Non-similarity combinatorial problems

Similarity problems intensively investigated in computational molecular biology have the following two stringology models: find the longest string included in any string of a given finite language, and find the shortest string including every string of a given finite language. These two problems are exemplified by the two well-known pairs of problems, the longest common subsequence (or substring) problem and the shortest common supersequence (or superstring) problem, interpretations. In this paper we consider opposite problems connected with string non-inclusion relations: find the shortest string included in no string of a given finite language and find the longest string including no string of a given finite language. The predicate "string alpha is not included in string beta" is interpreted either as "alpha is not a subsequence of beta" or as "alpha is not a substring of beta". The main purpose is to determine the complexity status of the non-similarity problems. Using graph approaches, we present NP-hardness proofs for the first interpretation and polynomial-time algorithms for the second one. Special cases of the problems, and related issues are discussed.     

Studies on the reliability of a novel absorption-lipophilicity approach to interpret the effects of the synthetic surfactants on drug and xenobiotic absorption

Some theoretical principles of the absorption/lipophilicity approach, which attempts to explain the effects of the synthetic surfactants on xenobiotic and drug intestinal absorption, are reviewed and experimentally checked by examining the correlations obtained between "in situ" absorption constants, ka, found in rat colon, and "in vitro" lipophilicity indexes, K', for two compound series (secondary aliphatic amines and phenylalkylamines) in the absence and in the presence of the nonionic surfactant Polysorbate 80, in the intestinal perfusion fluid. Evidence is given for the following actions of the synthetic surfactant: at its critical micelle concentration (CMC), it increases the polarity of the absorbing membrane and, at the same time, it disrupts the aqueous stagnant diffusion layer adjacent to the mucosal barrier. When a supramicellar concentration (SMC) is used, the above actions are almost totally masked by the micellar solubilization of the tested amines, which decreases their absorption constants relative to those found at CMC, as markedly as solute lipophilicity increases. As a consequence of these actions, the correlations between ka and K', which are clearly hyperbolic in free solution, become potential in the presence of the surfactant at its CMC, whereas at SMC a bilinear correlation is obtained. Absorption via lipophilic ionized species seems to take place for both compound series. Mathematical and physicochemical interpretations of this behaviour are outlined, and biopharmaceutical implications of these phenomena are discussed.     

Rate of tetracycline dissolution from tablets and capsules and the biological availability of the antibiotic

Relation between the rate of tetracycline dissolution from tablets and capsules and the biological acceptibility of the antibiotic in the host was studied. The antibiotic dissolution rate from the pharmaceutical forms was determined in a modernized apparatus "Rotary basket" in water, the speed of the basket rotation was 200 r.p.m. In addition the tetracycline blood levels in patients treated with the drug in the above pharmaceutical forms were estimated. It was found that the rate of the antibiotic dissolution characterized the antibiotic biological acceptibility. A test for the dissolution rate was developed. It may be used for estimation of production batches of tetracycline tablets.     

The functional activity of anti-endotoxin factors in viral hepatitis A and B

Bacterial endotoxins (BE) that are lipopolysaccharide complexes (LPS) are a structural component of the external membrane of gram-negative bacteria. In normalcy, BE interact with many types of cells in the mammals. In terms of the concentration, BE may cause cell damage or stimulate the production of many biological mediators, such as interleukins, prostaglandinds, alpha-TNF. Many gastrointestinal bacteria in humans are gram-negative and BE constantly enter the blood. In health, the absence of a toxic response to BE is explained by the presence of natural humoral and cellular antiendotoxic systems and the hepatic absorption of LPS. In patients with hepatitis A and B, the following indices of the blood antiendotoxic systems were determined: the level of antiendotoxic antibodies to Re-chemotype glycolipids was assessed by the passive hemagglutination reaction in the "Antiendotox-1-test"; the count of polymorphonuclear leukocyte (PMNL) fixating LPS on their own surface and endotoxin binding function of PMNL was in vitro measured by the strain ELISA and sandwich ELISA with Re-glycolipids, respectively (LPS-test); the endotoxin fixation function of serum high density lipoproteins (HDL) was also assessed. The humoral and cellular antiendotoxic systems in patients with mild advanced hepatitis A and B was studied when the disease was most clinically significant, at an early convalescence, and at convalescence itself. Finally, the findings indicate that there is a significant decrease in Re-antibody levels and there is a greater absorption ability of HDL than that in the control. Six different types of an antiendotoxic fixation reaction of PMNL were identified in patients with viral hepatitis in the different periods of the disease. The alterations observed may play an important role in the pathogenesis of toxemia in patients with viral hepatitis.     

