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PubMed1976

Adsorption of albumin on rabbit sperm membranes.

When mammalian sperm cells are exposed to solutions of albumin there are changes in the membranes of some species that resemble those that normally occur in the uterus prior to fertilization. We have shown that albumin molecules absorb on to the membranes of ejaculated rabbit sperm cells, and that the equilibrium binding constant, K, (1) varies inversely with the albumin concentration, (2) is independent of the sperm cell concentration in the range of 10(6)--10(7) per ml, (3) is independent of the time of exposure of the sperm cells to the albumin solution, and (4) decreases in the presence of Ca++ and Mg++ ions. An unusual aspect of the adsorption is that if the albumin concentration is given the symbol [A], K[A] is a constant in our measurements. This means that for virtually the entire range of [A] studied, the sperm cells bind albumin so that half of the available surface is coated and half remains uncoated. This situation is rather remarkable and it suggests a role that adsorption could play in the physical processes preceding fertilization. In purely physical systems, the optimum for the bridging and flocculation of particles that are coated with adsorbed macromolecular films occurs when half of the available surface is covered. The sperm cell appears to provide the optimal situation for interacting with itself or with another surface.

Adsorption↗
PubMed2006

In vitro and in vivo metabolism of paclitaxel poliglumex: identification of metabolites and active proteases.

BACKGROUND: The efficacy and tolerability of paclitaxel is limited by its low solubility, high systemic exposure, and a lack of selective tumor uptake. Paclitaxel poliglumex (PPX; XYOTAX) is a macromolecular drug conjugate that was developed to overcome these limitations; the 2' hydroxyl group of paclitaxel is linked to a biodegradable polymer, poly-L: -glutamic acid, to form an inactive polymeric conjugate. PPX was previously shown to accumulate in tumor tissue, presumably by taking advantage of the hyperpermeable tumor vasculature and suppressed lymphatic clearance in tumor tissue. METHODS: Because anti-tumor activity requires the release of paclitaxel from the polymer-drug conjugate, the current report characterizes PPX biodegradation and release of paclitaxel as determined by quantitative HPLC/mass spectral analysis. RESULTS: The identification of monoglutamyl-paclitaxel metabolites in tumor tissue confirmed the in vivo metabolism of PPX in a panel of mouse tumor models. In vitro characterization of the metabolic pathway suggests that PPX can enter tumor cells, and is metabolized to form both mono- and diglutamyl-paclitaxel cleavage products. The intracellular formation of these intermediate metabolites is at least partially dependent on the proteolytic activity of the lysosomal enzyme cathepsin B; PPX metabolism is inhibited by a highly selective inhibitor of cathepsin B, CA-074. Reduced metabolism of PPX in livers and spleens from cathepsin B deficient mice confirms that cathepsin B is an important mediator of PPX metabolism in vivo; however, other proteolytic enzymes may contribute as well. CONCLUSIONS: The cathepsin B-mediated release of paclitaxel may have therapeutic implications as cathepsin B is upregulated in malignant cells, particularly during tumor progression.

Animals↗
PubMed1982

The design and use of a hydraulically operated upward pressure-jump.

The construction of a hydraulically operated upward pressure-jump is described. Previous instruments with a comparable rate of pressurization used helium gas to pressurize an observation cell to approximately half of the operating pressure reached with the present design. The above instrument, which can pressurize the observation cell in 1.8-3.8 ms, is safe to use and has a maximum working pressure of 30 MPa (300 atm). The device is compact in design and can easily be fitted to any observation cell capable of withstanding the transient change in pressure and of effectively damping cell resonances. The instrument finds specific application in the study of macromolecular equilibria with a large difference in volume between the equilibrium partners. This allows the system to be perturbed far from the equilibrium position at atmospheric pressure; the relaxations obtained can be analysed as essentially unidirectional processes. Kinetic data for the reverse reaction would be obtained from experiments in a conventional downward pressure-jump. A study on the kinetics of the self-assembly of the myosin thick-filament is presented as a practical example.

Animals↗
PubMed1994

The concentration dependence of the activity coefficient of the human spectrin heterodimer. A quantitative test of the Adams-Fujita approximation.

