Evidence for the formation of a known toxin, P-cresol, from menthofuran

Menthofuran (II, 4,5,6,7-tetrahydro-3,6-dimethyl benzofuran), the proximate toxin of R-(+)-pulegone (I), was administered orally to rats (200 mg/kg of body weight/day) for three days and the urinary metabolites were investigated. Among the several metabolites formed, two of them viz. 4-Hydroxy-4-methyl-2-cyclohexenone (VII) and p-cresol (VIII) were indentified. In support of the formation of these metabolites, it has been demonstrated that phenobarbital induced rat liver microsomes readily convert 4-methyl-2-cyclohexenone (V) to 4-hydroxy-4-methyl-2-cyclohexenone (VII) and p-cresol (VIII) in the presence of NADPH and O2. Possible mechanism for the formation of these two metabolites (VII, VIII) from menthofuran (II) has been proposed.

Infinite dimensional slow modulations in a well known delayed model for cutting tool vibrations

We apply the method of multiple scales (MMS) to a well-known model of regenerative cutting vibrations in the large delay regime. By ``large'' we mean the delay is much larger than the timescale of typical cutting tool oscillations. The MMS up to second order, recently developed for such systems, is applied here to study tool dynamics in the large delay regime. The second order analysis is found to be much more accurate than the first order analysis. Numerical integration of the MMS slow flow is much faster than for the original equation, yet shows excellent accuracy in that plotted solutions of moderate amplitudes are visually near-indistinguishable. The advantages of the present analysis are that infinite dimensional dynamics is retained in the slow flow, while the more usual center manifold reduction gives a planar phase space; lower-dimensional dynamical features, such as Hopf bifurcations and families of periodic solutions, are also captured by the MMS; the strong sensitivity of the slow modulation dynamics to small changes in parameter values, peculiar to such systems with large delays, is seen clearly; and though certain parameters are treated as small (or, reciprocally, large), the analysis is not restricted to infinitesimal distances from the Hopf bifurcation.

Source localization in a partially known shallow?water channel

The source localization in shallow water is beset with problems arising from the presence of a large number of correlated multipaths. Nevertheless, given a complete knowledge of the water channel it is definitely possible to localize a source. A complete knowledge of the channel, however, is rarely available under most practical conditions. A new approach is proposed wherein the bottom reflection coefficients are not required; hence the bottom conditions need not be known. Further, because of the use of signal subspace for localization, the proposed approach is robust against the background noise (-20 dB) and channel depth uncertainty (10 lambda). All these nice features of the proposed approach are possible only when the array size is large (>40 sensors). (C) 1995 Acoustical Society of America.

Metabolic disposition of a monoterpene ketone, piperitenone, in rats: Evidence for the formation of a known toxin, p-cresol

It was shown earlier that the monoterpene ketone, piperitenone (I) is one of the major metabolites of R-(+)-pulegone, a potent hepatotoxin, In the present studies, the metabolic disposition of piperitenone (I) was examined in rats. Piperitenone (I) was administered orally (400 mg/kg of the b. wt./day) to rats for 5 days, The following urinary metabolites were isolated and identified by various spectral analyses: p-cresol (VI), 6,7-dehydromenthofuran (III), p-mentha-1,3,5,8-tetraen-3-ol (IX), p-mentha-1,3, 5-friene-3, 8-diol (X), 5-hydroxypiperitenone (VIII), 7-hydroxypiperitenone (XI), 10-hydroxypiperitenone (XII), and 4-hydroxypiperitenone (VII). Incubation of piperitenone (I) with phenobarbital-induced rat liver microsomes in the presence of NADPH resulted in the formation of five metabolites which have been tentatively identified as metabolites III, VII, VIII, XI, XII, on the basis of gas chromatography retention time and gas chromatography-mass spectrometry analysis. Based on these results, a probable mechanism for the formation of p-cresol from piperitenone (I) via the intermediacy of metabolite III has been proposed.

