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PubMed1988

Macromolecular metabolism of a differentiated rat keratinocyte culture system following exposure to sulfur mustard.

A method for producing a stratified, squamous epithelium in vitro by cultivating rat keratinocytes on nylon membranes has been developed in this laboratory. This epidermal-like culture is being used to obtain a better understanding of the mechanism of skin vesication after topical exposure to the sulfur mustard bis(beta-chloroethyl) sulfide (BCES) dissolved in a selected solvent. Radiolabeled macromolecular precursors (thymidine, uridine, and leucine) have been used to study the effect of BCES on the synthesis of DNA, RNA, and protein, respectively, after topical exposure to the mustard at concentrations of 0.01-500 nmol/cm2 dissolved in 70% dimethyl sulfoxide (DMSO). From these and other studies it has been determined that exposure to even the low concentration of 0.01 nmol BCES/cm2 for 30 min results in significant inhibition of [3H]thymidine incorporation, although complete recovery occurs by 24 h. Significant inhibition of [3H]uridine and [14C]leucine incorporation is observed only after exposure to much higher concentrations of BCES (10-500 nmol/cm2). This suggests a very early lesion in macromolecular metabolism with DNA being the primary target.

Animals↗
PubMed1979

Memory facilitation by post-training injection of ethanol.

Immediate post-training IP injection of ethanol (0.75--4.5 g/kg) significantly enhanced retention of a one-trial passive avoidance task in mice compared to saline controls. Ethanol (4.5 g/kg) in the absence of footshock did not affect test performance. The memory facilitation may reflect ethanol's effects on neurotransmitter, macromolecular, or hormonal systems, or a reduction in interference.

Animals↗
PubMed2003

Nucleocytoplasmic transport: taking an inventory.

In eukaryotic cells, the enclosure of the genetic information in the nucleus allows the spatial and temporal separation of DNA replication and transcription from cytoplasmic protein synthesis. This compartmentalization not only permits a high level of regulation of these processes but at the same time necessitates a system of selective macromolecular transport between the nucleus and the cytoplasm. Transfer of macromolecules between both compartments is mediated by soluble receptors that interact with components of nuclear pore complexes (NPCs) to move their specific cargos. Transport occurs by way of a great variety of different pathways defined by individual receptors and accessory factors. Often, processes in substrate biogenesis that precede transport concurrently recruit transport factors to substrates, thus making transport responsive to correct and orderly synthesis of substrates. Some current challenges are to understand how transport factor-substrate interactions are controlled and integrated with sequential steps in substrate biogenesis, how large macromolecular complexes are restructured to fit through the NPC channel and to understand how transport factor-NPC interactions lead to actual translocation through the NPC.

Active Transport, Cell Nucleus↗
PubMed1991

Clostridium difficile toxin A and its effects on cells.

Clostridium difficile toxin A in its native form is a high molecular weight (520-540 K) aggregate with five major biological activities. It is lethal, enterotoxic, cytotoxic and cytotonic, and induces hemagglutination of rabbit red blood cells. Possibly these activities are contained in separate components. A major subunit of c. 230-310 K has been defined but lower molecular weight components cannot be excluded. The major component has been cloned, and sequence analysis indicated a complicated pattern of repeating sequences in the C-terminal third of the molecule. This review deals mainly with the effects of toxin A on cultured cells. Most mammalian cells are sensitive to toxin A whose major effect is to stop cell division irreversibly. The toxin binds via its repeat sequences to a trisaccharide receptor expressed on rabbit red cells and on brush border membranes from hamster intestine. This receptor seems to be functional in the hemagglutination reaction and the enterotoxicity. Its role in the cytotoxic effect of the toxin is not clear, but no other receptor structure has as yet been identified. In order to exert its cytotoxic (antiproliferative) effect toxin A must first be internalized by endocytosis. Thus a latency period of at least 30 min after toxin binding to cells is consistently observed, and all cytotoxic effects can be prevented by blocking the endocytosis pathway. The first microscopically visible signs of cytotoxicity consist in retraction and rounding of intoxicated cells. In addition the nucleus becomes polarized to one side of the cell while other cell organelles are not significantly affected. These morphological changes seem to be the consequence of a cytoskeletal rearrangement, mainly involving some components of the microfilament system. Inhibition of macromolecular syntheses as well as permeabilization of the plasma membrane may follow the early cytoskeletal effects and finally lead to cell death. Attempts to identify metabolic pathways of significance in the cytotoxicity suggest that the cytosolic level of Ca2+ is not important, thus excluding certain mechanisms for cell killing. In this respect the cytotoxic mode of action of toxin A clearly differs from that of toxin B. However, the biochemical basis for the antiproliferative effect of toxin A remains unknown.