The heterodimer and tetramer states of human spectrin, in equilibrium at 30 degrees C, have been resolved by means of sedimentation velocity experiments at low temperature. This has allowed quantification of the concentrations of each oligomer at equilibrium, as a function of the total concentration of spectrin. In separate sedimentation equilibrium experiments, the thermodynamic activity of the heterodimer has been estimated as a function of the total spectrin concentration through the use of the Omega function. Combination of the concentration and thermodynamic activity of the spectrin heterodimer allowed estimation of the activity coefficient of the heterodimer as a function of total spectrin concentration. Over the accessible concentration range of 0-16 g/L, the logarithm of the activity coefficient of the heterodimer was linear in the total concentration, and the apparent equilibrium constant for tetramer formation was only weakly dependent on concentration, implying that a single virial coefficient is sufficient to describe the nonideality of this system over this concentration range.

Humans↗
PubMedDate not supplied

Effect of therapeutic macromolecules in spheroids.

Recent advances in biotechnology have allowed the production of new types of macromolecular therapeutic agents (antibodies, immunotoxins, cytokines, extracellular matrix molecule (ECM) proteins, vectors) that may eventually find broad clinical applications in the treatment of human tumors and other diseases. The model of the Multicellular Tumor Spheroids (MTS) represents a valuable tool to test the therapeutic potential of these new pharmacologic agents in a 3-D context. Specific questions pertaining to the behaviour in a 3-D setting of some of the macromolecules under evaluation for in vivo applications can also be addressed in the MTS model (e.g. 'binding site barrier', role of cell-cell and cell-ECM interactions). This paper reviews the most significant contributions regarding the delivery of macromolecules to MTS, the penetration and therapeutic effects of antibodies, radiolabelled antibodies, immunotoxins and other macromolecular compounds.

Antineoplastic Agents↗
PubMed2006

Stereoisomer discrimination in complexes of halogen-substituted difuranes and Li or Na cations.

The theoretical study of the stereoisomer discrimination of the 2:1 homo- and heterochiral complexes between chiral 5,5'-dihalogen bifuranes and lithium or sodium cations has been carried out using DFT methods. To understand the chiral effect produced by the introduction of a second bifurane molecule, the 1:1 complexes also have been calculated. All the 2:1 heterochiral complexes computed showed a nonplanar configuration around the metallic cation, but in the case of the homochiral complexes, the dibromo- and dichloro-bifurane systems around Na+ were quasi-planar. The nature of the interactions established between cations and bifurane systems has been analyzed by means of AIM and NBO, and correlations between the electron density topological parameters with the O...M distance and with the orbital interaction energy have been found. Stereodiscrimination is observed favoring the heterochiral complexes except for the Na+ complexes with chloro and bromo substituents in which the homochiral forms are more stable. Stereodiscrimination values correlate with the difference in electron density at the bond critical point and orbital interaction energy between homo- and heterochiral systems.

Cations↗
PubMed2002

Toward novel polyacetals by transacetalation techniques: dendrimeric diacetals.

[structure: see text] A new approach to polyacetal systems using sequential transacetalation and protection-deprotection techniques was developed for the preparation of macromolecular polyacetals and applied to secure new dendrimers with 2,4,8,10-tetraoxaspiro[5,5]undecane dendrons from pentaerythritol and polyaldehydes. These novel dendrimers, featuring a 1,3,5-benzene-tricarbaldehyde core, viz., the dodecaol (18) and its hexaacetal (19), were prepared, and molecular modeling revealed peculiar dendron convergent structures above the core, due to intramolecular pi-stacking interactions, reinforced by H-bonding of multifunctional termini.

Acetals↗
PubMed1996

Cancer prevention by adoptive transfer of antigen 60-activated immunocompetent cells.

The authors have already shown that A60, the thermostable macromolecular antigen complex of Mycobacterium bovis BCG, induced resistance to tumour challenge in several murine systems. In the present work, the authors provided evidence that activated macrophages played a major role, and cytolytic T lymphocytes a minor one, in both in vivo and in vitro A60-promoted cancer cell cytolysis. To identify the types of immunocompetent cells involved in this protective effect, macrophages and T lymphocytes from A60-primed mice donors were adoptively transferred to irradiated recipients prior to EMT 6 tumour challenge. In some groups, A60-primed donors were survivors of previous tumour challenges. Transfer of T lymphocytes from the spleen or lymph-nodes of A60-immunized mice induced 80-90% protection against tumour challenge. Conversely, transferred macrophages, although cytolytically active, did not induce resistance to tumour implantation. Furthermore, adoptive transfer with T lymphocytes from A60-immunized and EMT 6 challenge-surviving donors induced 100% protection. It is concluded that stimulation of T lymphocytes by A60 is the key step which leads to activation of the immunocompetent cells involved in tumour rejection.