A touch of history and a peep into the future of the lipid-quinone known as coenzyme Q and ubiquinone

Coenzyme Q (ubiquinone), a fully substituted benzoquinone with polyprenyl side chain, participates in many cellular redox activities. Paradoxically it was discovered only in 1957, albeit being ubiquitous. It required a person, F. L. Crane, a place, Enzyme Institute, Madison, USA, and a time when D. E. Green was directing vigorous research on mitochondria. Located at the transition of 2-electron flavoproteins and 1-electron cytochrome carriers, it facilitates electron transfer through the elegant Q-cycle in mitochondria to reduce O-2 to H2O, and to H2O2, now a significant signal-transducing agent, as a minor activity in shunt pathway (animals) and alternative oxidase (plants). The ability to form Q-radical by losing an electron and a proton was ingeniously used by Mitchell to explain the formation of the proton gradient, considered the core of energy transduction, and also in acidification in vacuoles. Known to be a mobile membrane constituent (microsomes, plasma membrane and Golgi apparatus), allowing it to reach multiple sites, coenzyme Q is expected to have other activities. Coenzyme Q protects circulating lipoproteins being a better lipid antioxidant than even vitamin E. Binding to proteins such as QPS, QPN, QPC and uncoupling protein in mitochondria, QA and QB in the reaction centre in R. sphaeroides, and disulfide bond-forming protein in E. coli (possibly also in Golgi), coenzyme Q acquires selective functions. A characteristic of orally dosed coenzyme Q is its exclusive absorption into the liver, but not the other tissues. This enrichment of Q is accompanied by significant decrease of blood pressure and of serum cholesterol. Inhibition of formation of mevalonate, the common precursor in the branched isoprene pathway, by the minor product, coenzyme Q, decreases the major product, cholesterol. Relaxation of contracted arterial smooth muscle by a side-chain truncated product of coenzyme Q explains its effect of decreasing blood pressure. Extensive clinical studies carried out on oral supplements of coenzyine Q, initially by K. Folkers and Y. Yamamura and followed many others, revealed a large number of beneficial effects, significantly in cardiovascular diseases. Such a variety of effects by this lipid quinone cannot depend on redox activity alone. The fat-soluble vitamins (A, D, E and K) that bear structural relationship with coenzyme Q are known to be active in their polar forms. A vignette of modified forms of coenzyme Q taking active role in its multiple effects is emerging.

IgG2 subclass isotype antibody and intrauterine infections

The foetus is dependent on its mother for passive immunity involving receptor-mediated specific transport of antibodies. IgG antibody is present in highest concentration in serum and is the only antibody type that can cross the placenta efficiently, except for its IgG2 subclass. Most of the pathogenic manifestations affecting the foetus involve capsular antigens and polysaccharides of pathogens and it is known that immune response to these antigens is primed to the predominant production of IgG2 type of antibody. Paradoxically, the IgG2 subclass cannot cross the placenta and neutralize such antigens; therefore, infections related to these antigens may persist and can lead to serious conditions like miscarriage and stillbirth. This article describes in brief the properties of IgG subclasses, intrauterine infections seen during pregnancy and discusses possible IgG-based strategies to manage infections to afford protection to the foetus.

A unified approach to known and unknown cases of Berge's conjecture

Berge's elegant dipath partition conjecture from 1982 states that in a dipath partition P of the vertex set of a digraph minimizing , there exists a collection Ck of k disjoint independent sets, where each dipath P?P meets exactly min{|P|, k} of the independent sets in C. This conjecture extends Linial's conjecture, the GreeneKleitman Theorem and Dilworth's Theorem for all digraphs. The conjecture is known to be true for acyclic digraphs. For general digraphs, it is known for k=1 by the GallaiMilgram Theorem, for k?? (where ?is the number of vertices in the longest dipath in the graph), by the GallaiRoy Theorem, and when the optimal path partition P contains only dipaths P with |P|?k. Recently, it was proved (Eur J Combin (2007)) for k=2. There was no proof that covers all the known cases of Berge's conjecture. In this article, we give an algorithmic proof of a stronger version of the conjecture for acyclic digraphs, using network flows, which covers all the known cases, except the case k=2, and the new, unknown case, of k=?-1 for all digraphs. So far, there has been no proof that unified all these cases. This proof gives hope for finding a proof for all k.

