Metabolic epoxidation of trans-4-acetylaminostilbene: a protective mechanism against its activation to a mutagen

Trans-4-acetylaminostilbene is activated by liver preparations to mutagens for Salmonella typhimurium. Since this compound is metabolized to the trans-alpha,beta-epoxide and since many epoxides are ultimate mutagens, this epoxide was tested for direct mutagenicity. It was, however, found to be non-mutagenic, and, in contrast to the parent compound, the epoxide was no longer activated by liver preparations to mutagens. The same was found for the beta-ketone and for the threo-alpha,beta-dihydrodiol, which are formed metabolically from trans-4-acetylaminostilbene and from its alpha,beta-epoxide. 4-Acetylaminobibenzyl showed a very weak mutagenic activity in the presence of the liver preparation. Thus, it is important to realize that where epoxides are formed from compounds which are known to be metabolized to mutagens, they are not necessarily responsible for the mutagenicity. Epoxidation may even prevent the possibility of bioactivation to mutagens.     

Sperm competition can drive a male-biased mutation rate

A pattern of male-biased mutation has been found in a wide range of species. The standard explanation for this bias is that there are greater numbers of mitotic cell divisions in the history of the average sperm, compared to the average egg, and that mutations typically result from errors made during replication. However, this fails to provide an ultimate evolutionary explanation for why the male germline would tolerate more mutations that are typically deleterious. One possibility is that if there is a tradeoff between producing large numbers of sperm and expending energetic resources in maintaining a lower mutation rate, sperm competition would select for males that produce larger numbers of sperm despite a higher resulting mutation rate. Here I describe a model that jointly considers the fitness consequences of deleterious mutation and mating success in the face of sperm competition. I show that a moderate level of sperm competition can account for the observation that the male germline tolerates a higher mutation rate than the female germline.     

P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins

The study of multidrug resistance (MDR) in tumor cell lines has led to the discovery of the plasma membrane P-glycoprotein (Pgp) molecule. This protein functions as an energy-dependent pump for the efflux of diverse anticancer drugs from MDR cells. It now appears that Pgp-mediated MDR tumor cells do occur in human cancers, and that they are likely to play a role in the ultimate response of patients to chemotherapy. Chemosensitizers, compounds able to reverse the MDR phenotype, have been identified and offer the exciting possibility of improving efficacy for some nonresponsive malignancies. Surprisingly, Pgp-like molecules can be found in evolutionarily distant species among both eukaryotes and prokaryotes. As a group, these proteins form a superfamily of ATP-dependent transport proteins. This finding has broad implications and provides new insights into how living organisms use this fundamental transport system to regulate the trafficking of diverse molecules across biological membranes.     

Phosphatidylcholine’s functions beyond that of a membrane brick

Abstract

Since its discovery in the 19th century, phosphatidylcholine (PC) has been regarded primarily as a structural lipid. However, more recent evidence, much of it in the last five years, strongly suggests that PC has other roles. Here, we explore some of that new evidence and consider the possibility that the ultimate role of phosphatidylcholine may not be predictable.     

Introducing selective supercritical fluid extraction as a new tool for determining sorption/desorption behavior and bioavailability of persistent organic pollutants in sediment

This review article intends to introduce the possibility of utilizing selective supercritical fluid extraction (SFE) as a tool to study sorption/desorption processes and bioavailability of persistent organic pollutants (POP) in sediment. Sorption/desorption behavior and bioavailability studies of POPs is a large research area, but still many unsolved problems exists. Therefore novel approaches to investigate mechanistic behavior of POPs in sediments are needed. Present literature on SFE points to the fact that selective SFE measurements can improve our knowledge, and recent investigations have been performed that demonstrate this. Results obtained with selective SFE can be connected to desorption of POPs in sediments under natural conditions in aquatic ecosytems. The ultimate goal is to use selective SFE as a way to determine the bioavailable fraction present within a matrix. A few preliminary results are presented here which may serve as a starting point for future studies.     

The effect of selection on genetic balance when the population size is varying

It is known that a reformulation for variable population size of the classical Sewall Wright model for balance between two genotypes can lead, under some circumstances, to a situation of balanced polymorphism when there is no selection present. In this note it is shown that the presence of selection prohibits the possibility of balance and assures ultimate homozygosity with probability one.     