Animals↗
PubMed2004

Nonequilibrium thermodynamics of membrane-confined electrophoresis.

Membrane-confined electrophoresis (MCE) is an electrophoretic transport method in which macromolecules in solution are confined within a cuvette through which a current flows. Small ions that can permeate the membranes permit current flow. The method is the electrophoretic analog to analytical ultracentrifugation. Systems in the MCE instrument are described by nonequilibrium thermodynamics. This description forms the basis of a program, implemented using finite element methods, that can model transport processes in such systems over an extended time, from arbitrary starting conditions to steady state. Issues relevant to the analysis of systems in which macromolecular species are involved in mass-action associations are discussed. Particular attention is given to steady-state electrophoresis, from which measurements of reduced molecular charge are sought. The relationship of such measurements to valence is discussed.

Biological Transport↗
PubMed2004

Electron microscopy studies on DNA recognition by DNA-PK.

Advances in transmission electron microscopy coupled to increasingly powerful biocomputing techniques are opening enormous possibilities to understand the structure and function of complex biological processes performed by large multi-protein assemblies. This is an exciting time for electron microscopists because we can combine our efforts with X-ray crystallographers and NMR spectroscopists to reach the prospect of studying the structure and dynamics of the so-called 'molecular machines'. One of these fascinating systems is the macromolecular complex formed around double-stranded DNA breaks (DSBs). Non-homologous end-joining (NHEJ) is the main DSBs repair pathway in mammalian cells, where a collection of proteins interact to rejoin two broken DNA ends. During NHEJ, DNA-dependent protein kinase (DNA-PK) binds damaged DNA with high affinity and acts as the main scaffold for other repair factors. Several studies have made use of the electron microscope to reveal the three-dimensional architecture of DNA-PK and the structural basis for the recognition of damaged DNA and the activation of DNA-PK's kinase activity.

Catalytic Domain↗
PubMed2000

Unbinding-binding transition induced by molecular snaps in model membranes.

We have used a lamellar phase made of a nonionic surfactant, dodecane and water, as a model membrane to investigate its interactions with macromolecular inclusions bringing together two membranes, i.e., acting as macromolecular snaps. In systems devoid of inclusions, the interlamellar distance depends on the total volume fraction of membranes Phi. We show that, in presence of a transmembrane protein, or of several de novo designed peptides of different length and composition, the lamellar phase undergoes a binding transition. Under such conditions, the interlamellar distance is no longer proportional to Phi(-1), but rather to the surface concentration of snaps within the membrane. It also appears that, in the presence of the hydrophobic segment of peptide snaps, the length of the inclusions must be at least equal to the hydrophobic length of the membrane to be active. Experimental results have been precisely fitted to a model of thermally stabilized membranes, decorated with snaps. However, in the presence of inclusions, the parameter describing the interactions between membranes, has to take into account the length of the inclusion to preserve good predictive capabilities.

Alkanes↗
PubMed2001

Examination of oxidized cellulose as a macromolecular prodrug carrier: preparation and characterization of an oxidized cellulose-phenylpropanolamine conjugate.

