Design and synthesis of inhibitors of dihydrofolate reductase

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

The detection of p-waves in ambulatory ECG recordings by the use of wavelet transforms

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

The potential for inhibitors of nuclear factor-κB (NF-κB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-κB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-κB inhibitor SN50 (18 μM) attenuated the expression of 205 proteasome α-subunits, two subunits of the 195 regulator MSSI and p42, and the ubiquitin-conjugating enzyme, E214k, as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-κB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 μM) and resveratrol (30 μM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2 14k. However, curcumin (150 and 300 mg kg-1) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg-1) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-κB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-κB may prove useful for the treatment of muscle wasting in cancer cachexia.

The coupling mechanism of P-glycoprotein involves residue L339 in the sixth membrane spanning segment

The transmembrane (TM) domains in P-glycoprotein (P-gp) contain the drug binding sites and undergo conformational changes driven by nucleotide catalysis to effect translocation. However, our understanding of exactly which regions are involved in such events remains unclear. A site-directed labelling approach was used to attach thiol-reactive probes to cysteines introduced into transmembrane segment 6 (TM6) in order to perturb function and infer involvement of specific residues in drug binding and/or interdomain communication. Covalent attachment of coumarin-maleimide at residue 339C within TM6 resulted in impaired ATP hydrolysis by P-gp. The nature of the effect was to reduce the characteristic modulation of basal activity caused by transported substrates, modulators and the potent inhibitor XR9576. Photoaffinity labelling of P-gp with [(3)H]-azidopine indicated that residue 339C does not alter drug binding per se. However, covalent modification of this residue appears to prevent conformational changes that lead to drug stimulation of ATP hydrolysis.

Communication between the nucleotide binding domains of P-glycoprotein occurs via conformational changes that involve residue 508

Our aim is to provide molecular understanding of the mechanisms underlying the (i) interaction between the two nucleotide binding domains (NBDs) and (ii) coupling between NBDs and transmembrane domains within P-glycoprotein (Pgp) during a transport cycle. To facilitate this, we have introduced a number of unique cysteine residues at surface exposed positions (E393C, S452C, I500C, N508C, and K578C) in the N-terminal NBD of Pgp, which had previously been engineered to remove endogenous cysteines. Positions of the mutations were designed using a model based on crystallographic features of prokaryotic NBDs. The single cysteine mutants were expressed in insect cells using recombinant baculovirus and the proteins purified by metal affinity chromatography by virtue of a polyhistidine tag. None of the introduced cysteine residues perturbed the function of Pgp as judged by the characteristics of drug stimulated ATP hydrolysis. The role of residues at each of the introduced sites in the catalytic cycle of Pgp was investigated by the effect of covalent conjugation with N-ethyl-maleimide (NEM). All but one mutation (K578C) was accessible to labeling with [3H]-NEM. However, perturbation of ATPase activity was only observed for the derivitized N508C isoform. The principle functional manifestation was a marked inhibition of the "basal" rate of ATP hydrolysis. Neither the extent nor potency to which a range of drugs could affect the ATPase activity were altered in the NEM conjugated N508C isoform. The results imply that the accessibility of residue 508, located in the alpha-helical subdomain of NBD1 in Pgp, is altered by the conformational changes that occur during ATP hydrolysis.

Analysis of P-Systems under a Multiagent Systems Perspective

Membrane computing is a recent area that belongs to natural computing. This field works on computational models based on nature's behavior to process the information. Recently, numerous models have been developed and implemented with this purpose. P-systems are the structures which have been defined, developed and implemented to simulate the behavior and the evolution of membrane systems which we find in nature. What we show in this paper is an application capable to simulate the P-systems based on a multiagent systems (MAS) technology. The main goal we want to achieve is to take advantage of the inner qualities of the multiagent systems. This way we can analyse the proper functioning of any given p-system. When we observe a P-system from a different perspective, we can be assured that it is a particular case of the multiagent systems. This opens a new possibility, in the future, to always evaluate the P-systems in terms of the multiagent systems technology.

Fractional Calculus of P-transforms

MSC 2010: 44A20, 33C60, 44A10, 26A33, 33C20, 85A99

Caesium bis­(5-bromo­salicyl­aldehyde thio­semicarbazonato-κ3O,N,S)ferrate(III): supramolecular arrangement of low-spin FeIII complex anions mediated by Cs+ cations

The synthesis and crystal structure determination (at 293 K) of the title complex, Cs[Fe(C8H6BrN3OS)2], are reported. The compound is composed of two dianionic O,N,S-tridentate 5-bromo­salicyl­aldehyde thio­semicarbazonate(2-) ligands coord­inated to an FeIII cation, displaying a distorted octa­hedral geometry. The ligands are orientated in two perpendicular planes, with the O- and S-donor atoms in cis positions and the N-donor atoms in trans positions. The complex displays inter­molecular N-H...O and N-H...Br hydrogen bonds, creating R44(18) rings, which link the FeIII units in the a and b directions. The FeIII cation is in the low-spin state at 293 K.

A knowledge based system of principled negotiation for complex business contract

Automated negotiation systems can do better than human being in many aspects, and thus are applied into many domains ranging from business to computer science. However, little work about automating negotiation of complex business contract has been done so far although it is a kind of the most important negotiation in business. In order to address this issue, in this paper we developed an automated system for this kind of negotiation. This system is based on the principled negotiation theory, which is the most effective method of negotiation in the domain of business. The system is developed as a knowledge-based one because a negotiating agent in business has to be economically intelligent and capable of making effective decisions based on business experiences and knowledge. Finally, the validity of the developed system is shown in a real negotiation scenario where on behalf of human users, the system successfully performed a negotiation of a complex business contract between a wholesaler and a retailer. © 2013 Springer-Verlag Berlin Heidelberg.