Framing postpartum hemorrhage as a consequence of human placental biology: an evolutionary and comparative perspective

Postpartum hemorrhage (PPH), the leading cause of maternal mortality worldwide, is responsible for 35 percent of maternal deaths. Proximately, PPH results from the failure of the placenta to separate from the uterine wall properly, most often because of impairment of uterine muscle contraction. Despite its prevalence and its well-described clinical manifestations, the ultimate causes of PPH are not known and have not been investigated through an evolutionary lens. We argue that vulnerability to PPH stems from the intensely invasive nature of human placentation. The human placenta causes uterine vessels to undergo transformation to provide the developing fetus with a high plane of maternal resources; the degree of this transformation in humans is extensive. We argue that the particularly invasive nature of the human placenta increases the possibility of increased blood loss at parturition. We review evidence suggesting PPH and other placental disorders represent an evolutionarily novel condition in hominins.     

The Wright-Fisher model with temporally varying selection and population size

The Wright-Fisher model is considered in the case where the population size is random and the magnitude of the selective advantage of one of the alleles varies with time. The central question addressed is the possibility of ultimate genetic polymorphism. Partial results are obtained in the general case and complete results in the case where the population size and selective advantage are not density dependent. Bounds on the fixation probability are obtained when the selective advantage is constant.     

The search for decisive factors in a study of the ultimate cause of cluster structure formation in water

The theory of nuclear ortho–para spin isomerism of water molecules proposes a putative ultimate cause for cluster structure formation in water. This theory appeared to be convincing enough to motivate numerous experiments aimed at validating it. However, a sound model of supramolecular structure is not yet available for water, despite many years of work by a number of research groups that expanded the number of models considerably. The possibility of validating the theory of nuclear ortho–para spin isomerism in a highly reliable way has been experimentally demonstrated in the present study. The emergence of crystallization centers related to the formation of oxygen near the anode upon the interaction of gas associates with cluster structure of the water in a metastable state has been revealed.

     

The momentum of a population whose birth rates gradually change to replacement levels

A formula is given for computing the ultimate size of a population whose birth rates change over a finite time to replacement levels. This formula is derived in the context of the usual discrete-time version of the one-sex model of population growth and represents an extension of work by Keyfitz and others. When birth and death rates tend over an infinite time to replacement levels, necessary and sufficient conditions are investigated for the ultimate population size to be finite and nonzero.     

Predicting amino acid residues responsible for enzyme specificity solely from protein sequences

We describe a general, modular method for developing protocols to identify the amino acid residues that most likely define the division of a protein superfamily into two subsets. As one possibility, we use PROBE to gather superfamily members and perform an ungapped alignment. We then use a modified BLOSUM62 substitution matrix to determine the discriminating power of each column of aligned residues. The overall method is particularly useful for predicting amino acids responsible for substrate or binding specificity when no structures are available. We apply our method to three pairs of protein classes in three different superfamilies, and present our results, some of which have been experimentally verified. This approach may accelerate the elucidation of enzymic substrate specificity, which is critical for both mechanistic insights into biocatalysis and ultimate application.     

TRILOBOXYLON ASHLANDICUM GEN. AND SP. N. FROM THE UPPER DEVONIAN OF NEW YORK

A new taxon is described from the Upper Devonian, Oneonta formation in the northern Cats-kills of New York. Triloboxylon gen. n. is represented by petrifactions showing two orders of branching. The main axis bears branches spirally and the latter bear the ultimate appendages spirally. Ultimate appendages branch dichotomously twice, in one plane. Primary xylem of the main axis and branches is three-armed with mesarch protoxylem extending in a continuous band within each arm. Primary xylem of the ultimate appendage is terete and dichotomizes twice. Metaxylem elements are characterized by scalariform and circular-bordered pitting on all walls. The cortex is composed entirely of isodiametrical parenchyma cells. Triloboxylon is compared with other genera with three-lobed protosteles. Its possible affinity with the Aneurophytales is shown. The morphological nature of the “frond” of the Aneurophytales and the possibility that the group possesses the morphological equivalent of simple leaves are discussed.     

