One Question,Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists

Fragment‐based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit‐to‐lead‐to‐drug optimization, the screening process should distinguish reliably between binders and non‐binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease‐relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361‐entry library by using a reporter‐displacement assay, saturation‐transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions.     

Gender difference in color preference across cultures: An archetypal pattern modulated by a female cultural stereotype

A gender difference in color preference among British participants has been repeatedly reported, in which both males and females show a preference for blue‐green colors, while females express an additional preference for pink‐purple colors. To investigate the robustness of gender difference in color preference in a different culture, we tested 81 young adult Indians from a school of design and compared them to 80 young British students in Psychology. The 35‐item International Personality Item Pool (IPIP) and Bem Sex Role Inventory (BSRI) questionnaires were also administered to explore possible links between personality traits, gender schemata, and color preferences. Results confirmed a gender difference in both cultures; participants collectively expressed a preference for cool over warm colors, while in addition females showed a preference for pink colors, with a warm bias for Indian females and a cool bias for British females. While these results extend gender difference to Indian culture and support the universality of an underlying pattern they also reveal a culture‐specific contribution essentially observed in females. In British participants, color preference was correlated exclusively with BSRI scores in females and overwhelmingly with IPIP scores in males; this gender‐specific pattern of correlation was not replicated in the Indian sample. Results point to an archetypal pattern of gender difference in color preference with a remarkable cross‐cultural similarity in men and a subtle but significant cultural difference in women whose origin is yet to be explained.     

The effect of different cementing strategies and adhesive interface aging on microtensile bond strength (μTBS) of lithium disilicate ceramics to dentin

This study evaluated the effect of different cementing strategies and adhesive interface aging on microtensile bond strength (μTBS) of lithium disilicate ceramic (IPS e.max CAD) to dentin. Forty coronal dentin fragments were randomly assigned to four groups according to the cementing strategy used to bond lithium disilicate ceramic to coronal dentin surface (n = 10): U200 (self-adhesive resin cement (RC) RelyX U200®/3 M ESPE), SBU (single-step self-etching adhesive system (AS) Single Bond Universal®/3 M ESPE + RelyX ARC®/3 M ESPE RC), AdperSB (two-step etch-and-rinse AS Single Bond 2®/3 M + RelyX ARC®/3 M ESPE RC) and Scotchbond (three-step etch-and-rinse AS Scotchbond Multi-Purpose®/3 M + RelyX ARC®/3 M RC). After 48 h, the ceramic-tooth blocks were sectioned perpendicular to the adhesive interface in the form of sticks and randomly subdivided into two groups according to when they were to be submitted to μTBS testing: immediately or 6 months after storage in water. Some sticks were kept for analysis of the adhesive interface by scanning electron microscopy (SEM). The μTBS test was performed in a universal testing machine (0.5 mm/min). The data (MPa) were analyzed using split-plot ANOVA and Tukey’s test (α = 0.05). Water storage decreased μTBS in all cementing strategies. The μTBS was greatest in the Scotchbond group and lowest in the U200 group, at both storage times. No signs of interface degradation were detected under SEM after water storage. In conclusion, water storage decreased bond strength, regardless of the adhesive cementation strategy, and that the three-step adhesive system/dual-cure resin cement ultimately performed better in terms of bond strength.     

Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Compounds that simultaneously activate peroxisome proliferator‐activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α‐ethoxyphenylpropionic acid bearing 5‐ or 6‐substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a . Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a , less potent as a dual PPARα/γ activator than 20 c , showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.     

Polyunsaturated Fatty Acid Concentrates of Carp Oil: Chemical Hydrolysis and Urea Complexation

The aims of this study were to compare three treatments in the chemical hydrolysis reaction of bleached oil from carp (Cyprinus carpio) heads and to obtain polyunsaturated fatty acid concentrates by urea complexation. The three treatments were carried out with different oil:ethanol molar ratios. In the treatment with a 1:39 molar ratio, a higher yield of free fatty acids was found. These fatty acids were submitted to urea complexation (−10 °C for 20 h, and urea–fatty acid ratio of 4.5–1). There was a 31.4% increase in monounsaturated and polyunsaturated fatty acids (MUFA and PUFA) content and a 75% decrease in saturated fatty acids (SAF) content. An increase of 85.4% in the EPA + DHA content was found. The non-urea complexing fraction can be considered a rich source of MUFA and PUFA with a total amount of 88.9%.     

