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PubMed1981

Molecular considerations relevant to the mechanism of active transport.

A small group of closely related proteins is responsible for all active transport in animal cells, and inorganic cations are the only substances transported by these enzymes. They share a common kinetic mechanism in which two fundamental conformations participate, each receiving and dispatching substrates from its unique side of the membrane. During transport, the cations must pass through their enzyme to cross the membrane and intense interest is currently focused on the possibility that the path which they follow lies within the interface between two discrete subunits in a dimeric structure. Although 'half-of-sites' behaviour, consistent with this hypothesis, has been reported, it is now known that systematic errors were responsible for this mistaken conclusion. The number of protomers which comprise a functional unit of active transport has not been determined.

Adenosine Triphosphatases↗

PubMed1996

Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle.

Peripheral lung tissue contains large numbers of T cells, strategically located for immune surveillance at the blood-air interface. Given the intensity of antigenic exposure at this site, it is clear that local T-cell activation events require strict control, in order to maintain tissue homeostasis. How this control is achieved in this unique tissue microenvironment is unknown, and the present study sought to elucidate the process via detailed analysis of the surface phenotypic characteristics of freshly isolated lung T cells. We report below that these cells display typical characteristic of 'postactivation', notably elevated basal Ca2+ concentrations, down-modulated T-cell receptors, expression of Ia and 'late' activation antigens and concomitant CD4/CD8. However, levels of interleukin-2 receptor and CD2 expression were below those expected of 'activated' T-cell populations, and virtually all of the cells were found to be in the G0/G1 phases of the cell cycle. These properties bear a remarkable similarity to those of T cells activated in the presence of endogenous tissue (alveolar) macrophages from the lung (see accompanying paper). We hypothesize that they reflect the in vivo operation of an endogenous macrophage-mediated T-cell anergy-induction process, the function of which is to limit the local clonal expansion of T cells in peripheral lung tissue after in situ activation.

Animals↗

PubMed1970

Bilateral symmetry in morphogenesis of embryos.

It is suggested that differentiated embryonic cells have a high specificity of molecular constitution as regards the surface layers surrounding their cellular membranes. Correspondingly, specific interface energies may characterize the early contacts between different cell types. The question is raised whether the morphology of the developing embryo may be understood in terms of cellular arrangements which minimize the total interface energy. Bilateral symmetry prevalent in early embryonic development of higher animals might be understood on the basis of the adoption of such a minimum energy principle if, in addition, one assumes that embryonic development is uniquely determined for a particular species.

Embryology↗

PubMed2003

A mutation in the integrin alphaIIb subunit that selectively inhibits alphaIIb beta3 receptor function.

The alpha(IIb) and alpha(v) integrins have been shown to play a significant role in a variety of disease processes. alpha(IIb)beta(3) is a platelet-specific fibrinogen receptor that is critical for thrombosis and hemostasis. Determination of the basis of ligand recognition by alpha(IIb)beta(3) is essential for modulation of platelet function. To identify alpha(IIb) residues involved in alpha(IIb)beta(3) ligand binding function, cells expressing a constitutively active variant of alpha(IIb)beta(3) were randomly mutagenized and selected for loss of alpha(IIb)beta(3) ligand binding function. One mutant isolated in this manner contained a single amino acid substitution at position 96 in alpha(IIb) (Ser9-->Leu). Cells expressing this alpha(IIb) mutant did not bind the ligand mimetic antibody PAC1 or adhere to fibrinogen. In addition, the mutant receptor did not bind to an RGD affinity matrix. Substitution of conserved serine residues at position 1 in beta strand A of all seven repeats of alpha(IIb) similarly inhibited ligand binding to alpha(IIb)beta(3). alpha(IIb)S96 maps to the central cavity of the beta-propeller fold of the alpha(IIb) subunit immediately adjacent to a structurally important sequence at the center of the alphaand beta subunit interface. In contrast, substitution of the analogous residues in alpha(v) or alpha(4) did not disrupt the ligand binding function of alpha(v)beta(3) or alpha(4)beta(1). These data support a potential unique structural or mechanistic role for this residue in alpha(IIb)beta(3) receptor function.

Amino Acid Substitution↗

PubMed1989

Refined atomic model of glutamine synthetase at 3.5 A resolution.