Animals↗
PubMed2003

Affinity purification-mass spectrometry. Powerful tools for the characterization of protein complexes.

Multi-protein complexes are emerging as important entities of biological activity inside cells that serve to create functional diversity by contextual combination of gene products and, at the same time, organize the large number of different proteins into functional units. Many a time, when studying protein complexes rather than individual proteins, the biological insight gained has been fundamental, particularly in cases in which proteins with no previous functional annotation could be placed into a functional context derived from their 'molecular environment'. In this minireview, we summarize the current state of the art for the retrieval of multiprotein complexes by affinity purification and their analysis by mass spectrometry. The advances in technology made over the past few years now enable the study of protein complexes on a proteomic scale and it can be anticipated that the knowledge gathered from such projects will fuel drug target discovery and validation pipelines and that the technology is also going to prove valuable in the emerging field of systems biology.

Animals↗
PubMed2002

Molecules within molecules: recognition through self-assembly.

Synthetic molecular receptors that completely surround their target molecules can be created through the use of noncovalent interactions. These molecular capsules selectively sequester guest molecules from the influence of bulk solvent and other molecules on the basis of size, shape, and chemical complementarity. This reversible isolation spawns unique behavior within the confines of the host; the catalysis of chemical reactions and the stabilization of reactive species are possible outcomes that have been recently demonstrated. Compartmentalization of reagents can also have a dramatic effect on reactions that take place outside of the capsule, producing nonlinear kinetics in relatively simple reaction systems.

Catalysis↗
PubMed1997

DNA damage-dependent recruitment of nucleotide excision repair and transcription proteins to Escherichia coli inner membranes.

The entire process of nucleotide excision repair (NER) in Escherichia coli has been reconstituted in vitro from purified proteins and defined DNA substrates. However, how this system is organized in vivo in unclear. We report here the isolation and characterization of macromolecular assemblies containing NER and transcription proteins from E. coli. This ensemble consists of at least 17 proteins. They are recruited, as a consequence of DNA damage induced by UV irradiation, to the inner membrane. The UV-induced 6-4 photoproducts are also relocated to the inner membrane following UV-irradiation of the cells. This recruitment process is dependent on the uvrA, uvrC and recA gene products. These results suggest that at least part of the repair process may associate with the inner membrane and also provide insights into understanding the cellular organization of repair processes.

Adenosine Triphosphatases↗
PubMed1987

Separation of cytoplasmic ribosomal proteins of Microsporum canis.

The cytoplasmic ribosomal proteins of Microsporum canis were characterised in basic-acidic and basic-SDS two-dimensional polyacrylamide gel electrophoresis systems. The small subunit contained 28 proteins and the large subunit 38 proteins. The molecular weights of these proteins were in the range of 32,500 to 7600 and 48,000 to 11,000 in the small and large subunits, respectively. The 80S ribosomes showed 65 and 66 protein spots in basic-acidic and basic-SDS gel systems, respectively.

Electrophoresis, Polyacrylamide Gel↗
PubMed2004

The synaptic vesicle cycle.

Neurotransmitter release is mediated by exocytosis of synaptic vesicles at the presynaptic active zone of nerve terminals. To support rapid and repeated rounds of release, synaptic vesicles undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the docking and priming of the vesicles for another round of exo- and endocytosis. Recent studies have led to a better definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how the vesicular Rab3 protein regulates release by binding to the active zone proteins RIM1 alpha and RIM2 alpha has advanced our understanding of neurotransmitter release. The present review attempts to relate these molecular data with physiological results in an emerging view of nerve terminals as macromolecular machines.

Animals↗
PubMed2005

Magnetization transfer imaging in multiple sclerosis.

