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PubMedDate not supplied

Protein kinase C: an example of a calcium-regulated protein binding to membranes (review).

The location of the calcium-binding domain on protein kinase C is being addressed by mutational and structural studies. This work can be complemented by detailed studies of the properties of the binding of the enzyme to membranes. These binding studies have revealed a number of unique pieces of information about the properties of Ca(2+)-prompted membrane partitioning, including the fact that there is only one Ca(2+)-binding site which regulates the partitioning of the enzyme and that this site is located 0.3 nm from the membrane interface. Furthermore, the binding of protein kinase C to membranes has been shown to enhance the affinity of the enzyme for Ca(2+) by several orders of magnitude. We illustrate how contributions of the interactions of proteins with other molecules also affect the concentration of calcium required to affect membrane partitioning. Only when all of these factors are considered can a quantitative description of Ca(2+)-regulated protein binding to membranes be achieved. Thus conformational studies, together with classical thermodynamic studies, can provide a more detailed understanding of the functional, as well as, the structural, properties of amphitropic proteins.

Binding Sites↗

PubMed1986

Ultrastructural histochemical evaluation of growth plate cartilage matrix from healthy and osteochondritic swine.

A contributing factor to the lack of understanding the cause of osteochondritic syndromes has been incomplete knowledge of the morphology of lesions in subclinical stages of the disease. In osteochondritic growth plate cartilage from growing swine, the morphology of the pericellular matrix surrounding hypertrophic zone chondrocytes is abnormal and is characteristic of a matrix in which the ordered interactions of matrix macromolecules with each other and with the plasma membrane have been altered. In the present study, ultrastructural histochemical techniques were used to analyze the nature of macromolecular interactions in the pericellular matrix in normal growth plate cartilage, and selective enzyme digestions of normal growth plate cartilage were used to simulate the morphology found in osteochondritic lesions. Results showed that a pericellular macromolecular material which was both ferrocyanide positive and trypsin sensitive was essential for stabilizing the cell membrane/pericellular interface in normal growth plates. The highly variable morphology of this same material in osteochondritic lesions was simulated by hyaluronidase digestion. Since similar pericellular matrix abnormalities have not been described in other diseases of growth plate cartilage, they may represent a matrix abnormality unique to the vascularization failure of osteochondritic syndromes. Our ability to simulate the ultrastructural morphology of subclinical osteochondritic lesions enhances the potential for understanding the macromolecular changes found in the pericellular matrix of osteochondritic cartilage. Based on these results, a new hypothesis is presented for the early sequence of events in the pathogenesis of osteochondrosis.

Animals↗

PubMed2001

The many essential interfaces of clinical pharmacology.

1. Clinical pharmacology requires numerous skills and most activities involve interactions with other specialities, both clinical and experimental. 2. A range of experts has had a major influence on the nature and design of my research, which is illustrated by the evolution of my knowledge of adverse drug reactions and how to prevent them. 3. Clinical pharmacologists are uniquely placed to coordinate programmes to achieve quality use of medicines. but we will only achieve our aims if multiple interactions with other experts are encouraged and developed.

Adverse Drug Reaction Reporting Systems↗

PubMed2002

The operating version of the Eye Tracker, a system to measure saccadic eye movements.

The operating version of the Eye Tracker, a transducer and system using a technique to bounce infrared light off the eye to measure saccadic eye movements in any X-Y position is presented in this paper. Discussed is the method of reading and analyzing eye movement data using a 24-channel infrared optoelectronic array and computer algorithms that utilize a linear regression model to interpret and determine eye location, the 24-channels used to ensure accurate reading of eye position. Accuracy is also maintained by a signal processing system that attenuates incident light as well as ambient light. Also discussed is a novel method of mounting the infrared array on hemispherical shaped eyepieces that in turn are mounted on goggles styled after an ophthalmologist's test frames that is comfortably worn and adjustable in size to fit any subject. A computer controlled, wall mounted light bank facilitates targeting for eye movements. The Eye Tracker is built to meet standards of a professional medical device manufacturer following typical mechanical, electrical, and safety techniques unique to device packaging.

Diagnosis, Computer-Assisted↗

PubMedDate not supplied

A unique feature of lipid dynamics in small intestinal brush border membrane.