Expression of the Mls-1a superantigen results in an increased frequency of V beta 14+ T cells.

Minor lymphocyte-stimulating (Mls) Ag are alloantigens that stimulate T cells expressing specific V beta regions. Recent studies have established that Mls Ag are examples of endogenous superantigens encoded by the products of endogenous mouse mammary tumor virus (MLV) genomes. In a mouse strain that expresses a given mammary tumor virus (Mls) Ag, reactive T cells expressing the corresponding V beta region are profoundly deficient, due at least in part to clonal deletion of the cells during their development. Expression of Mls and other endogenous superantigens, therefore, results in profound alterations in the ultimate repertoire of T cells in an animal. A role for endogenous superantigens in positive selection of T cells has not been previously established. Here we present evidence that expression of Mls-1a leads to a specific increase in the abundance of V beta 14+ T cells. Genetic studies indicate linkage of the effect to the Mls-1a gene. Neonatal tolerance studies argue against the possibility that the increase is due solely to the deletion of Mls-reactive V beta 14- T cells. The results are consistent with the Mls-1a product playing a role in the positive selection of V beta 14+ T cells.     

Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats

In vivo metabolic studies have revealed that haloperidol is converted to the corresponding pyridinium metabolite which has been characterized in both urine and brain tissues isolated from haloperidol treated rats. Unlike the corresponding conversion of the structurally related Parkinsonian inducing agent MPTP to the ultimate neurotoxic pyridinium metabolite MPP+, the oxidative biotransformation of haloperidol is not catalyzed by MAO-B. Microdialysis studies in the rat indicate that intrastriatal administration of this pyridinium metabolite is about 10% as effective as MPP+ in causing the irreversible depletion of striatal nerve terminal dopamine. The results point to the possibility that some of the neurological disorders observed in experimental animals and man during the course of chronic haloperidol treatment may be mediated by this pyridinium metabolite.     

Ionic Basis of Inhibitory Presynaptic Modulation in Rat Cortical Synaptosomes

We have investigated the possibility that, regardless of the involvement of a second messenger system, the ultimate effect of presynaptic, receptor-activated inhibitory modulation is the opening of a K channel. With the consequent hyperpolarization of the terminal, less Ca2+ would enter and this would result in the observed diminished release of a neurotransmitter. This possibility was explored utilizing rat cortical synaptosomes that were prelabeled with either 86Rb or [3H]acetylcholine, depolarizing with either K+ or veratridine, and measuring either efflux of 86Rb or release of [3H]acetylcholine in the presence or absence of inhibitory presynaptic modulators. The modulating agents used were 2-chloroadenosine, carbamylcholine, clonidine, and morphine. In all instances, these agents promoted an increased efflux of 86Rb, indicating hyperpolarization, and decreased release of acetylcholine. These results are compatible with our suggestion that an increase in K conductance may be responsible for presynaptic inhibition of the release of neurotransmitters.     

On Zeeman's equations for the nerve impulse

A model for the nerve impulse due to Zeeman (1972) and based on catastrophe theory is compared with alternative models and criticisms of Zeeman's model by Sussmann and Zahler (1977, 1978) are assessed. The criticisms of Zeeman's motivation for his model are found to carry some weight. Sussmann and Zahler (1977, 1978) list numerous features of Zeeman's model which, they state, are not in agreement with experiment. These statements as they stand are largely erroneous, and the model still remains to be tested by a critical series of experiments. However, a detailed analysis reveals defects in Zeeman's model, not among those claimed by Sussmann and Zahler, showing that the explicit equations of the model cannot be correct. The possibility of a modified approach along similar lines and its ultimate adoption remains open.     

Bioengineering strategies to generate vascularized soft tissue grafts with sustained shape

Tissue engineering offers the possibility for soft tissue reconstruction and augmentation without autologous grafting or conventional synthetic materials. Two critical challenges have been addressed in a number of recent studies: a biology challenge of angiogenesis and an engineering challenge of shape maintenance. These two challenges are inter-related and are effectively addressed by integrated bioengineering strategies. Recently, several integrated bioengineering strategies have been applied to improve bioengineered adipose tissue grafts, including internalized microchannels, delivery of angiogenic growth factors, tailored biomaterials and transplantation of precursor cells with continuing differentiation potential. Bioengineered soft tissue grafts are only clinically meaningful if they are vascularized, maintain shape and dimensions, and remodel with the host. Ongoing studies have begun to demonstrate the feasibility towards an ultimate goal to generate vascularized soft tissue grafts that maintain anatomically desirable shape and dimensions.     