Identification of Active Sources in Single-Channel Convolutive Mixtures Using Known Source Models

We address the problem of identifying the constituent sources in a single-sensor mixture signal consisting of contributions from multiple simultaneously active sources. We propose a generic framework for mixture signal analysis based on a latent variable approach. The basic idea of the approach is to detect known sources represented as stochastic models, in a single-channel mixture signal without performing signal separation. A given mixture signal is modeled as a convex combination of known source models and the weights of the models are estimated using the mixture signal. We show experimentally that these weights indicate the presence/absence of the respective sources. The performance of the proposed approach is illustrated through mixture speech data in a reverberant enclosure. For the task of identifying the constituent speakers using data from a single microphone, the proposed approach is able to identify the dominant source with up to 8 simultaneously active background sources in a room with RT60 = 250 ms, using models obtained from clean speech data for a Source to Interference Ratio (SIR) greater than 2 dB.

Implications of program phase behavior on timing analysis

Knowledge about program worst case execution time (WCET) is essential in validating real-time systems and helps in effective scheduling. One popular approach used in industry is to measure execution time of program components on the target architecture and combine them using static analysis of the program. Measurements need to be taken in the least intrusive way in order to avoid affecting accuracy of estimated WCET. Several programs exhibit phase behavior, wherein program dynamic execution is observed to be composed of phases. Each phase being distinct from the other, exhibits homogeneous behavior with respect to cycles per instruction (CPI), data cache misses etc. In this paper, we show that phase behavior has important implications on timing analysis. We make use of the homogeneity of a phase to reduce instrumentation overhead at the same time ensuring that accuracy of WCET is not largely affected. We propose a model for estimating WCET using static worst case instruction counts of individual phases and a function of measured average CPI. We describe a WCET analyzer built on this model which targets two different architectures. The WCET analyzer is observed to give safe estimates for most benchmarks considered in this paper. The tightness of the WCET estimates are observed to be improved for most benchmarks compared to Chronos, a well known static WCET analyzer.

NUcache: an efficient multicore cache organization based on next-use distance

The effectiveness of the last-level shared cache is crucial to the performance of a multi-core system. In this paper, we observe and make use of the DelinquentPC - Next-Use characteristic to improve shared cache performance. We propose a new PC-centric cache organization, NUcache, for the shared last level cache of multi-cores. NUcache logically partitions the associative ways of a cache set into MainWays and DeliWays. While all lines have access to the MainWays, only lines brought in by a subset of delinquent PCs, selected by a PC selection mechanism, are allowed to enter the DeliWays. The PC selection mechanism is an intelligent cost-benefit analysis based algorithm that utilizes Next-Use information to select the set of PCs that can maximize the hits experienced in DeliWays. Performance evaluation reveals that NUcache improves the performance over a baseline design by 9.6%, 30% and 33% respectively for dual, quad and eight core workloads comprised of SPEC benchmarks. We also show that NUcache is more effective than other well-known cache-partitioning algorithms.