The lipid composition of the brush border membrane (BBM) or apical plasma membrane of enterocytes is characterized by a remarkably high glycosphingolipid content (glycosphingolipid: phospholipid:neutral lipid mole ratio of about 1:1:1). A manifestation of the high glycolipid content of the BBM is the lipid fluidity which is low compared to other mammalian plasma membranes and related to it a steep flexibility gradient: hydrocarbon chain segments close to the lipid-water interface have quasi-crystalline packing while hydrocarbon chain segments close to the centre of the lipid bilayer behave like a fluid. An important function of the BBM is the absorption of dietary lipids. The absorption of cholesterol from bile salt micelles has been shown to be protein-mediated. The integral membrane protein responsible for this activity has features similar to non-specific lipid transfer proteins. Another remarkable property of the BBM is described here: phospholipids are exchanged between the lipid bilayer of the BBM and the lipid bilayers of small unilamellar egg phosphatidylcholine (PC) vesicles. In the course of this probably 1:1 exchange, endogenous BBM phospholipids move out of the BBM and the lipid loss is compensated by the insertion of exogenous PC from the small unilamellar vesicles. This exchange activity is probably due to the same protein(s) responsible for lipid absorption in this membrane or at least related to the absorptive capacity of the BBM. The unique feature of small intestinal BBM is that the on- and off-rate of certain lipids is remarkably high: the underlying structure of this activity is still unknown.

Animals↗

PubMed2006

Electrochemistry of TEMPO in the aqueous liquid/vapor interfacial region: measurements of the lateral mobility and kinetics of surface partitioning.

A new method is described to simultaneously determine the kinetics of surface partitioning and the lateral diffusion constant of redox active amphiphiles. It concerns water-soluble amphiphiles for which the surface adsorption equilibrium constant and the solution diffusion constant are measured independently. The method involves cyclic voltammetric experiments carried out at the air/water interface with microband electrodes aligned with the plane of the water surface. Typically, 100 nm wide, 1.0 cm long microband electrodes are fabricated by the vacuum vapor deposition of gold films on glass. The front face of the electrode substrates are coated with impermeable, dimensionally stable, polymer barrier films with thickness L in the range of approximately 0.1-1.0 microm. Fracturing such gold-coated glass substrates exposes gold microbands. The recorded voltammetric current sensitively depends on the barrier film thickness, the surfactant surface diffusion constant, Dsurf, and its rate constant of desorption, kdes. For a given surfactant, such as the nitroxyl piperidine free radical TEMPO featured in this report, large currents are observed with microband electrodes that do not carry a barrier film (L = 0). This is because the surfactant surface population diffusing along the air/water interface can be directly electro-oxidized at the edge of the microband. Smaller currents are measured in the presence of a barrier film, since, in those instances, the surface population may contribute to the voltammetric current only via a mechanism involving surfactant desorption from the water surface into bulk, where it contributes to the three-dimensional solution diffusion processes. The quantitative interpretation of the voltammetric experiments was made possible with finite element simulations with FEMLAB. These produce a set of calibration curves, Dsurf versus log kdes, for each value of the barrier film thickness. The intersection of the calibration curves determines the unique values of Dsurf and kdes. For TEMPO, Dsurf = 4.4 +/- 1.2 x 10(-5) cm2/s and kdes >/= 2 x 10(4) s(-1). Surfactant desorption rate constants of this magnitude have not been previously experimentally accessible. Since, in our earlier report (Wu, D. G.; Malec, A. D.; Head-Gordon, M.; Majda, M. J. Am. Chem. Soc. 2005, 27, 4490-4496), we showed that TEMPO is not immersed in water and that it diffuses along the interface hydrogen-bonded to just one or two water molecules, its Dsurf value approximates the water diffusion constant in the aqueous liquid-vapor interfacial region.

Journal Article↗

PubMed1982

Glial outgrowth along spinal nerve roots in amyotrophic lateral sclerosis.

Formation of glial bundles in the proximal portion of the ventral nerve roots is described in a 51-year-old patient with the sporadic form of amyotrophic lateral sclerosis (ALS). Although the bundles were relatively fewer, they were identical in morphology and distribution to those consistently found in Werdnig-Hoffmann disease (WHD). The occurrence of glial bundles in ALS, albeit rare, indicates that this phenomenon is not a unique feature of WHD. Similar changes have been observed in several other unrelated conditions, always in association with degeneration of neurons or axons. Thus, outgrowth of astrocytes in the form of glial bundles should be considered a special type of astrocytic reaction at the interface of the central and peripheral nervous systems.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Helix-helix packing in a membrane-like environment.

