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PubMed2006

Configurational statistics of macromolecules in solution from correlations of liquid molecules.

We address the relevant quest for a simple formalism describing the microstructure of liquid solutions of polymer chains. On the basis of a recent relativistic-type picture of self-diffusion in (simple) liquids named Brownian relativity (BWR), a covariant van Hove's distribution function in a Vineyard-like convolution approximation is proposed to relate the statistical features of liquid and chain molecules forming a dilute polymer solution. It provides an extension of the Gaussian statistics of ideal chains to correlated systems, allowing an analysis of macromolecular configurations in solution by the only statistical properties of the liquid units (and vice versa). However, the mathematical solution to this issue is not straightforward because, when the liquid and polymer van Hove's functions are equated, an inverse problem takes place. It presents some conceptual analogies with a scattering experiment in which the correlation of the liquid molecules acts as the radiation source and the macromolecule as the scatterer. After inverting the equation by a theorem coming from the Tikhonov's approach, it turns out that the probability distribution function of a real polymer can be expressed from a static Ornstein-Uhlenbeck process, modified by correlations. This result is used to show that the probability distribution of a true self-avoiding walk polymer (TSWP) can be modeled as a universal Percus-Yevick hard-sphere solution for the total correlation function of the liquid units. This method suits in particular the configurational analysis of single macromolecules. The analytical study of arbitrary many-polymer systems may require further mathematical investigation.

Journal Article↗
PubMed1993

Molecules and cognition: the latterday lessons of levels, language, and lac. Evolutionary overview of brain structure and function in some vertebrates and invertebrates.

The characteristics of the nervous systems of a number of organisms in different phyla are examined at the recombinant DNA, protein, neuroanatomic, neurophysiological, and cognitive levels. Among the invertebrates, special attention is paid to the advantages as well as the shortcomings of the fly Drosophila melanogaster, the worm Caenorhabditis elegans, the honey bee Apis mellifera, the sea hare Aplysia californica, the octopus Octopus vulgaris, and the squid Loligo pealei. Among vertebrates, the focus is on Homo sapiens, the mouse Mus musculus, the rat Rattus norvegicus, the cat Felis catus, the macaque monkey Macaca fascicularis, the barn owl Tyto alba, and the zebrafish Brachydanio rerio. Vertebrate nervous systems have also been compared in fossil vs. extant organisms. I conclude that complex nervous systems arose in the Early Cambrian via a big bang that was underpinned by a modular method of construction involving massive pleiotropy of gene circuits. This rapidity of construction had enormous implications for the degrees of freedom that were subsequently available to evolving nervous systems. I also conclude that at the level of neuronal populations and interactions of neuropiles there is no model system between phyla except at the basic macromolecular level. Further, I argue that to achieve a significant understanding of the functions of extant nervous systems we need to concentrate on fewer organisms in greater depth and manipulate genomes via transgenic technologies to understand the behavioral outputs that are possible from an organism. Finally, I analyze the concepts of "perceptual categorization" and "information processing" and the difficulties involved in the extrapolation of computer analogies to sophisticated nervous systems.

Animals↗
PubMed1996

Brefeldin A is a potent inducer of apoptosis in human cancer cells independently of p53.

Brefeldin A (BFA) is a natural product that affects the structure and function of the Golgi apparatus and is in development for cancer chemotherapy. We observed that a wide range of cancer cells could undergo DNA fragmentation associated with apoptosis after BFA treatment. This DNA fragmentation was induced within 15 h in HL60 leukemia cells and after 48 h in K562 leukemia and HT-29 colon carcinoma cells with BFA concentrations as low as 0.1 microM. The DNA fragmentation had the typical internucleosomal pattern in HL60 and HT-29 cells. Apoptotic cells were also detected by microscopy. BFA-induced apoptosis is p53-independent as HL60 and K562 cells are p53 null and HT-29 are p53 mutant cells. BFA could potentiate UCN-01 and staurosporine-induced DNA fragmentation in HL60 cells. Cyclin B1/Cdc2 kinase activity decreased after BFA treatment in HL60 cells, indicating that BFA-induced DNA fragmentation was independent of a cyclin B1/Cdc2 kinase upregulation pathway. Cycloheximide could not prevent BFA-induced DNA fragmentation in HL60 cells, suggesting that protein synthesis is not needed for HL60 cells to undergo apoptosis. On the contrary, cycloheximide blocked BFA-induced DNA fragmentation in HT-29 cells, indicating that apoptosis in HT-29 cells requires macromolecular synthesis. Cell-free system experiments suggested that cytosolic proteins play an important role in triggering DNA fragmentation during apoptosis induced by BFA. Our results show that transduction signaling pathways play central roles in apoptotic regulation.

