Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.

BackgroundHistorically, two categories of computational algorithms (alignment-based and alignment-free) have been applied to sequence comparison–one of the most fundamental issues in bioinformatics. Multiple sequence alignment, although dominantly used by biologists, possesses both fundamental as well as computational limitations. Consequently, alignment-free methods have been explored as important alternatives in estimating sequence similarity. Of the alignment-free methods, the string composition vector (CV) methods, which use the frequencies of nucleotide or amino acid strings to represent sequence information, show promising results in genome sequence comparison of prokaryotes. The existing CV-based methods, however, suffer certain statistical problems, thereby underestimating the amount of evolutionary information in genetic sequences.ResultsWe show that the existing string composition based methods have two problems, one related to the Markov model assumption and the other associated with the denominator of the frequency normalization equation. We propose an improved complete composition vector method under the assumption of a uniform and independent model to estimate sequence information contributing to selection for sequence comparison. Phylogenetic analyses using both simulated and experimental data sets demonstrate that our new method is more robust compared with existing counterparts and comparable in robustness with alignment-based methods.ConclusionWe observed two problems existing in the currently used string composition methods and proposed a new robust method for the estimation of evolutionary information of genetic sequences. In addition, we discussed that it might not be necessary to use relatively long strings to build a complete composition vector (CCV), due to the overlapping nature of vector strings with a variable length. We suggested a practical approach for the choice of an optimal string length to construct the CCV.

This paper concerns Fredholm theory in several variables, and its applications to Hilbert spaces of analytic functions. One feature is the introduction of ideas from commutative algebra to operator theory. Specifically, we introduce a method to calculate the Fredholm index of a pair of commuting operators. To achieve this, we define and study the Hilbert space analogs of Samuel multiplicities in commutative algebra. Then the theory is applied to the symmetric Fock space. In particular, our results imply a satisfactory answer to Arveson's program on developing a Fredholm theory for pure d-contractions when d = 2, including both the Fredholmness problem and the calculation of indices. We also show that Arveson's curvature invariant is in fact always equal to the Samuel multiplicity for an arbitrary pure d-contraction with finite defect rank. It follows that the curvature is a similarity invariant. XIANG FANG GAFAversion of a classical theorem of J.-P. Serre in local algebra [Se, p. 57, Theorem 1]. The novelty of our approach is the extensive use of ideas from commutative algebra in a Hilbert space setting. Among the applications to operator theory we mention two results next. Theorem 11 implies a satisfactory answer to Arveson's program [Ar5] on developing a Fredholm theory for pure d-contractions when d = 2, including both the Fredholmness problem and the calculation of indices. It is noteworthy that the Fredholmness problem is usually quite subtle, and previous results are scarce [Ar4,5]. Theorem 18 shows that Arveson's curvature invariant is in fact always equal to the Samuel multiplicity, a notion borrowed from algebra, for an arbitrary pure d-contraction with finite defect rank.This provides an answer to Arveson's question [Ar3,4] on how to express the curvature invariant in terms of other invariants which are determined by the d-contraction directly, and can immediately imply that the curvature is an integer. From Theorem 18 it follows that the curvature is a similarity invariant, which was previously unknown.Next we discuss some background information and motivations. In the past much of the effort in higher dimensional Fredholm theory was devoted to the study of general Fredholm complexes, especially their stability under various perturbations. See Ambrozie-Vasilescu [AV], R. Curto [Cu1,3], Eschmeier-Putinar [EsP], Segal [S], Vasilescu [V], and the references therein (most of these contain extensive bibliographies). What is more relevant to this paper is the study of numerical invariants. Along this line, CareyPincus [P], Levy [Le2,3], Putinar [Pu2] and the last chapter of the book of Eschmeier-Putinar [EsP], establish many connections between multivariable Fredholm theory and various areas in mathematics, such as K-theory, index theory, geometric measure theory, sheaf theory, and even cyclic cohomology in noncommutative geometry. Also, see Arveson's expository paper [Ar5] for a recent development along a different line. However, as far as the calculation of multivariable Fredholm indices is concerned, stil...

2016-12-26T15:02:54