Correlation between local structural dynamics of proteins inferred from NMR ensembles and evolutionary dynamics of homologues of known structure

Conformational changes in proteins are extremely important for their biochemical functions. Correlation between inherent conformational variations in a protein and conformational differences in its homologues of known structure is still unclear. In this study, we have used a structural alphabet called Protein Blocks (PBs). PBs are used to perform abstraction of protein 3-D structures into a 1-D strings of 16 alphabets (a-p) based on dihedral angles of overlapping pentapeptides. We have analyzed the variations in local conformations in terms of PBs represented in the ensembles of 801 protein structures determined using NMR spectroscopy. In the analysis of concatenated data over all the residues in all the NMR ensembles, we observe that the overall nature of inherent local structural variations in NMR ensembles is similar to the nature of local structural differences in homologous proteins with a high correlation coefficient of .94. High correlation at the alignment positions corresponding to helical and beta-sheet regions is only expected. However, the correlation coefficient by considering only the loop regions is also quite high (.91). Surprisingly, segregated position-wise analysis shows that this high correlation does not hold true to loop regions at the structurally equivalent positions in NMR ensembles and their homologues of known structure. This suggests that the general nature of local structural changes is unique; however most of the local structural variations in loop regions of NMR ensembles do not correlate to their local structural differences at structurally equivalent positions in homologues.

Ramachandran analysis of conserved glycyl residues in homologous proteins of known structure

High conservation of glycyl residues in homologous proteins is fairly frequent. It is commonly understood that glycine tends to be highly conserved either because of its unique Ramachandran angles or to avoid steric clash that would arise with a larger side chain. Using a database of aligned 3D structures of homologous proteins we identified conserved Gly in 288 alignment positions from 85 families. Ninety-six of these alignment positions correspond to conserved Gly residue with (phi, ) values allowed for non-glycyl residues. Reasons for this observation were investigated by in-silico mutation of these glycyl residues to Ala. We found in 94% of the cases a short contact exists between the C atom of the introduced Ala with the atoms which are often distant in the primary structure. This suggests the lack of space even for a short side chain thereby explaining high conservation of glycyl residues even when they adopt (phi, ) values allowed for Ala. In 189 alignment positions, the conserved glycyl residues adopt (phi, ) values which are disallowed for Ala. In-silico mutation of these Gly residues to Ala almost always results in steric hindrance involving C atom of Ala as one would expect by comparing Ramachandran maps for Ala and Gly. Rare occurrence of the disallowed glycyl conformations even in ultrahigh resolution protein structures are accompanied by short contacts in the crystal structures and such disallowed conformations are not conserved in the homologues. These observations raise the doubt on the accuracy of such glycyl conformations in proteins.

El problema del innatismo en Antonio Rosmini : (parte II)

Resumen: Esta parte del artículo repasa las principales teorías modernas sobre el innatismo, analizando sus puntos fuertes y débiles a partir de la teoría rosminiana de la presencia innata de la idea de ser. Se subraya la simplicidad de esta teoría, lo que le confiere un elevado carácter explicativo, en contraste con los dificultades que suscitan las filosofías de Descartes, Locke, Leibniz, Malebranche y Kant.

La teoría de la justicia de Amartya Sen y los orígenes del concepto católico de justicia social en Antonio Rosmini

Resumen: El autor propone en este artículo reflexionar sobre algunos aspectos del libro The Idea of Justice de Amartya Sen a la luz d e la obra del filósofo italiano Antonio Rosmini, difusor de la expresión “justicia social” en los orígenes del pensamiento social católico. En primer lugar, el autor muestra las coincidencias de Sen y Rosmini sobre el lugar de la razón en el análisis de la idea de justicia social frente a los planteos puramente emocionales y pragmáticos. En segundo lugar, propone una comparación entre las críticas que desarrollan Sen y Rosmini a las denominadas por el primero “teorías trascendentales” de la justicia y a los llamado s “cambios estructurales” así como la necesidad de cambios graduales para llegar a una sociedad justa. En tercer lugar, intenta mostrar cómo la opción por las personas y sus capacidades elegida por Sen puede ser iluminada y profundizada desde la teoría rosminiana de las capacidades. En cuarto lugar, describe el giro cognitivo que propone Sen para las instituciones y las políticas públicas. Finalmente, el autor enuncia algunas objeciones que pudieran hacerse al planteo propuesto en el artículo junto con unos comentarios finales sobre las mismas.