Targeting an EGFR Water Network with 4-Anilinoquin(az)oline Inhibitors for Chordoma

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18 ), which is the most potent inhibitor (IC₅₀=310 nm ) of the UCH-2 chordoma cell line to date.     

Temperature optimisation of a diesel engine using exhaust gas heat recovery and thermal energy storage (diesel engine with thermal energy storage)

Modern automotive diesel engines are so energy efficient that they are heating up slowly and tend to run rather cold at subzero temperatures. The problem is especially severe in mail delivery operations where the average speed is low and the drive cycle includes plenty of idling. The problem is typically solved by adding a diesel fuelled additional engine heater which is used for the preheating of the engine during cold start and additional heating of the engine if the coolant temperature falls below a thermostat set point during the drive cycle. However, this additional heater may drastically increase the total fuel consumption and exhaust gas emissions of the vehicle. In this study the additional heater was replaced by a combination of exhaust gas heat recovery system and latent heat accumulator for thermal energy storage. The system was evaluated on a laboratory dynamometer using a simulated drive cycle and in field testing in the city of Oulu (65°N), Finland in February 2009.     

Lake whitefish (Coregonus clupeaformis) energy and nutrient partitioning in lakes Michigan,Erie and Superior

A concurrent decrease in lake whitefish (Coregonus clupeaformis) condition and Diporeia spp. abundance in Lake Michigan has spurred investigations into possible links between the two phenomena. We examined female lake whitefish δ¹³C and δ¹⁵N stable isotopes, growth, reproductive investment, dorsal muscle total lipid and docosahexaenoic acid (DHA) contents from lakes Erie, Michigan and Superior to determine whether differences in food source were correlated with measures of stock success. Stocks with higher somatic growth rates and mean reproductive potential had higher energy stores in terms of percent total lipid. Stocks with low muscle lipid concentration also had smaller egg sizes as egg number increased. Diet varied among stocks as evidenced by δ¹³C and δ¹⁵N stable isotope analyses; however, muscle total lipid and DHA were not correlated to apparent Diporeia spp. prey use. When compared to stocks from lakes Erie and Superior, Lake Michigan stocks had lower growth, reproduction, and lipid stores. While stocks in Lake Michigan with access to declining Diporeia spp. populations may still feed on the amphipod, it appears that they are unable to consume the quantities necessary to maintain historical growth and reproduction. Stable isotope analyses of lakes Erie and Superior stocks, with higher growth rates and lipid values, indicated different feeding strategies with no indication of reliance on Diporeia spp. While differences in prey resources may have an effect on lake whitefish stocks, differences in Diporeia spp. abundance alone cannot explain differences in lake whitefish condition observed among the Great Lakes included in this study.     

A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor

Transforming growth factor beta (TGFbeta) signal transduction is mediated by two receptor Ser/Thr kinases acting in series, type II TGFbeta receptor (TbetaR-II) phosphorylating type I TGFbeta receptor (TbetaR-I). Because the failure of interaction cloning, thus far, to identify bona fide TbetaR-I substrates might reasonably have been due to the use of inactive TbetaR-I as bait, we sought to identify molecules that interact specifically with active TbetaR-I, employing the triple mutation L193A,P194A,T204D in a yeast two-hybrid system. The Leu-Pro substitutions prevent interaction with FK506-binding protein 12 (FKBP12), whose putative function in TGFbeta signaling we have previously disproved; the charge substitution at Thr204 constitutively activates TbetaR-I. Unlike previous screens using wild-type TbetaR-I, where FKBP12 predominated, none of the resulting colonies encoded FKBP12. A novel protein was identified, TbetaR-I-associated protein-1 (TRAP-1), that interacts in yeast specifically with mutationally activated TbetaR-I, but not wild-type TbetaR-I, TbetaR-II, or irrelevant proteins. In mammalian cells, TRAP-1 was co-precipitated only by mutationally activated TbetaR-I and ligand-activated TbetaR-I, but not wild-type TbetaR-I in the absence of TGFbeta. The partial TRAP-1 protein that specifically binds these mutationally and ligand-activated forms of TbetaR-I can inhibit signaling by the native receptor after stimulation with TGFbeta or by the constitutively activated receptor mutation, as measured by a TGFbeta-dependent reporter gene. Thus, TRAP-1 can distinguish activated forms of the receptor from wild-type receptor in the absence of TGFbeta and may potentially have a functional role in TGFbeta signaling.     

Comparison of clustering methods: A case study of text-independent speaker modeling

Clustering is needed in various applications such as biometric person authentication, speech coding and recognition, image compression and information retrieval. Hundreds of clustering methods have been proposed for the task in various fields but, surprisingly, there are few extensive studies actually comparing them. An important question is how much the choice of a clustering method matters for the final pattern recognition application. Our goal is to provide a thorough experimental comparison of clustering methods for text-independent speaker verification. We consider parametric Gaussian mixture model (GMM) and non-parametric vector quantization (VQ) model using the best known clustering algorithms including iterative (K-means, random swap, expectation-maximization), hierarchical (pairwise nearest neighbor, split, split-and-merge), evolutionary (genetic algorithm), neural (self-organizing map) and fuzzy (fuzzy C-means) approaches. We study recognition accuracy, processing time, clustering validity, and correlation of clustering quality and recognition accuracy. Experiments from these complementary observations indicate clustering is not a critical task in speaker recognition and the choice of the algorithm should be based on computational complexity and simplicity of the implementation. This is mainly because of three reasons: the data is not clustered, large models are used and only the best algorithms are considered. For low-order models, choice of the algorithm, however, can have a significant effect.     

