounted payback period, profitability index, yield unit cost, yield unit revenue and break-even turnkey cost. Their outcome makes it possible to answer the question whether installing a PVGCS in Flanders is a responsible financial investment for companies. Furthermore, the paper estimates whether the corporate environment is ready for a subsidy legislation change. This change has recently been announced and as such it is possible to gauge whether the current market situation is profitable given future legislation.     

Assessment of atmospheric heavy metal deposition in the Tarkwa gold mining area of Ghana using epiphytic lichens

In situ lichens (Parmelia sulcata) have been used to assess atmospheric heavy metal deposition in the Tarkwa gold mining area of Ghana. Total heavy metal concentrations obtained by instrumental neutron activation analysis (INAA) were processed by positive matrix factorization (PMF), principal component (PCA) and cluster (CA) analyses. The pollution index factor (PIF) and pollution load index (PLI) criteria revealed elevated levels of Sb, Mn, Cu, V, Al, Co, Hg, Cd and As in excess of the background values. The PCA and CA classified the examined elements into anthropogenic and natural sources, and PMF resolved three primary sources/factors: agricultural activities and other non-point anthropogenic origins, natural soil dust, and gold mining activities. Gold mining activities, which are characterized by dominant species of Sb, Th, As, Hg, Cd and Co, and significant contributions of Cu, Al, Mn and V, are the main contributors of heavy metals in the atmosphere of the study area.     

View from the Top: Wilhelm von Herford on the great pyramid, 1856

Abstract

The two photographs shown¹ are perhaps the first ever taken from the top of the Great (or Cheops) Pyramid. They can be dated to 1856 when the German amateur photographer Wilhelm von Herford (1814–1866) became a Prussian consular officer in Cairo.¹     

Reduced configuration set for the multi-step method applied to machine and probe error separation on a CMM

This paper presents a refinement and further analysis of an application of the multi-step method for the separation of machine and probe errors on a CMM using multiple redundancy probing of the machine’s own master ball. The objective is to reduce the amount of data required and so minimize the test time in order to reduce the industrial cost of such periodic verifications.     

Modification of surface layers of quick-speed powdered metal steels using welding heat sources

Powdered metal steel S390 and its equivalents are manufactured in a traditional way, that is, steel 10-4-3-10 (SK10V) which is subjected to modification of its surface layer. An analysis was made of the changes to the structure and mechanical properties of the above-mentioned steels at each individual stage of a heat treatment process carried out after soft annealing, quenching, tempering, and joint penetration surface treatment. The scope of this analysis included optimization of the joint penetration parameters, macro-, and micro-testing with utilization of scanning and light microscopy, preliminary tests of phase composition as well as comparative hardness measurement. The major practical purpose of the experiment was to assess the feasibility of using welding heat sources for joint penetration surface treatment of quick-speed steels.