An atomic model of 43,692 non-hydrogen atoms has been determined for the 12-subunit enzyme glutamine synthetase from Salmonella typhimurium, by methods of x-ray diffraction including restrained least-squares atomic refinement against 65,223 unique reflections. At 3.5 A resolution the crystallographic R-factor (on 2 sigma data) is 25.8%. As reported earlier for the unrefined structure, the 12 subunits are arranged in two layers of six; at the interface of pairs of subunits within each layer, cylindrical active sites are formed by six anti-parallel beta strands contributed by one subunit and two strands by the neighboring subunit. This interpretation of the electron density map has now been supported by comparison with glutamine synthetase from Escherichia coli by the Fourier difference method. Each active site cylinder holds two Mn2+ ions, with each ion having as ligands three protein side chains and two water molecules (one water shared by both metals), as well as a histidyl side chain just beyond liganding distance. The protein ligands to Mn2+ 469 are Glu-131, Glu-212, and Glu-220; those to Mn2+ 470 are Glu-129, His-269, and Glu-357. The two layers of subunits are held together largely by the apolar COOH terminus, a helical thong, which inserts into a hydrophobic pocket formed by two neighboring subunits on the opposite ring. Also between layers, there is a hydrogen-bonded beta sheet interaction, as there is between subunits within a ring, but hydrophobic interactions account for most of the intersubunit stability. The central loop, which extends into the central aqueous channel, is subject to attack by at least five enzymes and is discussed as an enzyme "passive site."

Binding Sites↗

PubMed1991

Ultrasonographic diagnosis of chondromalacia of the femoropatellar joint.

In 35 patients suffering from femoropatellar arthralgia, ultrasound of the cartilage at the femoral side of the FP joint and double contrast computed arthrotomography were obtained. The criteria for chondromalacia in these examination techniques are discussed. In US the sharpness of the cartilage-bone interface and the relative reflectivity of the quadriceps tendon in comparison to the cartilage appeared to be relevant. US seemed to be a very specific technique in comparison with double contrast ARCT, but those patients with unique degeneration of the cartilage of the patella were missed with US (22%). Because US is a non-invasive, cheap and widely available procedure, we believe that US is a very useful screening procedure in the approach of the patient suspected of chondromalacia.

Adolescent↗

PubMed1993

Characterization of placentation-specific binucleate cell glycoproteins possessing a novel carbohydrate. Evidence for a new family of pregnancy-associated molecules.

The ovine binucleate cell-specific glycoproteins recognized by the monoclonal antibody SBU-3 first appear at the initiation of placentation, and their expression continues throughout gestation. These placenta-specific proteins have not been detected in any other adult or fetal sheep tissues and are specific to the materno-fetal interface. The SBU-3 monoclonal antibody recognizes the carbohydrate epitope common to a group of proteins ranging in molecular mass from 30 to 200 kDa whose function during pregnancy remains undefined. The biochemical properties of these uniquely expressed glycoproteins were investigated by analyzing both the carbohydrate and protein portion of the molecules. Analysis of phytohemagglutinin and concanavalin A binding to electrophoretically separated SBU-3 proteins revealed that the major proteins between 40 and 70 kDa bind phytohemagglutinin. In contrast, concanavalin A bound only to minor proteins in the SBU-3 glycoprotein preparation. Analysis of the carbohydrate conjugated to the SBU-3 glycoproteins revealed that the major chains are sialylated O-linked and complex partially sialylated multiple antennary N-linked chains. The presence of N-glycolylneuraminic acid in an N-linked structure indicates the unique nature of this carbohydrate epitope. The differential binding to phytohemagglutinin and concanavalin A provided a method for further purification and characterization of the major protein components with monoclonal antibody immunoaffinity-purified SBU-3 proteins being further separated by concanavalin A-Sepharose chromatography. Microsequence analysis of the major non-concanavalin A-binding proteins (69, 62, and 57 kDa) revealed partial homology to ovine and bovine pregnancy-associated glycoprotein and rabbit pepsinogen F. Immunoblot analysis of the SBU-3 proteins showed cross-reactivity with polyclonal antisera directed against ovine placental-associated glycoprotein and pregnancy-specific glycoprotein B. These results suggest that together these glycoproteins represent members of a binucleate cell-derived family of pregnancy-associated molecules in the ruminant placenta.

Amino Acid Sequence↗

PubMed1998

Human beta-tryptase is a ring-like tetramer with active sites facing a central pore.