Alkaloids↗
PubMed1990

Experimental determination and mathematical model of the transient incorporation of cholesterol in the arterial wall.

Experimental data of the radial incorporation of labeled cholesterol [14C-4] into the artery wall is regressed against a mathematical model that predicts macromolecular transport in this biological system. Data is obtained using excised canine carotid arteries that are perfused in vitro under pulsatile hemodynamic conditions for 2 hr. Vessels are exposed to either normotensive hemodynamics, hypertensive hemodynamics, or simulations in which the rate of flow or vessel compliance is deliberately altered. Several arteries are studied under normotensive conditions following balloon catheter deendothelialization. Transmural concentration profiles of [14C-4] activity are determined by microcryotomy of longitudinal sections of perfused vessels. Nonlinear Marquardt regression on 12 experimental cases yields parameter estimates of effective diffusivity, D and solute filtration velocity, V. Results of this experimental investigation support our hypothesis that hemodynamics and the endothelial lining influence wall flux in intact vessels. Exposure to altered (vs normotensive) hemodynamics is associated with increased incorporation of labeled cholesterol. A similar observation is made for deendothelialized vessels (e.g. a greater accumulation of label and a rise in convective flux). Based upon our companion measurements of vessel wall forces and endothelial cellular morphology accompanying hemodynamic simulations, we suggest that hemodynamically induced alterations to endothelial structures lead to the increased permeability, convection and incorporation that we observe in this work.

Animals↗
PubMed2001

Influence of betacyclodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices.

The release behavior of poorly soluble drugs (naproxen and ketoprofen) from inert (acrylic resins) and hydrophilic swellable (high-viscosity hydroxypropylmethylcellulose) tableted matrices containing betacyclodextrin (betaCD) was investigated. The results demonstrated that, in both cases, betaCD can enhance the rate of drug release. Matrices obtained from formulations in which lactose replaced betaCD were also evaluated. BetaCD in inert matrices causes a dramatic increase in the rate of drug release, higher than that promoted by lactose which merely acts as a channelling agent. This result suggests that possible in situ formation of the drug-betaCD complex. which causes an improvement in apparent drug solubility, could have a greater influence on the rate of drug release than the possible increase of water uptake by a soluble filler. Indeed, if the opposite were true, lactose would be more effective in increasing the rate of drug release than betaCD, because of its greater solubility in water. On the contrary, in the case of hydrophilic matrices, lactose proves to be much more effective in promoting drug release than betaCD. It seems that, while the bulky interaction compound can freely diffuse through water-filled pores of inert systems, its diffusion through swollen macromolecular chains of hydrophilic matrices may be hindered. This hypothesis was supported by data obtained from binary (drug/polymer) and ternary (drug/polymer/betaCD) hydrophilic matrices using a betaCD-containing dissolution media.

Biocompatible Materials↗
PubMed2000

Subcellular localization determines the availability of non-targeted proteins to plasmodesmatal transport.

BACKGROUND: Individual plant cells are encased in a cell wall. To enable cell-to-cell communication, plants have evolved channels, termed plasmodesmata, to span thick walls and interconnect the cytoplasm between adjacent cells. How macromolecules pass through these channels is now beginning to be understood. RESULTS: Using two green fluorescent protein (GFP) reporters and a non-invasive transfection system, we assayed for intercellular macromolecular traffic in leaf epidermal cells. Plasmodesmata were found in different states of dilation. We could distinguish two forms of protein movement across plasmodesmata, non-targeted and targeted. Although leaves have generally been considered closed to non-specific transport of macromolecules, we found that 23% of the cells had plasmodesmatal channels in a dilated state, allowing GFP that was not targeted to plasmodesmata to move into neighboring cells. GFP fusions that were targeted to the cytoskeleton or to the endoplasmic reticulum did not move between cells, whereas those that were localized to the cytoplasm or nucleus diffused to neighboring cells in a size-dependent manner. Superimposed upon this non-specific exchange, proteins that were targeted to the plasmodesmata could transit efficiently between 62% of transfected cells. CONCLUSIONS: A significant population of leaf cells contain plasmodesmata in a dilated state, allowing macromolecular transport between cells. Protein movement potential is regulated by subcellular address and size. These parameters of protein movement illustrate how gradients of signaling macromolecules could be formed and regulated, and suggest that non-cell-autonomous development in plants may be more significant than previously assumed.