The unique ability of the glycophorin A transmembrane helix to dimerize in SDS has previously been exploited in studies of the sequence specificity of helix-helix packing in a micellar environment. Here, we have made different insertion mutants in the critical helix-helix interface segment, and find that efficient dimerization can be mediated by a wider range of sequence motifs than suggested by the earlier studies. We also show that certain mutants that are unable to dimerize can nevertheless form relatively high amounts of tetramers, and that specific tetramerization can be induced by duplication of the critical interface motif on the lipid-exposed side of the transmembrane helix.

Alanine↗

PubMedDate not supplied

A fibrin matrix modulates the proliferation, hormone secretion and morphologic differentiation of cultured human placental trophoblast.

Term placental trophoblast epithelialize fibrin deposits attached to villi in vitro and trophoblast cultured on a fibrin matrix form an epithelial bilayer typical of the trophoblast layer on term villi. We compared the morphology of cells grown on fibrin with cells grown on substrates of type IV collagen, laminin, type I collagen, or Matrigel. We also used autoradiography, hormone assays, electron microscopy, and immunofluorescence to determine what functional activities were influenced by trophoblast-fibrin interactions. Cultured cellular trophoblast from term placentae differentiated to form syncytial trophoblast and to secrete estrogen, progesterone, and hCG in the presence or absence of matrices. Trophoblast proliferation was lower in cells grown on matrices and was inversely related to cell height after 24 h in culture. Cells grown on fibrin remained the tallest and had the lowest labelling index. Cells grown for 72 h on fibrin had the most dilated rough endoplasmic reticulum but the lowest media hormone levels. Only cells grown on a fibrin matrix formed a basal lamina-like structure at the trophoblast-substrate interface, and only a fibrin matrix facilitated trophoblast to form an epithelial bilayer in culture. However, this histology was not accompanied by a change in the amount of syncytial trophoblast formed by the cells grown on fibrin. The results suggest that a fibrin matrix uniquely modulates the trophoblast phenotype, away from the secretion of placental specific products like hCG in favour of a repair-oriented phenotype that forms basement membrane and a trophoblast bilayer.

Cell Differentiation↗

PubMed1993

TGF-beta 2 gene and protein expression in maternal and fetal tissues at various stages of murine development.

The transforming growth factor beta family of peptides have diverse actions on the reproductive tracts of primates and rodents. In this study we report the expression of high levels of mRNA of one member of this superfamily, TGF-beta 2, in the pregnant mouse uterus. Using Northern blot analysis and in situ hybridization techniques, we have examined the pattern of expression of TGF-beta 1, TGF-beta 2 and colony-stimulating factor (CSF-1) in mouse maternal and fetal tissue at specific days of gestation. We report here that TGF-beta 2 is synthesized primarily in maternal decidual and uterine epithelial tissues. We observed a shift in the major site of synthesis from decidua to uterus between days 8.5 and 10.5 of gestation. These data demonstrate that the expression of TGF-beta 2 is differentially regulated in the decidua and uterine epithelial cells at various times during gestation. Small amounts of TGF-beta 2 mRNAs were detected in the fetus, and none was detected in placenta, yolk sac, or amniotic membrane. The uterus is likely the major site of synthesis of the TGF-beta 2 found in mouse amniotic fluid. TGF-beta 1 mRNAs are expressed in the uterus at markedly lower levels when compared to TGF-beta 2 mRNAs in both the decidua and uterus. Our results suggest that there is a unique regulation of TGF-beta 2 during pregnancy which may depend on pregnancy hormone(s) and differentiates it from the other mammalian isoforms of the TGF-beta s. TGF-beta 2 may play an important, albeit unknown, role at the maternal/fetal interface.

Amniotic Fluid↗

PubMed2006

The structure of CorA: a Mg(2+)-selective channel.

The crystal structure of a closed form of the CorA Mg2+ transporter from Thermatoga maritima completes a set of representative structures of transport systems for all of the major biological elements, Mg2+, Ca2+, Na+, K+ and Cl-. The CorA monomer has a C-terminal membrane domain containing two transmembrane segments and a large N-terminal cytoplasmic soluble domain. In the membrane, CorA forms a homopentamer shaped like a funnel. Comparison of the structure of CorA with that of other ion channels and transporters suggests numerous common features, but, as might be predicted from the unique chemistry of the Mg2+ cation, the structure of CorA has several unusual features. Among these are initial binding in the periplasm of a fully hydrated Mg2+ ion; a ring of positive charge external to the ion-conduction pathway at the cytosolic membrane interface; and highly negatively charged helices in the cytosolic domain that appear capable of interacting with the ring of positive charge to facilitate Mg2+ entry. Finally, there are bound Mg2+ ions in the cytosolic domain that are well placed to control the interaction of the ring of positive charge and the negatively charged helices, and thus control Mg2+ entry.