Human tryptase, a mast-cell-specific serine proteinase that may be involved in causing asthma and other allergic and inflammatory disorders, is unique in two respects: it is enzymatically active only as a heparin-stabilized tetramer, and it is resistant to all known endogenous proteinase inhibitors. The 3-A crystal structure of human beta-tryptase in a complex with 4-amidinophenyl pyruvic acid shows four quasi-equivalent monomers arranged in a square flat ring of pseudo 222 symmetry. Each monomer contacts its neighbours at two different interfaces through six loop segments. These loops are located around the active site of beta-tryptase and differ considerably in length and conformation from loops of other trypsin-like proteinases. The four active centres of the tetramer are directed towards an oval central pore, restricting access for macromolecular substrates and enzyme inhibitors. Heparin chains might stabilize the complex by binding to an elongated patch of positively charged residues spanning two adjacent monomers. The nature of this unique tetrameric architecture explains many of tryptase's biochemical properties and provides a basis for the rational design of monofunctional and bifunctional tryptase inhibitors.

Amino Acid Sequence↗

PubMed2006

A flexible interface between DNA ligase and PCNA supports conformational switching and efficient ligation of DNA.

DNA sliding clamps encircle DNA and provide binding sites for many DNA-processing enzymes. However, it is largely unknown how sliding clamps like proliferating cell nuclear antigen (PCNA) coordinate multistep DNA transactions. We have determined structures of Sulfolobus solfataricus DNA ligase and heterotrimeric PCNA separately by X-ray diffraction and in complex by small-angle X-ray scattering (SAXS). Three distinct PCNA subunits assemble into a protein ring resembling the homotrimeric PCNA of humans but with three unique protein-binding sites. In the absence of nicked DNA, the Sulfolobus solfataricus DNA ligase has an open, extended conformation. When complexed with heterotrimeric PCNA, the DNA ligase binds to the PCNA3 subunit and ligase retains an open, extended conformation. A closed, ring-shaped conformation of ligase catalyzes a DNA end-joining reaction that is strongly stimulated by PCNA. This open-to-closed switch in the conformation of DNA ligase is accommodated by a malleable interface with PCNA that serves as an efficient platform for DNA ligation.

Amino Acid Sequence↗

PubMed1998

A buried polar interaction can direct the relative orientation of helices in a coiled coil.

Coiled coils consist of bundles of two or more alpha-helices that are aligned in a parallel or an antiparallel relative orientation. The designed peptides, Acid-p1 and Base-p1, associate in solution to form a parallel, heterodimeric two-stranded coiled coil [O'Shea, E. K., Lumb, K. J., and Kim, P. S. (1993) Curr. Biol. 3, 658]. The buried interface of this complex is formed by hydrophobic Leu residues, with the exception of an Asn residue from each strand that is positioned to engage in a buried polar interaction. Substitution of these buried Asn residues by Leu residues results in a loss of structural uniqueness, as evidenced by a lack of a particular helix orientation in the Acid-Base coiled-coil complex [Lumb, K. J., and Kim, P. S. (1995) Biochemistry 34, 8642]. Here, we alter the positions of the Asn residues in the Acid and Base peptides such that a buried polar interaction is only expected to occur when the helices are in an antiparallel orientation. The resulting peptides, Acid-a1 and Base-a1, associate to form a helical heterodimer, as shown by circular dichroism (CD) and equilibrium sedimentation centrifugation. The helix orientation preference has been measured using covalently linked, disulfide-containing heterodimers in which the constituent peptides are constrained to interact in either a parallel or an antiparallel orientation. Although both the parallel and antiparallel heterodimers form stable, helical structures, the antiparallel heterodimer is the predominant species at equilibrium when the heterodimers are allowed to undergo thiol-disulfide exchange. In addition, the antiparallel heterodimer is more stable to chemical denaturation than the parallel counterpart by approximately 2.3 kcal/mol. These results demonstrate that a single buried polar interaction in the interface between the helices of a coiled coil is sufficient to determine the relative orientation of its constituent helices.

Amino Acid Sequence↗

PubMed1997

Determination of ethylenediaminetetraacetic acid as the nickel chelate in environmental water by solid-phase extraction and capillary electrophoresis/tandem mass spectrometry.