Biolistics↗
PubMed1996

Autocatalyzed protein folding.

Proline isomerization, an intrinsically slow process, kinetically traps intermediates in slow protein folding reactions. Thus, enzymes that catalyze proline isomerization (prolyl isomerases) often catalyze protein folding. We have investigated the folding kinetics of FKBP, a prolyl isomerase. The main conclusion is that FKBP catalyzes its own folding. Altogether, the FKBP refolding kinetics are resolved into three exponential phases: a fast phase, tau 3; an intermediate phase, tau 2; and a slow phase, tau 1. Unfolding occurs in a single phase, the unfolding branch of phase tau 2. In the presence of native FKBP, both the intermediate (tau 2) and slow (tau 1) phases are faster, suggesting that folding phases tau 1 and tau 2 involve proline cis-trans isomerization. In the absence of added native FKBP, autocatalytic folding of FKBP is detected. For refolding starting with all the FKBP unfolded initially, the slowest folding phase (tau 1) is almost 2-fold faster at a final concentration of 14 microM FKBP than at 2 microM FKBP, suggesting that catalytically active FKBP formed in the fast (tau 3) or intermediate (tau 2) folding phases catalyzes the slow folding phase (tau 1). Moreover, autocatalysis of folding is inhibited by FK506, an inhibitor of the FKBP prolyl isomerase activity. The results show that the slow phase in FKBP folding is an autocatalyzed formation of native FKBP from kinetically trapped species with non-native proline isomers. While the magnitude of the catalytic effects reported here are modest, FKBP folding may provide a prototype for autocatalysis of kinetically trapped macromolecular conformational changes in other systems.

Amino Acid Isomerases↗
PubMed2002

Bacterial conjugation: a two-step mechanism for DNA transport.

Bacterial conjugation is a promiscuous DNA transport mechanism. Conjugative plasmids transfer themselves between most bacteria, thus being one of the main causal agents of the spread of antibiotic resistance among pathogenic bacteria. Moreover, DNA can be transferred conjugatively into eukaryotic host cells. In this review, we aim to address several basic questions regarding the DNA transfer mechanism. Conjugation can be visualized as a DNA rolling-circle replication (RCR) system linked to a type IV secretion system (T4SS), the latter being macromolecular transporters widely involved in pathogenic mechanisms. The scheme 'replication + secretion' suggests how the mechanism would work on the DNA substrate and at the bacterial membrane. But, how do these two parts come into contact? Furthermore, how is the DNA transported? T4SS are known to be involved in protein secretion in different organisms, but DNA is a very different macromolecule. The so-called coupling proteins could be the answer to both questions by performing a dual role in conjugation: coupling the two main components of the machinery (RCR and T4SS) and actively mediating DNA transport. We postulate that the T4SS is responsible for transport of the pilot protein (the relaxase) to the recipient. The DNA that is covalently linked to it is initially transported in a passive manner, trailing on the relaxase. We speculate that the pilus appendage could work as a needle, thrusting the substrate proteins to cross one or several membrane barriers into the recipient cytoplasm. This is the first step in conjugation. The second step is the active pumping of the DNA to the recipient, using the already available T4SS transport conduit. It is proposed that this second step is catalysed by the coupling proteins. Our 'shoot and pump' model solves the protein-DNA transport paradox of T4SS.

Bacteria↗
PubMed1973

The effect of poly-L-lysine on the uptake of reovirus double-stranded RNA in macrophages in vitro.