Absence of a structural basis for intracellular recognition and differential localization of nuclear and plasma membrane-associated forms of simian virus 40 large tumor antigen.

The simian virus 40 large tumor antigen (T-ag) is found in both the nuclei (nT-ag) and plasma membranes (mT-ag) of simian virus 40-infected or -transformed cells. It is not known how newly synthesized T-ag molecules are recognized, sorted, and transported to their ultimate subcellular destinations. One possibility is that these events depend upon structural differences between nT-ag and mT-ag. To test this possibility, we compared the structures of nT-ag and mT-ag from simian virus 40-infected cells. No differences between the two forms of T-ag were detected by migration in polyacrylamide gels, by Staphylococcus aureus V8 partial proteolytic mapping of methionine- or proline-containing peptides, or by two-dimensional tryptic peptide mapping of methionine-containing peptides. The carboxy-terminal, methionine-containing tryptic peptide was identified in the two-dimensional maps and was shown to be identical in nT-ag and mT-ag. Thus, a structural basis for the recognition and differential localization of T-ags could not be demonstrated. The carboxy terminus of the T-ag encoded by mutant dlA2413 is derived from the alternate open reading frame of the simian virus 40 early region, in analogy with the theoretical early gene product, T*-ag. We used this mutant to identify peptides unique to T*-ag. None of these peptides were detected in maps of mT-ag; only wild-type T-ag-specific peptides were found. These findings suggest that T*-ag does not represent the membrane-associated form of T-ag, but that mT-ag is encoded within the same reading frame used for nT-ag.     

Searching algorithm for type IV secretion system effectors 1.0: a tool for predicting type IV effectors and exploring their genomic context

Type IV effectors (T4Es) are proteins produced by pathogenic bacteria to manipulate host cell gene expression and processes, divert the cell machinery for their own profit and circumvent the immune responses. T4Es have been characterized for some bacteria but many remain to be discovered. To help biologists identify putative T4Es from the complete genome of α- and γ-proteobacteria, we developed a Perl-based command line bioinformatics tool called S4TE (searching algorithm for type-IV secretion system effectors). The tool predicts and ranks T4E candidates by using a combination of 13 sequence characteristics, including homology to known effectors, homology to eukaryotic domains, presence of subcellular localization signals or secretion signals, etc. S4TE software is modular, and specific motif searches are run independently before ultimate combination of the outputs to generate a score and sort the strongest T4Es candidates. The user keeps the possibility to adjust various searching parameters such as the weight of each module, the selection threshold or the input databases. The algorithm also provides a GC% and local gene density analysis, which strengthen the selection of T4E candidates. S4TE is a unique predicting tool for T4Es, finding its utility upstream from experimental biology.     

Predicting the failure response of cement-bone constructs using a non-linear fracture mechanics approach

A non-linear fracture mechanics approach was used to predict the failure response of complex cement-bone constructs. A series of eight mechanical tests with a combination of tensile and shear loading along the cement-bone interface was performed. Each experiment was modeled using the finite element method with non-linear constitutive models at the cement-bone interface. Interface constitutive parameters were assigned based on the quantity of bone interdigitated with the cement. There was a strong correlation (r2 = 0.80) between experimentally measured and finite element predicted ultimate loads. The average error in predicted ultimate load was 23.9 percent. In comparison to the ultimate load predictions, correlations and errors for total energy to failure (r2 = 0.24, avg. error = 38.2 percent) and displacement at 50 percent of the ultimate load (r2 = 0.27, avg. error = 52.2 percent) were poor The results indicate that the non-linear constitutive laws could be useful in predicting the initiation and progression of interface failure of cemented bone-implant systems. However improvements in the estimation of post-yield interface properties from the quantity of bone interdigitated with cement are needed to enhance predictions of the overall failure response.