The purpose of this study was to investigate the use of 6-carboxycellulose (OC), a biocompatible and bioresorbable polymer, as a prodrug carrier for amine drugs. Phenylpropanolamine hydrochloride (PPA.HCl) was used as a model drug. OC and PPA were reacted in dimethylformamide (DMF) in the presence of 1,3-dicyclohexylcarbodiimide (DCC) for 2.5 days at room temperature. Filtration, followed by washing with methanol, and subsequent drying under vacuum, produced the conjugate in 65-78% yield. The amount of PPA in the product, determined from the difference in the carboxylic content before and after the reaction, was 24.2% (w/w), corresponding to a degree of substitution (DS) value of 0.7. The Fourier transform-infra red (FT-IR) spectrum of the conjugate, compared with that of OC and PPA.HCl, showed a new band at about 1533 cm(-1) attributable to a C = O (amide II) stretching and N single bond H (amide I and amide II) bending vibrations, a decrease in intensity of the characteristic free carboxylic acid carbonyl stretching band at about 1748 cm(-1), and a strong band at 1663 cm(-1) due to C = O (amide I) stretching vibration, suggesting that the OC is linked to PPA via an amide bond. The solid-state carbon-13 cross polarization/magic angle spinning nuclear magnetic resonance ((13)CCP/MAS NMR) spectrum of the conjugate was also consistent with this structure. The release studies performed in pH 4.5, 5.5, and 7.4 buffer solutions and in rat liver homogenate (pH 7.4), showed the conjugate to be more susceptible to hydrolysis at a lower pH and in the presence of rat liver homogenate. In conclusion, the results presented show that OC can be covalently linked to amine drugs via an amide bond in DMF using DCC as a coupling agent, and provide a macromolecular prodrug delivery system.

Cellulose↗
PubMed2006

ACE gene insertion/deletion polymorphism modulates capillary permeability in hypertension.

A D/D (deletion/deletion) polymorphism within the ACE (angiotensin 1-converting enzyme) gene increases the risk of microalbuminuria, a predictor of atherosclerotic vascular disease, in essential hypertension. It is unknown, however, whether this genetic profile is accompanied by disturbed macromolecular permeability of systemic capillary endothelium, possibly in the context of generalized endothelial dysfunction. In the present study, the ACE gene polymorphism was determined by PCR in 79 never-treated uncomplicated hypertensive men and 16 normotensive men as controls. Evaluation variables were TERalb (transcapillary escape rate of albumin; the 1-h decline rate of intravenous (125)I-albumin, a measure of integrity of systemic capillary endothelium), albuminuria and forearm vasodilation to intra-arterial acetylcholine, an index of NO (nitric oxide)-mediated vasomotion, in addition to a series of sensitive parameters of albumin permeation (blood pressure, metabolic status and smoking habits). Analyses were done by comparing D/D homozygotes with grouped I/D (insertion/deletion) and I/I (insertion/insertion) subjects. TERalb was higher in D/D hypertensives, who had higher albuminuria, more frequent microalbuminuria and comparable forearm responsiveness to intra-arterial acetylcholine. Fasting glucose and insulin, insulin sensitivity, 24-h blood pressure, smoking habits and metabolic parameters did not differ between the two groups. TERalb and urine albumin values were positively associated in the hypertensive subjects. In conclusion, ACE D/D homozygosis, independently of several confounding factors, associates with higher TERalb in men with essential hypertension. This may reflect noxious genetic influences on systemic vascular permeability, a critical control mechanism for atherogenesis in the absence of grossly impaired NO-mediated arteriolar responsiveness. The parallel behaviour of TERalb and albuminuria suggests some shared genetically mediated determinant of renal and systemic microvascular abnormalities in hypertension.

Albuminuria↗
PubMed1996

Coating the surface: a model for expression of capsular polysialic acid in Escherichia coli K1.