Bacteria↗

PubMed1999

The Internal Medicine Center--an integrated solution for information on internal medicine on the World Wide Web.

The World Wide Web (WWW) has grown from being a resource center for a select group of scientists to a large database of information that is available to both professionals and public. The amount of medical information on the Web has been increasing exponentially and thus, it has become increasingly difficult for anyone to be able to search for a specific quantum of information among this mass. Even in mid 1996, it was noted that the amount of information on internal medicine was growing rapidly. Hence, on 21 March 1997, the Internal Medicine Center (IMC) was created and launched. The IMC is an unique concept and it represents the first time that medical data on the web has been organized into a form that intimately parallels clinical medicine. The rationale behind the creation of the IMC can be summarized in three words: information, speed and convenience. The interface used by this center reflects these goals because overuse of large image files are avoided, hence decreasing the access time and yet keeping the information in an easily comprehensible manner. In conclusion, the IMC serves as a useful tool for the layman as well as the expert because the comprehensive information that it offers can be accessed rapidly and conveniently.

Information Services↗

PubMed1998

An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells.

Vascular endothelial growth factor (VEGF) is a potent mitogen with a unique specificity for endothelial cells and a key mediator of aberrant endothelial cell proliferation and vascular permeability in a variety of human pathological situations, such as tumor angiogenesis, diabetic retinopathy, rheumatoid arthritis, or psoriasis. VEGF is a symmetric homodimeric molecule with two receptor binding interfaces lying on each pole of the molecule. Herein we report on the construction and recombinant expression of an asymmetric heterodimeric VEGF variant with an intact receptor binding interface at one pole and a mutant receptor binding interface at the second pole of the dimer. This VEGF variant binds to VEGF receptors but fails to induce receptor activation. In competition experiments, the heterodimeric VEGF variant antagonizes VEGF-stimulated receptor autophosphorylation and proliferation of endothelial cells. A 15-fold excess of the heterodimer was sufficient to inhibit VEGF-stimulated endothelial cell proliferation by 50%, and a 100-fold excess resulted in an almost complete inhibition. By using a rational approach that is based on the structure of VEGF, we have shown the feasibility to construct a VEGF variant that acts as an VEGF antagonist.

Binding Sites↗

PubMed2004

MultiPLX: automatic grouping and evaluation of PCR primers.

UNLABELLED: MultiPLX is a new program for automatic grouping of PCR primers. It can use many different parameters to estimate the compatibility of primers, such as primer-primer interactions, primer-product interactions, difference in melting temperatures, difference in product length and the risk of generating alternative products from the template. A unique feature of the MultiPLX is the ability to perform automatic grouping of large number (thousands) of primer pairs. AVAILABILITY: Binaries for Windows, Linux and Solaris are available from http://bioinfo.ebc.ee/download/. A graphical version with limited capabilities can be used through a web interface at http://bioinfo.ebc.ee/multiplx/. The source code of the program is available on request for academic users. CONTACT: maido.remm@ut.ee.

Algorithms↗

PubMed1999

Crystal structure of a tandem pair of fibronectin type III domains from the cytoplasmic tail of integrin alpha6beta4.

The integrin alpha6beta4 is an essential component of hemidesmosomes but it also plays a dynamic role in invasive carcinoma cells. The cytoplasmic tail of the beta4 subunit is uniquely large among integrins and includes two pairs of fibronectin type III domains separated by a connecting segment. Here we describe the crystal structure of the first tandem domain pair, a module that is critical for alpha6beta4 function. The structure reveals a novel interdomain interface and candidate protein-binding sites, including a large acidic cleft formed from the surfaces of both domains and a prominent loop that is reminiscent of the RGD integrin-binding loop of fibronectin. This is the first crystal structure of either a hemidesmosome component or an integrin cytoplasmic domain, and it will enable the intracellular functions of alpha6beta4 to be dissected at the atomic level.

Amino Acid Sequence↗

PubMed2002

Painting with a molecular brush: genomic/proteomic interfacing to define the drug action profile of novel solid-tumor selective anticancer agents.