The effect of polycations on cultured mouse peitoneal macrophages has been examined. Polycations, at concentrations greater than 5 microg/ml, are toxic for macrophages) as measured by failure of the cells to exclude vital dyes. At toxic concentrations polycations bind in large amounts to nuclei and endoplasmic reticulum, while at nontoxic levels polycations bind selectively to the cell surface. Nontoxic concentrations of polycations stimulate binding of reovirus double-stranded (ds) RNA to the macrophages by forming polycation-dsRNA complexes either in the medium or at the cell surface. These complexes enter the cell in endocytic vacuoles and are concentrated in secondary lysosomes. Despite exposure to the acid hydrolases within this cell compartment, the dsRNA and the polycation (poly-L-lysine) are conserved in a macromolecular form within the vacuolar system. The mechanism(s) by which the uptake of infectious nucleic acids and the induction of interferon by dsRNA are stimulated by polycations are discussed.

Animals↗
PubMed1996

Impairment of endothelial and subendothelial sites by a circulating plasma factor associated with minimal change disease.

BACKGROUND: The pathogenesis of albuminuria in minimal change disease (MCD) is unknown. A human plasma factor (denoted as 100KF) is able to induce minimal change-like glomerular alterations, i.e. loss of glomerular sialoglycoproteins and decreased expression of glomerular ecto-ATPase, following in vitro incubation with kidney tissue. In addition, increased (selective) permeability for plasma proteins occurs after perfusion of 100KF into the rat kidney ex vivo. As in kidney tissue from subjects with minimal change disease, subendothelial injury has also been observed, i.e. reduced anionic sites in the lamina rara interna, the question was raised whether injury induced by the plasma factor 100KF involves vascular endothelium or subendothelial matrix of the glomerular capillary wall. METHODS: Permeability studies were carried out by using confluent endothelial monolayers (HUVEC) cultured on a standard two-compartment system. The permeability for a macromolecular marker (horse radish peroxidase) was tested following incubation of the monolayers with either the native plasma factor 100KF or the control factor (heat-inactivated 100KF), in combination with histochemical evaluation of the cells for ecto-ATPase expression. Also quantification of glomerular anionic sites at the ultrastructural level was carried out, after ex vivo perfusion of 100KF or control factor into rat kidneys. RESULTS: The plasma factor 100KF is able to increase the permeability of human endothelial monolayers for macromolecules in a dose-dependent manner (relative increase 122.4 +/- 24, 178.4 +/- 34 and 236.1 +/- 58% after preincubation with 0.05; 0.5 and 1.5 mg/ml 100KF respectively), concomitant with induction of minimal change-like histochemical alterations such as reduced expression of ecto-ATPase. The number of anionic sites in the lamina rara interna of the glomerular capillary wall is significantly diminished following perfusion with the plasma factor 100KF versus control factor (7.58 +/- 1.60 versus 12.57 +/- 2.05 per 1000 nm; P < or = 0.02); in contrast to the lamina rara externa (22.71 +/- 3.15 versus 22.27 +/- 2.92 per 1000 nm; statistically not significant). CONCLUSIONS: Endothelial cells and subendothelial matrix along the glomerular filtration barrier may be considered as target structures for the plasma factor 100KF, leading to initial minimal change-like alterations associated with glomerular albumin leakage.

Animals↗
PubMed1988

Factors determining the proton T1 relaxivity in solutions containing Gd-DTPA.

The relaxation times T1 and nuclear Overhauser effects were measured in the 13C nuclear magnetic resonance (NMR) spectra of the diamagnetic calcium (Ca) and lanthanum (La) analogs of Gd-DTPA. From these data the correlation times for the molecular reorientation tau R were calculated; it is suggested that this term is the dominant one in the evaluation of the paramagnetic relaxation equation. The similar tau R values obtained in water and blood serum ruled out the occurrence of any adduct formation between Gd-DTPA complex and the macromolecular framework in the latter system. The difference in relaxivity shown by Gd-DTPA in the two media is interpreted in terms of influence of the serum components on the dissociation equilibrium of Gd-DTPA.

Blood↗
PubMed1995

Zinc-directed inhibitors for zinc proteinases.