Degradative and mechanical properties of a novel resorbable plating system during a 3-year follow-up in vivo and in vitro

We tested the tissue reactions and mechanical strength of a novel biodegradable craniomaxillofacial plating system, Inion CPS™, in the course of degradation. Plates and screws composed of l-lactide, d-lactide and trimethylene carbonate were implanted to the mandible and dorsal subcutis of 12 sheep. The animals were sacrificed at 6–156 weeks. Histological evaluation was done using paraffin and methylmetacrylate techniques. Degradative and mechanical properties during the follow-up were measured both of in vivo and in vitro implants. In light microscopy, the in vivo implant material began to fragment at 52 weeks and could not be detected at 104 weeks. No significant foreign body reactions were seen in the mandibles. The dorsal subcutis disclosed mild reactions, which were, however, not of clinical significance. The implants in vitro maintained their entire mass for 26 weeks and lost 63–80% of the mass by week 104. The inherent viscosity of the implants in vitro and in vivo diminished uniformly. The screws retained their shear strength for 12–16 weeks. The plates maintained their tensile strength for at least 6 weeks. The maximum capacity of the plates in 3-point bending tests diminished gradually by 87% in 26 weeks. In conclusion, the plates and screws examined maintain adequate strength for the healing period of a bone fracture or osteotomy, producing no harmful foreign body reactions. Dr Nieminen is a consultant for Inion Ltd., while the other co-authors do not have any conflicts of interest. Inion Ltd. has financed the costs related to the study sheep, including their housing.     

High school students' perceptions of affect and collaboration during virtual science inquiry learning

This study examined affect during high school students' face‐to‐face collaborative inquiry learning in science, supported by the web‐based software Virtual Baltic Sea Explorer. Self‐reported affective states during the inquiry process in peer groups were related to evaluations of a group's collaboration and performance in three phases of interdisciplinary science inquiry (biology and chemistry). Results indicate that despite high cognitive demands, positive affect prevailed whereas negative affect was infrequent. Structural equation modelling was used to analyse the significance of affect on collaboration and group performance. The relationship between affect, collaboration, and the groups' productive outcome revealed that self‐assurance had a significant effect on collaboration and support, intertwined with scientific understanding and group performance. Furthermore, a cross‐lagged analysis showed a reciprocal relation between positive affect, scientific understanding, collaboration, and support. These outcomes contribute to the scarce literature on the nature and importance of affect in the process of face‐to‐face computer‐supported collaborative inquiry and learning in science.     

Properties and durability of alkali-activated ladle slag

This paper examines the durability of alkali activated ladle slag mortars. Ladle slag, currently an under-utilized crystalline metallurgical by-product, is a promising raw material for alkali activation. However, there is no information about the durability of this material. The aim of this study is to investigate the durability of the alkali activated ladle slag mortar and the effect of aggregate content on the properties. The mechanical strength tests were carried out at 7, 28, 56 and 90 days. In addition, the samples were subjected to drying shrinkage, freeze–thaw, and water absorption tests. Furthermore, the reaction products conversion related to the strength properties were also analysed through thermal analysis. Overall, significant strength and durability properties was attained and significantly influenced by the mix design.     

Ethanol production from wood via concentrated acid hydrolysis,chromatographic separation,and fermentation

BACKGROUND: Production of bioethanol from wood using concentrated acid hydrolysis has received less attention than the dilute acid hydrolysis route. The feasibility of producing lignocellulosic bioethanol from spruce and birch via concentrated acid hydrolysis was studied experimentally. Hydrolysis with sulfuric acid, chromatographic purification of the hydrolysate, and fermentation of the monosaccharides were investigated. RESULTS: Monosaccharide yields of 70% were obtained in the hydrolysis of spruce and birch. Only low amounts of by‐products were formed. With chromatographic purification of the hydrolysate, over 90% of the hydrolysis acid was recovered for recycling, and furfural and HMF were removed completely. Most of the acetic acid was recovered in a separate fraction. The monosaccharide yield in a single pass separation was approximately 70%. In the fermentation, S. cerevisiae produced higher amounts of ethanol and more efficiently than P. stipitis. Chromatographically purified hydrolysates gave higher ethanol productivities and yields than Ca(OH)₂ neutralized hydrolysates. CONCLUSIONS: Chromatographic purification of concentrated acid lignocellulosic hydrolysates has advantages when compared with neutralization with Ca(OH)₂. With chromatography, most of the inhibitory compounds can be removed from the hydrolysates. In addition, due to the recycling of the hydrolysis acid, the economy of the bioethanol manufacturing process is increased considerably. Copyright © 2011 Society of Chemical Industry