XK469 is an investigational anticancer agent that exhibits antiproliferative activity in tumor-bearing animal models. We examined the drug-action profile of this agent at the molecular level regarding alterations induced in gene expression and proteins in HCT-116 human colon adenocarcinoma cells. We used a unique cDNA microarray (GeneMap(TM) Cancerarray) comprising 1152 human tumor-related genes and 2-D gel electrophoresis, respectively, following a 24-hour exposure to a drug concentration that killed a two-log fraction of HCT-116 clonogenic cells. Functional gene cluster profile (FGCP) analysis of the 71 out of 1152 genes that displayed a >2-fold increase or decrease in expression (over untreated control) identified a drug-specific involvement of the MAPK signal transduction pathway. MAPK signaling together with the involvement of ubiquitin proteins from 2-D gel electrophoresis suggest a novel drug-action profile at the molecular level for the in vitro antiproliferative activity of XK469.

Adenocarcinoma↗

PubMed1996

Some perspectives on the interpretation of proton NMR spin diffusion data in terms of polymer morphologies.

Proton spin diffusion data yield morphological information over dimensions covering approximately the 2-50 nm range. In this article, the interpretation of such data for polymers is emphasized, recognizing that the mathematical framework for much of this interpretation already exists in the literature. Practical issues are considered, for example, a useful scaling of plotted data is suggested, key attributes of the data are identified and ambiguities in the mapping of data into morphological models are spelled out. Discussion is limited to two-phase systems, where it is assumed that, by employing multiple-pulse methods polarization gradients can be generated, whose spunal sharpness is limited solety by the morphological definition of the interfaces. Interpretation of data in terms of morphology and stoichiometry is emphasized, where stoichiometric issues pertain only to chemically heterogeneous systems. Extraction of stoichiometric information from spin diffusion data is not commonly attempted; the discussion included herein allows for the possibility that the composition of phases may be chemically mixed. Methods for generating gradients are discussed only briefly. A standardized spin diffusion plot is proposed and the initial slope of this plot is tocussed on for providing information about morphology and stoichiometry. Ambiguities of interpretation considered include the dimensionality of the deduced morphology and, for systems with chemical heterogeneity the uniqueness of the compositional characterization of each phase. In addition, funite difference methods are used to simulate entire spin diffusion curves for idealized lamellar and hexagonal rod/matrix morphologies. Comparisons of these curves show that distinguishing 1-D and 2-D morphologies on the basis of experimental data is unlikely to be successful over the range of stoichiometrics where such morphologies are expected. Several examples of spin diffusion data are presented. Brief treatments of the following topics are included: finite interface width, estimation of spin diffusion constants, and incorporation of longitudinal relaxation effects. Finally, a short experimental discussion on the preparation of polarization gradients is given including those preparations which make use of differences in the multiple-pulse relaxation time, T1xz. It is noted that T1xz decays may be strongly perturbed in the presence of magic angle spinning, therefore, strategies are also outlined for minimizing these effects.

Chemical Phenomena↗

PubMed1990

Relaxometry of brain: why white matter appears bright in MRI.

The remarkable success of magnetic resonance imaging of adult brain relates to the unusually large ratio of the longitudinal relaxation rates 1/T1 of white and gray matter, approximately 2:1 at physiological temperature and traditional imaging fields. Several investigators have conjectured that myelin is the source of the greater 1/T1 of white matter without, however, suggesting details of the molecular mechanisms responsible. From measurements of the magnetic field dependence of 1/T1 (NMRD profiles) of adult and neonatal gray and white matter at 5 and 35 degrees C, we find a thermally activated contribution to the NMRD profile of adult white matter that is not present in the profiles of either adult gray or neonatal gray and white matter. We attribute this contribution to myelin and develop a quantitative model that accounts for the unique relaxation behavior of myelinated white matter. We find that myelin water, 15% of the total, has a relatively short T1 that arises from an unexpectedly large interaction with myelin lipid; when cast in terms of an interaction over the entire myelin bilipid-water interface, it is sevenfold greater than the analogous protein-water interfacial interaction. Its magnitude remains to be accounted for, but cholesterol, known to alter the relaxation rates of lipid protons, may play an important role. The contribution of myelin to 1/T1 at physiological temperatures is attributed to thermally activated transmembrane diffusion of water and, hence, more rapid mixing of axonal and the rapidly relaxing myelin water molecules.

Adult↗