On realizability of p-groups as Galois groups

2000 Mathematics Subject Classification: 12F12, 15A66.

Deconvolution of magnetic acoustic change complex (mACC)

Objective: The aim of this study was to design a novel experimental approach to investigate the morphological characteristics of auditory cortical responses elicited by rapidly changing synthesized speech sounds. Methods: Six sound-evoked magnetoencephalographic (MEG) responses were measured to a synthesized train of speech sounds using the vowels /e/ and /u/ in 17 normal hearing young adults. Responses were measured to: (i) the onset of the speech train, (ii) an F0 increment; (iii) an F0 decrement; (iv) an F2 decrement; (v) an F2 increment; and (vi) the offset of the speech train using short (jittered around 135. ms) and long (1500. ms) stimulus onset asynchronies (SOAs). The least squares (LS) deconvolution technique was used to disentangle the overlapping MEG responses in the short SOA condition only. Results: Comparison between the morphology of the recovered cortical responses in the short and long SOAs conditions showed high similarity, suggesting that the LS deconvolution technique was successful in disentangling the MEG waveforms. Waveform latencies and amplitudes were different for the two SOAs conditions and were influenced by the spectro-temporal properties of the sound sequence. The magnetic acoustic change complex (mACC) for the short SOA condition showed significantly lower amplitudes and shorter latencies compared to the long SOA condition. The F0 transition showed a larger reduction in amplitude from long to short SOA compared to the F2 transition. Lateralization of the cortical responses were observed under some stimulus conditions and appeared to be associated with the spectro-temporal properties of the acoustic stimulus. Conclusions: The LS deconvolution technique provides a new tool to study the properties of the auditory cortical response to rapidly changing sound stimuli. The presence of the cortical auditory evoked responses for rapid transition of synthesized speech stimuli suggests that the temporal code is preserved at the level of the auditory cortex. Further, the reduced amplitudes and shorter latencies might reflect intrinsic properties of the cortical neurons to rapidly presented sounds. Significance: This is the first demonstration of the separation of overlapping cortical responses to rapidly changing speech sounds and offers a potential new biomarker of discrimination of rapid transition of sound.

The effects of a professional development course on the teaching practices of P--12 classroom teachers

This follow-up study examined the long term effects of a staff development model on P–12 classroom teachers' instructional practices and dispositions regarding a curricular innovation. The sample, 44 private school practitioners who participated in the staff development program that used the model, was administered a survey at three checkpoints over a three year period to gather quantitative data regarding the participants' concerns about the curricular innovation. A comparison group of 19 practitioners also completed the survey. Qualitative data, gathered through interviews conducted with ten of the 44 participants, contributed to understanding the participants' perspectives on changes they perceived in their teaching practices as a result of the staff development. Elements of the model that were most instrumental in effecting those changes were identified. ^ The findings indicated that the participants demonstrated changes in the quality of their concerns, moving from self concerns and task concerns to impact concerns immediately following the training. The decrease in self concerns was sustained three years after the staff development, while task concerns increased and impact concerns returned to pre staff development levels. A significant difference in stages of concern between the participant and the comparison groups was noted at self and impact stages. ^ Findings revealed that participants changed their teaching practices and beliefs about instructional processes as a result of the staff development, becoming more collaborative and confident in implementing innovative approaches; they were perceived as leaders among their peers. Elements of the staff development model that participants identified as being influential in the change process included the opportunity for collaboration, authenticity of the training activities, and ongoing and comprehensive nature of the training. ^

Petrology and geochemistry of some high pressure rocks from northern part of Rio San Juan complex, Dominican Republic

The Rio San Juan Complex is an important occurrence of high pressure/low temperature rocks in the circum-Caribbean region which contains both coherent blueschist units and two varieties of melange in the same area. The melanges contain a diverse assemblage of blocks of various sizes, different degrees of metamorphism, and mineral assemblages. Some high pressure blocks show two stages of metamorphism. The earliest stage is characterized by high pressure-low temperature conditions and the second stage is characterized by high pressure-lower temperature conditions. The geochemistry of thirteen samples from the Rio San Juan Complex has been studied and data have been compared with rocks of adjacent regions. Geochemical evidence indicates that rocks from the Rio San Juan Complex have predominant calc-alkaline affinities with subordinate tholeiitic affinities. This suggests that they have a multiple tectonic provenance.

Environmental analysis of polar herbicides in complex organic-rich matrices by high performance liquid chromatography atmospheric pressure ionization mass spectrometry (HPLC-API-MS)

A comprehensive forensic investigation of sensitive ecosystems in the Everglades Area is presented. Assessing the background levels of contamination in these ecosystems represents a vital resource to build up forensic evidence required to enforce future environmental crimes within the studied areas. This investigation presents the development and validation of a fractionation and isolation method for two families of herbicides commonly applied in the vicinity of the study area, including phenoxy acids like 2,4-D, MCPA, and silvex; as well as the most common triazine-based herbicides like atrazine, prometyne, simazine and related metabolites like DIA and DEA. Accelerated solvent extraction (ASE) and solid phase extraction (SPE) were used to isolate the analytes from abiotic matrices containing large amounts of organic material. Atmospheric-pressure ionization (API) with electrospray ionization in negative mode (ESP-), and Chemical Ionization in the positive mode (APCI+) were used to perform the characterization of the herbicides of interest.

Mafteaḥ leshon ha-ḳodesh, That is the Key of the Holy Tongue : Wherein is contained, First the Hebrue Grammer (in a manner) word for word out of P. Martinius : Englished for the benefit of those that (being ignorant in the Latine) are desirous to learne the holy tongue

by John Udall ; Carefully corrected, and many faults amended which were found both in the Latine and English copies By a Jew Rabine