DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders

Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the noncovalent binding framework is important to improve potency and selectivity of covalent binders toward the desired target. Significant efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction. To highlight the value of the noncovalent complex in the covalent binding process, here we describe a new protocol using tethered and constrained docking in combination with Dynamic Undocking (DUck) as a tool to privilege strong protein binders for the identification of novel covalent inhibitors. At the end of the protocol, dedicated covalent docking methods were used to rank and select the virtual hits based on the predicted binding mode. By validating the method on JAK3 and KRas, we demonstrate how this fast iterative protocol can be applied to explore a wide chemical space and identify potent targeted covalent inhibitors.     

Secular trend in body height since the Neolithic period

Rat mesangial cells express two unique isoforms of laminin which can be modulated by culture medium composition. To define further the nature of laminin expressed by cultured rat mesangial cells, synthesis of individual laminin chains, as well as their trimeric association, was examined. Based on data from Northern analysis of mRNA expression, immunoblots, immunofluorescence staining and radioimmunoprecipitation of biosynthetically labeled proteins, mesangial cells express laminin beta1, beta2, and gamma1 chains. Mesangial cells do not express laminin alpha1 or alpha2. MC produce a unique alpha chain, designated alpha'm. These laminin chains assemble into two major isoforms. One contains alpha'mbeta1gamma1, co-precipitates with entactin and is assembled into the fibrillar extracellular matrix. The second isoform contains alpha'mbeta2 and a presumed gamma chain that migrates in gel slightly ahead of gamma1. The beta2-containing isoform is concentrated in punctate sites on the cell surface. In addition, mesangial cells display different phenotypes when plated on laminin-1 (alpha1beta1gamma1), as compared to purified beta2. An LRE-containing peptide of laminin beta2 serves as an attachment site for mesangial cells and is sufficient to induce the phenotype observed with intact beta2. These data suggest that laminin isoform expression plays an important role in mesangial cell phenotype and function.     

Temporal relation of ATP-sensitive potassium-channel activation and contractility before cardioplegia

BACKGROUND: Pharmacologic treatment using potassium-channel openers (PCOs) before cardioplegic arrest has been demonstrated to provide beneficial effects on left ventricular performance with subsequent reperfusion and rewarming. However, the PCO treatment interval necessary to provide protective effects during cardioplegic arrest remains to be defined. The present study was designed to determine the optimum period of PCO treatment that would impart beneficial effects on left ventricular myocyte contractility after simulated cardioplegic arrest. METHODS: Left ventricular porcine myocytes were assigned randomly to three groups: (1) normothermic control = 37 degrees C for 2 hours; (2) cardioplegia = K+ (24 mEq/L) at 4 degrees C for 2 hours followed by reperfusion and rewarming; and (3) PCO and cardioplegia = 1 to 15 minutes of treatment with the PCO aprikalim (100 micromol/L) at 37 degrees C followed by hypothermic (4 degrees C) cardioplegic arrest and subsequent rewarming. Myocyte contractility was measured after rewarming by videomicroscopy. A minimum of 50 myocytes were examined at each treatment and time point. RESULTS: Myocyte velocity of shortening was reduced after cardioplegic arrest and rewarming compared with normothermic controls (63+/-3 microm/s versus 32+/-2 microm/s, respectively; p < 0.05). With 3 minutes of PCO treatment, myocyte velocity of shortening was improved after cardioplegic arrest to values similar to those of normothermic controls (56+/-3 microm/s). Potassium channel opener treatment for less than 3 minutes did not impart a protective effect, and the protective effect was not improved further with more prolonged periods of PCO treatment. CONCLUSIONS: A brief interval of PCO treatment produced beneficial effects on left ventricular myocyte contractile function in a simulated model of cardioplegic arrest and rewarming. These results suggest that a brief period of PCO treatment may provide a strategy for myocardial protection during prolonged cardioplegic arrest in the setting of cardiac operation.     

CAD and Management of Construction Projects

The increasing interest in computer‐aided design (CAD) has prompted research that is aimed at identifying the opportunities for construction managers and building contractors. It has been found that the use of CAD systems in the U.K. is mainly confined to the production of detailed drawings. Indeed, most of the systems used are 2‐D drafting tools and incapable of supporting the integration of even modest amounts of nongraphical (construction) data. On the other hand, many 3‐D modeling systems have the potential to integrate construction data, although they appear to be almost ignored. The use of 3‐D modeling systems is considered to be the most suitable vehicle for successfully integrating these data. However, this is likely to necessitate the introduction of separate databases, preferably of the relational type. The use of 3‐D modeling systems in assessing the construction implications of outline designs also presents interesting possibilities and is discussed.     

Effects of eating abnormalities and gender on perceptions of desirable body shape.