Capsules are well-studied components of the bacterial surface that modulate interactions between the cell and its environment. Generally composed of polysaccharide, they are key virulence determinants in invasive infections in humans and other animals. Genetic determinants involved in capsule expression have been isolated from a number of organisms, but perhaps the best characterized is the kps cluster of Escherichia coli K1. In this review, the current understanding of the functions of the kps gene products is summarized. Further, a proposed mechanistic model for capsule expression is presented and discussed. The model is based on the premise that the numerous components of the kps cluster form a hetero-oligomeric complex responsible for synthesis and concurrent translocation of the capsular polysialic acid through sites of inner and outer membrane fusion. We view the ATP-binding cassette (ABC) transporter, KpsMT, to be central to the functioning of the complex, interacting with the biosynthetic apparatus as well as the extracytoplasmic components of the cluster to co-ordinate synthesis and translocation. The model provides the basis for additional experimentation and reflects emerging similarities among systems responsible for macromolecular export in Gram-negative bacteria.

ATP-Binding Cassette Transporters↗
PubMed1976

Free energy levels and entropy production associated with biochemical kinetic diagrams.

"Basic" and "gross" free energy levels are defined for the discrete states of a macromolecular biochemical kinetic system such as a free energy transducing enzyme (e.g., myosin or Na,K-ATPase). Basic free energy level differences are related to the first-order rate constants for transitions between states while gross free energy differences, along with the corresponding fluxes, determine the rate of entropy production in the system. In muscle contraction the analysis is complicated by the possibility of the system doing external mechanical work. The question of the sign of the flux or of the gross free energy level change in a given transition is examined for both single-cycle and multi-cycle models. More definite statements can be made in single-cycle cases. Some numerical examples are included. The more complicated cases are reserved for a subsequent paper.

Adenosine Triphosphatases↗
PubMed1974

Steroid inhibition of protein incorporation by isolated amphibian oocytes.

The relationship between blood protein (vitellogenin) incorporation and nuclear maturation was studied in individual amphibian oocytes after in vitro exposure to desoxycorticosterone acetate (DOCA). Isolated Rana pipiens oocytes were incubated in vitro with radioactively labeled oocyte yolk precursor ([(3)H]vitellogenin) obtained from estrogenized Xenopus laevis. Incorporation of labeled vitellogenin into the oocytes continued over a 24-h period. Oocytes simultaneously exposed to DOCA and to labeled vitellogenin exhibited both inhibition of vitellogenin incorporation and stimulation of nuclear maturation and cortical changes. Inhibition of vitellogenin incorporation was observed after approximately 9 h of incubation and was correlated with the time of nuclear breakdown. Preincubation of oocytes in steroid for 9 h essentially terminated vitellogenin incorporation. Incorporation of vitellogenin occurred after removal of follicle cells from the oocyte by a short treatment with EDTA. These results demonstrate the macromolecular vitellogenin transport system remains operative in oocytes which can undergo nuclear maturation and that the steroid DOCA can affect its function. Evidence suggests that the mechanism of steroid inhibition is in part the result of inhibition of the micropinocytotic process in the oocyte cortex.

Animals↗
PubMed1992

DNA binding provides a signal for phosphorylation of the RNA polymerase II heptapeptide repeats.

Isolated transcription complexes contain a protein kinase that phosphorylates the heptapeptide repeats of the carboxy-terminal domain (CTD) of the RNA polymerase II (RNAP II) large subunit in an apparently promoter-dependent manner. We now show that the essential features of this reaction can be reproduced in a reconstituted system containing three macromolecular components: a fusion protein consisting of the CTD of RNAP II fused to a heterologous DNA-binding domain, an activating DNA fragment containing the recognition sequence for the fusion protein, and a protein kinase that binds nonspecifically to DNA. This kinase closely resembles a previously known DNA-dependent protein kinase. Evidently, the association of the CTD with DNA provides a key signal for phosphorylation. There appears to be no absolute requirement for specific contacts with other DNA-bound transcription factors.