Zinc proteinases have been recognized as a distinct class of proteolytic enzymes in which at least one ion of zinc is involved directly in catalysis. This family includes a growing number of biologically important enzymes which are attractive targets for rational drug design. In this paper we examine the special features of the zinc binding environment of these enzymes in order to gain information which could be useful in the preparation of 'zinc-directed' selective inhibitors. Carboxypeptidase A (CPA) is presented as a model for one class of zinc proteinases, and the active-site zinc and its interactions are examined with the primary focus on geometrical considerations. The three-dimensional structure of the native and apoenzyme are discussed, together with the high-resolution structure of several enzyme-inhibitor complexes. This paper will first present a structural analysis of CPA derivatives and then discuss a series of zinc model compounds which have been prepared and characterized in order to examine the ligand and geometrical preferences of the zinc in an unstrained system. X-ray crystallography (macromolecular and small molecule) is the main experimental method used for the structural analyses, while complementary computational methods have been used for the examination of electrostatic potentials. The results from the various experimental efforts are assembled in order to draw general conclusions on the potential use of the zinc ion as the primary target for inhibitor binding. The results of these studies suggest that the zinc ion is important for both the binding and the catalytic activation of the substrate as well as for stabilization of the tetrahedral reaction intermediate.

Journal Article↗
PubMed1984

Antitumor agent poly (amino acid) conjugates as a drug carrier in cancer chemotherapy.

Antitumor agent melphalan was conjugated through a carbodiimide-catalyzed reaction to poly (L-lysine) (71.3K and 2K) and poly (L-glutamic acid) (60K and 14K) at a ratio of approximately one molecule per 7-lysyl and 23-glutamate residues, respectively. These conjugates had 40-70% of alkylating activities by themselves in vitro as compared with free melphalan. Poly (glutamic acid) conjugates showed the antitumor activity in vivo against Yoshida sarcoma in rats. In addition, poly (glutamic acid) conjugates containing 3H-phenylalanine which was used as a model compound instead of melphalan had a sustained release property of radioactivity and the release rates could be regulated by exopeptidases. After subcutaneous injection as the first choice of routes of administration, moreover, the conjugates were found to be absorbed through the lymphatic transport system, probably due to the macromolecularity. These results suggest that the melphalan-poly (amino acid) conjugates are one of good candidates to attain the sustained release and targeting of drugs in cancer chemotherapy.

Absorption↗
PubMed1986

The role of microvascular permeability in the pathogenesis of asthma.

Proposed mediators of asthma act on specific pulmonary target tissues including the tracheobronchial microvasculature. Inflammatory extravasation of protein-rich plasma is obviously due to active mediator-induced formation of gaps between endothelial cells in the post-capillary venules of systemic microvessels. Because of this macromolecular permeability plasma exudate may accumulate interstitially and generate airway submucosal and mucosal oedema. The exudate apparently also passes into the airways lumen and has been suggested to affect the function and the attachment of the ciliated epithelial lining. The microvascular permeability to macromolecules is subject to specific physiological and pharmacological control. Both the mucosal (epithelial) and the microvascular barrier may exhibit an increased permeability in asthma, but must be considered two separate elements of the inflamed airway.

Animals↗
PubMed1984

Action of delta 9-tetrahydrocannabinol on the pool of acid soluble nucleotides.

The effects of delta 9-tetrahydrocannabinol (THC) treatment on acid soluble pools of uridine nucleoside and nucleotides were investigated in Tetrahymena pyriformis and in isolated mouse lymphocytes and spermatogenic cells. In THC treated Tetrahymena and mouse lymphocytes the uptake of labelled precursor into acid soluble pools of uridine nucleoside and nucleotides fluctuated, whereas in pachytene spermatocytes and round spermatid cells the labelled pool was reduced. The reduction in the labelled pool measured in mouse spermatogenic cells was attributed primarily to a reduction in radioactively labelled uridine nucleoside. Treatment of Tetrahymena in high concentrations of THC (960 and 3,200 microM) resulted in an increase of labelled uridine nucleoside and a reduction in the amount of labelled uridine nucleotides. Expansion of the acid soluble pool with radioactive uridine resulted in small differences in labelled nucleoside and nucleotides in control and THC treated Tetrahymena and mouse lymphocytes. The results are discussed in terms of the effects of THC on macromolecular synthesis in various cellular systems.