Possibility of developing low-power reactors with a pebble-bed core

The possibilities of a two-section pebble-bed core with coolant delivered along the radial direction are examined for a water-cooled water-moderated 100–400 MW(t) reactor with 4 mm in diameter fuel pebbles. The construction of the two-section core includes two ring-shaped fuel layers (inner and outer) separated by a ring-shaped channel for coolant delivery. Water filters through the inner fuel layer from the periphery toward the center and through the outer layer from the center toward the periphery. The basic characteristics of such a reactor are determined. It is shown that the power density of such a core with 4 mm in diameter fuel pellets is two times higher than that in a VVÉR-1000 reactor, and there is a substantial margin with respect to the average specific heat flux. Thermohydraulic and neutron-physical calculations showed that two-section pebble-bed cores in low-power nuclear power reactors are promising.Translated from Atomnaya Énergiya, Vol. 97, No. 3, pp. 168–172, September, 2004.     

Engineering an enzyme to resist boiling

In recent years, many efforts have been made to isolate enzymes from extremophilic organisms in the hope to unravel the structural basis for hyperstability and to obtain hyperstable biocatalysts. Here we show how a moderately stable enzyme (a thermolysin-like protease from Bacillus stearothermophilus, TLP-ste) can be made hyperstable by a limited number of mutations. The mutational strategy included replacing residues in TLP-ste by residues found at equivalent positions in naturally occurring, more thermostable variants, as well as rationally designed mutations. Thus, an extremely stable 8-fold mutant enzyme was obtained that was able to function at 100 degrees C and in the presence of denaturing agents. This 8-fold mutant contained a relatively large number of mutations whose stabilizing effect is generally considered to result from a reduction of the entropy of the unfolded state ("rigidifying" mutations such as Gly --> Ala, Ala --> Pro, and the introduction of a disulfide bridge). Remarkably, whereas hyperstable enzymes isolated from natural sources often have reduced activity at low temperatures, the 8-fold mutant displayed wild-type-like activity at 37 degrees C.     

Apoptosis in heart failure

A characteristic feature of heart failure is the progressive worsening of ventricular function over months or years despite the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of residual viable cardiac myocytes, or to ongoing degeneration and loss of myocytes, or both. This report will address the concept of ongoing cardiac myocyte loss that may occur during the course of evolving heart failure viewed from the perspective of apoptosis or "programmed cell death" as the potential mediator of cardiac muscle cell loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Recent studies have shown that cardiac myocyte apoptosis also occurs after acute myocardial infarction, as well as in the hypertrophied heart and the aging heart, conditions frequently associated with the development of heart failure. Considerable work has also been conducted and novel concepts advanced to explain potential molecular triggers of cardiac myocyte apoptosis in heart failure. Although available data support the existence of myocyte apoptosis in the failing heart, questions essential to our understanding of the importance of myocyte apoptosis in this disease process remain unanswered. Lacking are studies aimed at identifying physiological factors inherent to heart failure that trigger myocyte apoptosis. Also lacking are studies that address the importance of myocyte apoptosis in the progression of left ventricular dysfunction. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if factors that trigger apoptosis in the heart can be identified, such knowledge can potentially lead to the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.     

A quantitative definition of exposure and related concepts

This paper develops a unified theoretical framework for understanding exposure to environmental pollutants and other agents. It reviews the scientific literature to describe the many diverse and often confusing ways in which the term "exposure" is being used. Using six criteria proposed for a useful framework, a set of quantitative definitions, which encompass and expand upon existing definitions, is developed. After "agent" (e.g., a pollutant) and "target" (e.g., a person's hand) are defined, "exposure" is defined as the contact between an agent and a target. An "instantaneous point exposure" is defined as the joint occurrence of two events: 1) point i of a target is located at (xi, yi, zi) at time t, and 2) an agent of concentration Ci is present at location (xi, yi, zi) at time t. It is shown that the definition of instantaneous point exposure is fundamental in that all other functions of exposure with respect to space or time-such as the average exposure and the integrated exposure-can be derived from it. Because exposure and dose are closely related and often confused, our framework also includes a general definition of dose that is consistent with common usage. Finally, the definitions in this unified theoretical framework are shown to apply to inhalation exposure, dermal exposure, and ingestion exposure. In addition to the literature review and the quantitative definitions of exposure, this paper includes a glossary of terms that are proposed to help establish a common language for the exposure sciences.