Animals↗
PubMed2006

Direct measurement of the full, sequence-dependent folding landscape of a nucleic acid.

Nucleic acid hairpins provide a powerful model system for understanding macromolecular folding, with free-energy landscapes that can be readily manipulated by changing the hairpin sequence. The full shapes of energy landscapes for the reversible folding of DNA hairpins under controlled loads exerted by an optical force clamp were obtained by deconvolution from high-resolution, single-molecule trajectories. The locations and heights of the energy barriers for hairpin folding could be tuned by adjusting the number and location of G:C base pairs, and the presence and position of folding intermediates were controlled by introducing single-nucleotide mismatches.

Base Pair Mismatch↗
PubMed2006

Curli biogenesis and function.

Curli are the major proteinaceous component of a complex extracellular matrix produced by many Enterobacteriaceae. Curli were first discovered in the late 1980s on Escherichia coli strains that caused bovine mastitis, and have since been implicated in many physiological and pathogenic processes of E. coli and Salmonella spp. Curli fibers are involved in adhesion to surfaces, cell aggregation, and biofilm formation. Curli also mediate host cell adhesion and invasion, and they are potent inducers of the host inflammatory response. The structure and biogenesis of curli are unique among bacterial fibers that have been described to date. Structurally and biochemically, curli belong to a growing class of fibers known as amyloids. Amyloid fiber formation is responsible for several human diseases including Alzheimer's, Huntington's, and prion diseases, although the process of in vivo amyloid formation is not well understood. Curli provide a unique system to study macromolecular assembly in bacteria and in vivo amyloid fiber formation. Here, we review curli biogenesis, regulation, role in biofilm formation, and role in pathogenesis.

Amino Acid Sequence↗
PubMed2005

Stimulus-controlled delivery of drugs and genes.

Macromolecular and colloidal systems used for the systemic delivery of drugs and genes promise to improve the way we treat and prevent numerous diseases. New generations of drug and gene delivery systems (DGDS) are being designed to enhance further efficiency by using a range of endogenous and external stimuli. This review focuses on three qualitatively distinct ways a stimulus can improve the efficiency of DGDS; namely, by selectively triggering release of the therapeutic agent from the DGDS, by modulating physical properties of DGDS and by favourably altering physiological properties of tissues to enhance DGDS transport. Recent developments in these areas are discussed to illustrate the potential of stimulus-controlled DGDS in the development of new generations of therapeutics.

Animals↗
PubMedDate not supplied

[Several physical aspects of intracellular energy transformation].

Physical principles underlying the chemiosmotic hypothesis of membrane phosphorylation are analysed. The utilization of free energy determined by dydrogen ions concentration difference across the membrane for ATP synthesis requires ATP-synthetase to be an entropy machine able to perform work on account of heat. The chemiosmotic hypothesis assumes the possibility of interchangeable utilization of both components of proton electrochemical potential-the membrane electrical difference and proton concentration gradient-for ATP synthesis. This assumption requires the fulfillment of practically unrealizable conditions. Energetic coupling of intracellular chemical reactions must be realized by means of a mechanism in which every act of energydonating reaction leads compulsory to one act of energyaccepting reaction. For such a mechanism both reactions ought to proceed essentially in one elementary act. For intracellular macromolecular and supramolecular systems it implies the necessity of excitation of specific mechanical slowly relaxing degrees of freedom.

Adenosine Triphosphatases↗
PubMed1988

Calyculins, potent antitumour metabolites from the marine sponge Discodermia calyx: biological activities.

Calyculins A-D, extraordinary metabolites of the Japanese marine sponge Discodermia calyx, showed marked cytotoxicity against murine leukaemia cells and echinoderm embryos. The major compound, calyculin A, also had potent antitumour activity, although it was highly toxic in mice. Its mode of action in L1210, rat fibroblasts and fertilized sea urchin eggs has been studied, which led the authors to predict that calyculins affect primarily a system other than macromolecular syntheses.

Animals↗