Magnetization transfer (MT) is a relatively new way of generating contrast in magnetic resonance (MR) images that is sensitive to the density of the macromolecules found throughout tissue structures such as membranes, myelin, and organelles. MT imaging (MTI) can provide a quantitative measure of macromolecular density, and therefore of tissue damage, and has been applied in the central nervous system in multiple sclerosis (MS) and other diseases. This article introduces the contrast mechanisms behind MTI and gives some practical guidance about implementing MTI and about quantitative analysis of the MT scans. An overview of MT measurements made in animal studies, in postmortem tissue samples, and in other demyelinating diseases attempts to rationalize the pathological basis of changes in MT contrast in MS. The application of MTI to MS is reviewed, with emphasis on the contribution that MTI has made to the current understanding of the MS disease process, both its natural history and the response to treatment. The pathological basis of abnormal MT contrast is still open to debate, with many conflicting reports; indeed, it is unlikely that a simple measure of MT effect will reveal the details of pathology that is a combination of inflammation, demyelination, remyelination, and axonal loss. There is no doubt, however, that MT measurements have contributed to the current understanding of both disease progression and the response to treatment and will prove to be a valuable tool in the future, particularly if more refined techniques can be applied practically in multicenter studies.

Brain↗
PubMed1981

Development of gastrointestinal mucosal barrier. I. The effect of age on intestinal permeability to macromolecules.

Indirect evidence has suggested that increased quantities of antigen may penetrate the intestinal mucosa and enter the systemic circulation during the newborn period compared to adult life. However, no direct measurement of macromolecular transport has been reported as a function of perinatal age. To study this process, we administered 100 mg of tritiated bovine serum albumin ([3H]BSA) by gavage to rabbits at birth, one wk, 2 wk, 6 wk, and one year of age and measured plasma radioactivity 4 hr after gavage. Plasma concentration of trichloroacetic acid insoluble radioactivity and immunoreactive bovine serum albumin radioactivity decreased significantly after one wk of age. When adult animals were gavaged with the same amount of [3H]BSA per body weight as the one-wk-old animals, they failed to transport as much of the antigen as the younger animals. This study, therefore, provides objective evidence that the intestinal mucosal barrier of newborns may be incompletely developed at birth and allow increased intestinal transport of antigens into the circulation.

Age Factors↗
PubMed2004

Sedimentation equilibrium studies.

The reversible formation of protein-protein interactions plays a crucial role in many biological processes. In order to carry out a thorough quantitative characterization of these interactions, it is essential to establish the oligomerization state of the individual components first. The sedimentation equilibrium method is ideally suited to perform these studies because it allows a reliable, accurate, and absolute value of the solution molecular weight of a macromolecule to be obtained. This technique is independent of the shape of the macromolecule under investigation and allows the determination of equilibrium constants for a monomer-multimer self-associating system.

Animals↗
PubMed1975

Purification of mRNA guanylyltransferase and mRNA (guanine-7-) methyltransferase from vaccinia virions.

The sequences m7G(5')pppGm-and m7G(5')pppAm-are located at the 5' termini of vaccinia mRNAs. Two novel enzymatic activities have been purified from vaccinia virus cores which modify the 5' terminus of unmethylated mRNA. One activity transfers GMP from GTP to mRNA and is designated a GTP: mRNA guanylyltransferase. The second activity transfers a methyl group from S-adenosylmethionine to position 7 of the added guanosine and is designated a S-adenosylmethionine: mRNA (guanine-7-)methyltransferase. Advantage was taken of the selective binding of these activities to homopolyribonucleotides relative to DNA to achieve a 200-fold increase in specific activity. The guanylyl- and methyltransferase remained inseparable during chromatography on DNA-agarose, poly(U)-Sepharose, poly(A)-Sepharose, and Sephadex G-200 and during sedimentation through sucrose density gradients suggesting they were associated. A Stokes radius of 5.0 nm, an S20,w of 6.0 and a molecular weight of 127,000 were obtained by gel filtration on Sephadex G-200 and sedimentation in sucrose density gradients. Under denaturing conditions of sodium dodecyl sulfate-polyacrylamide gel electrophoresis two major polypeptides were detected in purified enzyme preparations. Their molecular weights of 95,000 and 31,400 suggested they were polypeptide components of the 127,000 molecular weight enzyme system.

Guanine Nucleotides↗
PubMed2003

Solid state approach in biophoton research.

Main characteristics of the delayed luminescence (DL) emitted in the seconds range from biological systems is analyzed. The correlation between change in DL and cell's organization, and similarity with some characteristics of DL from solid state system suggest to connect DL in biological system to decay of collective electron states, formed during energy and charge transport along the macromolecular ordered structures which form the cell. Results of a proposed soliton model are discussed, together with some phenomenological evidence which emphasize the possibility of using DL measurements as an intrinsic probe in biophysical investigations.

Luminescent Measurements↗