A. E. Fallon and P. Rozin (see record 1985-14553-001) found that men and women differ when choosing the figure drawings that most resemble (a) their own current figures ({current}), (b) their ideal figures ({ideal}), and (c) the figure thought most attractive to the opposite sex ({opposite}). In the present experiment, women with high Eating Attitude Test (EAT) scores, indicating abnormal eating patterns, choose differently from those with low scores. All women's {ideal} and {opposite} figures are thinner than their {current} figures, whereas men rate all three nearly identically. Only the high-scoring women choose an {ideal} figure thinner than their {opposite}. This suggests that whereas men are satisfied with their figures, women desire to be thinner than they think they are, and women with abnormal eating behaviors desire to be even thinner than what they think men find attractive. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Diazo Compounds in the Photocopying Industry

The relationship between the structures of diazos used in the industry and their chemical and physical properties are discussed. Photocopying processes using diazos are surveyed and the properties required by the diazos employed are considered.     

Gravimetric and spectroscopic studies of the chemical combination of moisture by as-fired and reheated terracotta

The application of microbalance measurements to investigate the chemical recombination of moisture with fired clay ceramics is demonstrated. The kinetics of mass gain at constant temperature and relative humidity (RH) are studied for terracotta fired at temperatures between 800 °C and 1200 °C. The experimental results show that mass gain proceeds in two stages. The second stage mass gain is taken as a measure of the capacity for long-term chemical combination with moisture based on the (time)^1/4 law. A maximum rate of mass gain is obtained for terracotta fired at 1000 °C. It is shown that reheating a sample of fired terracotta at any temperature between 500 °C and the original firing temperature will return the material to its as-fired state. This is supported by Raman spectroscopy. Exceeding the original firing temperature during reheating alters the subsequent rate of reaction to moisture, suggesting a method for determining the original firing temperature of ceramic artefacts.     

Evaluation of leaf-derived extracts as an environmentally sustainable source of essential oils by using gas chromatography-mass spectrometry and enantioselective gas chromatography-olfactometry

In consideration of the world's present environmental situation and the threat of species extinction, investigations concerning alternative sustainable sources of natural substances represent an extremely important issue. In this respect, the present research is focused on the analytical evaluation of Brazilian rosewood (Aniba rosaeodora Ducke) leaves, as an alternative source (with respect to wood) of rosewood essential oil and, as such, of natural linalool, which is extensively used in perfumery. Enantioselective-gas chromatography-olfactometry (Es-GC-O) was used as a tool for the simultaneous stereodifferentiation and olfactive evaluation of the volatile optically active components present in the analyzed samples. In addition to Es-GC-O analyses, direct olfactive analyses were also performed, enabling the evaluation of the global aroma exerted by each sample and the influence of each linalool antipode, as also other minor compounds. The samples were also submitted to gas chromatography-mass spectrometric analysis, thus establishing their chemical profiles. The assessment of enantiopure chiral compounds through Es-GC-O, along with direct olfactive analyses, confirmed that the leaves are a potential substituent for wood in the extraction of Brazilian rosewood essential oil, representing a sustainable nonwood source of natural linalool.     

Widespread presence of naturally occurring perchlorate in high plains of Texas and New Mexico

Perchlorate (CLO4-) occurrence in groundwater has previously been linked to industrial releases and the historic use of Chilean nitrate fertilizers. However, recently a number of occurrences have been identified for which there is no obvious anthropogenic source. Groundwater from an area of 155,000 km2 in 56 counties in northwest Texas and eastern New Mexico is impacted bythe presence of ClO4-. Concentrations were generally low (<4 ppb), although some areas are impacted by concentrations up to 200 ppb. ClO4- distribution is not related to well type (public water system, domestic, agricultural, or water-table monitoring) or aquifer (Ogallala, Edward Trinity High Plains, Edwards Trinity Plateau, Seymour, or Cenozoic). Results from vertically nested wells strongly indicate a surface source. The source of ClO4- appears to most likely be atmospheric deposition. Evidence supporting this hypothesis primarily relates to the presence of ClO4- in tritium-free older water, the lack of relation between land use and concentration distribution, the inability of potential anthropogenic sources to account for the estimated mass of ClO4-, and the positive relationship between conserved anions (e.g., IO3-, Cl-, SO4(-2)) and ClO4-. The ClO4- distribution appears to be mainly related to evaporative concentration and unsaturated transport. This process has led to higher ClO4- and other ion concentrations in groundwater where the water table is relatively shallow, and in areas with lower saturated thickness. Irrigation may have accelerated this process in some areas by increasing the transport of accumulated salts and by increasing the number of evaporative cycles. Results from this study highlight the potential for ClO4- to impact groundwater in arid and semi-arid areas through long-term atmospheric deposition.     

Gestaltung hybrider Wertschöpfung mittels Architekturen – Analyse am Beispiel des Business Engineering

The increasing competition forces enterprises to establish differentiation strategies more than ever. The creation of innovative bundles, consisting of material and immaterial elements, is such a strategy and known as “hybrid value creation”. In order to support enterprises during their change towards a hybrid solution supplier, procedures and techniques are needed which are embedded in a certain structure. Architecture Frameworks can support such a structured transformation of enterprises. The intention of the paper is to identify requirements for architectures for hybrid value creation and to check these requirements by using the St. Gallen Business Engineering Framework.