Ceramics based on partly stabilized zirconium dioxide: technology,structure, properties,and behavior under dynamic action

Technology is described for manufacturing dense ceramic from very fine powder based on zirconium dioxide partly stabilized with yttrium oxide. Some engineering properties of the manufactured ceramic are defined. Its microstructure and phase composition are studied. Ceramic properties with impact-wave loading are studied, and values of dynamic elastic limit and spalling strength are obtained.     

A representative and comprehensive review of the electrical and thermal properties of polymer composites with carbon nanotube and other nanoparticle fillers

In this review we present the results of our literature investigation into the electrical and thermal properties of carbon nanotube polymer composites. A short selection of data relating to conductive polymer composites with various fillers is provided for comparison. The effects of filler properties such as type and size, the use of hybrid fillers, fabrication methods for polymer composites and the importance of the modeling of the electronic and thermal transport mechanisms are discussed, as are more general factors influencing the properties of these composites. This review represents a comprehensive survey and constructive study and should serve as a useful reference tool for industrial and academic researchers working in this field. © 2017 Society of Chemical Industry     

On some distinctive features of the structure of composite ceramic materials obtained by the method of directed reaction impregnation

The method of directed reaction impregnation (DRI), known as a Lanxide process in foreign countries, provides a wide spectrum of ceramic composite materials with a variable content of metallic phase, which possess high physicomechanical properties. An important advantage of the method is the absence of shrinkage, which diminishes substantially the amount of heat-treatment rejects and the cost of the finishing mechanical treatment. The structural characteristics of composites obtained by impregnation of the pore space of -SiC and A1₂O₃ ceramic matrices with an aluminum alloy with 5 wt.% Si and 2 wt.% Mg are presented. The former matrix is obtained by free pouring of a granular powder of silicon carbide, and the latter matrix is represented by a densely sintered alumina preform with through cylindrical channels. The process is conducted at 1150 – 1200‡C for 24 h in air. The structure of the composites bears Al₂O₃ crystals and a mixed Al/Al₂O₃ phase formed from the metallic melt. The microhardness of the phases that compose the structure of the composite with a silicon carbide matrix is determined (HV = 28.4 – 73.2 GPa for Al₂O₃,HV = 10.3 – 19.7 GPa for SiC, andHV = 0.5 – 0.8 GPa for A1/A1₂O₃). Directed reaction impregnation through cylindrical channels of the aluminum oxide matrix yields highly porous fibers with a typical dimple structure. The impregnation process in this composite is considered from the standpoint of equilibrium (the Le Chatelier principle). Its occurrence in different stages is considered from the standpoint of thermodynamics. Transleted from Ogneupory i Technicheskaya Keramika, No. 8, pp. 14 – 20, August, 2000.     

Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight

It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Although the exact mechanisms are unknown, a role for Ca²⁺ dysregulation has been suggested. The sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA) pump actively brings cytosolic Ca²⁺ into the SR, eliciting muscle relaxation and maintaining low intracellular Ca²⁺ ([Ca²⁺]_i). SERCA dysfunction contributes to elevations in [Ca²⁺]_i, leading to cellular damage, and may contribute to the muscle weakness and atrophy observed with spaceflight. Here, we investigated SERCA function, SERCA regulatory protein content, and reactive oxygen/nitrogen species (RONS) protein adduction in murine skeletal muscle after 35–37 days of spaceflight. In male and female soleus muscles, spaceflight led to drastic impairments in Ca²⁺ uptake despite significant increases in SERCA1a protein content. We attribute this impairment to an increase in RONS production and elevated total protein tyrosine (T) nitration and cysteine (S) nitrosylation. Contrarily, in the tibialis anterior (TA), we observed an enhancement in Ca²⁺ uptake, which we attribute to a shift towards a faster muscle fiber type (i.e., increased myosin heavy chain IIb and SERCA1a) without elevated total protein T-nitration and S-nitrosylation. Thus, spaceflight affects SERCA function differently between the soleus and TA.