Animals↗
PubMed1979

Mouse C4 (Ss): three-step purification of its C4c fragment and production of a monospecific antiserum.

We report here that a large fragment of mouse C4 (C4c) can be easily purified from serum with good recoveries, and used to produce a monospecific antiserum. The method of isolation of C4c is based on the observation that C4 is easily activated and fragmented in mouse serum. The fragments bind to the C4-binding protein (C4-bp), a newly described macromolecular component of the complement system. The high m.w. complexes were precipitated by dialysis of the serum against 0.1 M acetate buffer, pH 5.0, and purified by passage of the dissolved precipitate through a Sephadex G-200 column. The complexes were dissociated at high salt concentration, and the C4 fragments were isolated by passage of the mixture through a second Sephadex G-200 column. One of the C4 fragments (C4c) was used to immunize rabbits, and a monospecific antiserum was obtained, which showed a reaction of identity between C4 and Slp. Therefore the C4c fragment of C4 and the Slp protein are structurally related.

Animals↗
PubMed1998

Hemin binding and oxidation of lipoproteins in serum: mechanisms and effect on the interaction of LDL with human macrophages.

Most models of lipoprotein oxidation by free radicals have excluded macromolecular plasma components from the system. This limits their biological significance because oxidation of lipoproteins appears to occur in the intima in the presence of a plasma ultrafiltrate. Hemin, a product of in vivo hemoglobin degradation, binds and oxidizes purified lipoproteins. However, it is not known whether this occurs in the presence of plasma components that may sequester hemin. We found that hemin in serum diluted to protein levels of the extracellular fluid (10-30%) binds to low and high density lipoproteins (LDL, HDL) with association constants in the nmol/L range. In the presence of H2O2, hemin oxidizes both lipoproteins in diluted serum with formation of conjugated dienes, thiobarbituric acid reacting substances, and F2-isoprostanes. This appeared to be caused by the high affinity of hemin with LDL and by the Fe3+ liberated that remains associated with the particles after hemin is degraded. Spectrophotometric and fluorescence experiments and electrophoresis of porphyrins complex with LDL indicated that the heme ring is buried in the lipoprotein surface-monolayer with the carboxylic groups in contact with positive regions of the protein and the solvent. Human macrophages associated and degraded 3- to 4-times more hemin-oxidized LDL in diluted serum than native LDL. It is possible then that at sites of LDL, accumulation in the extracellular intima, hemin and H2O2 production could cause oxidation with potential atherogenic consequences for cellular lipoprotein processing. This may occur even when other macromolecules of the extracellular fluid are present.

Biological Transport↗
PubMed2003

Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications.

Most solid tumors are known to exhibit highly enhanced vascular permeability, similar to or more than the inflammatory tissues. Common denominators affecting both cancer and inflammatory lesions are now well known: bradykinin (BK), nitric oxide (NO), peroxynitrite (ONOO(-)), prostaglandins (PGs), collagenases or matrix metalloproteinases (MMPs) and others. Incidentally, enzymes involved in these mediator syntheses are upregulated or activated. Initially described vascular permeability factor (VPF) (proteinaceous) was later identified to be the same as vascular endothelial growth factor (VEGF), which promotes angiogenesis of cancer tissues as well. These mediators cross-talk or co-upregulate each other, such as BK-NO-PGs system. Therefore, vascular permeability observed in solid tumor may reflect the other side of the coin (angiogenesis). The vascular permeability and accumulation of plasma components in the interstitium described here is applicable for predominantly macromolecules (molecular weight, Mw>45 kDa), but not for low molecular compounds as most anticancer agents are. Macromolecular compounds (e.g., albumin, transferrin) or many biocompatible water-soluble polymers show this effect. Furthermore, they are not cleared rapidly from the sites of lesion (cancer/inflammatory tissue), thus, remain for prolonged time, usually for more than a few days. This phenomenon of "enhanced permeability and retention effect" observed in cancer tissue for macromolecules and lipids is coined "EPR effect", which is now widely accepted as a gold standard for anticancer drug designing to seek more cancer-selective targeting using macromolecular drugs. Consequently, drastic reduction of the systemic side effect is observed, while the macromolecular drugs will continuously exert antitumor activity. Other advantages of macromolecular drugs are also discussed.

Animals↗