An automated extraction procedure using solid-phase extraction (SPE) disk technology was developed for the qualitative and quantitative determination of ethylenediaminetetraacetic acid (EDTA) in water samples. The procedure involves conversion of all free and chelated EDTA present into the nickel EDTA chelate followed by extraction on strong anion exchange extraction disks, A 5 mL water sample is extracted and concentrated to 30 microL. This extract is then analyzed by capillary electrophoresis (CE) using ion spray-tandem mass spectrometry (MS) for selective detection. An amine-coated capillary column is used to separate anions using negative voltage and high electroosmotic flow. A self-aligning liquid junction is used as the CE/MS interface. The sample is injected using field amplification for enhanced concentration detection limits down to 0.15 microgram/L. This detection limit is about five times lower than any report we have found in the literature and provides the unique specificity afforded by mass spectrometry. Total sample preparation and run time was forty minutes per sample, including evaporation steps and capillary rinsing between runs. A tray of 24 vials, including samples and standards, was analyzed for these experiments and was easily finished within one day. These experiments demonstrate that CE/MS can be a rugged, quantitative technique, which, with proper sample preparation and focusing techniques, can compete with the concentration sensitivity of established analytical methods.

Chelating Agents↗

PubMed1994

Harmonic 'signatures' of microorganisms.

The frequency/amplitude effect of various microorganisms exposed to periodic (time varying) electric fields, when proximate to immersed electrodes, has been studied using a novel analytical instrument. The harmonic distribution, in complex signals caused by cells exposed to harmonic free waveforms and occupying part of the electrode/suspension interface volume, was shown to be almost entirely due to the change in the standing interfacial transfer function by the (dielectrically nonlinear) presence of cells. Thus, the characteristic interfacial non-linearity is viewed as variable, being uniquely modulated by the presence of particular cells in the interfacial region. Little can be attributed to bulk (far field) effects. The tendency for subtle (characteristic) signal distortion to occur as a function of particulate (cell or molecular) occupancy of the near electrode interfacial region under controlled current conditions leads to the method of sample characterisation by harmonic (Fourier) analysis. We report here, as a sequel to our original studies (Hutchings et al., 1993; Hutchings and Blake-Coleman, 1993), preliminary results of the harmonic analysis of microbial suspensions under controlled signal conditions using a three-electrode configuration. These data provide three-dimensional graphical representations producing harmonic 'surfaces' for various microorganisms. Thus, cell type differences are characterised by their 'harmonic signature'. The visual distinction provided by these 'surface' forming three-dimensional plots is striking and gives a convincing impression of the ability to identify and enumerate specific microorganisms by acquisition of cell-modulated electrode interfacial Fourier spectra.

Candida↗

PubMed2004

Surface-induced dissociation of ions produced by matrix-assisted laser desorption/ionization in a fourier transform ion cyclotron resonance mass spectrometer.

Intermediate pressure matrix-assisted laser desorption/ionization (MALDI) source was constructed and interfaced with a 6-T Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) specially configured for surface-induced dissociation (SID) studies. First MALDI-SID results in FT-ICR are presented, demonstrating unique advantages of SID over conventional FT-ICR MS ion activation techniques for structural characterization of singly protonated peptide ions. Specifically, we demonstrate that SID on a diamond surface results in a significantly better sequence coverage for singly protonated peptides than SORI-CID. A combination of two effects contributes to the improved sequence coverage: shattering of peptide ions on surfaces opens up a variety of dissociation channels at collision energies above 40 eV, and second, wide internal energy distribution deposited by collision with a stiff diamond surface provides an efficient mixing between the primary reaction channels that are dominant at low internal energies and extensive fragmentation at high internal excitation that results from shattering. Activation of MALDI-generated ions by collisions with surfaces in FT-ICR MS is a new powerful method for characterization and identification of biomolecules

Journal Article↗

PubMed2005

Alpha-methylacyl-CoA racemase from Mycobacterium tuberculosis. Mutational and structural characterization of the active site and the fold.

Alpha-methylacyl-CoA racemase (Amacr) catalyzes the racemization of alpha-methyl-branched CoA esters. Sequence comparisons have shown that this enzyme is a member of the family III CoA transferases. The mammalian Amacr is involved in bile acid synthesis and branched-chain fatty acid degradation. In human, mutated variants of Amacr have been shown to be associated with disease states. Amino acid sequence alignment of Amacrs and its homologues from various species revealed 26 conserved protic residues, assumed to be potential candidates as catalytic residues. Amacr from Mycobacterium tuberculosis (MCR) was taken as a representative of the racemases. To determine their importance for efficient catalysis, each of these 26 protic residues of MCR was mutated into an alanine, respectively, and the mutated variants were overexpressed in Escherichia coli. It was found that four variants (R91A, H126A, D156A, and E241A) were properly folded but had much decreased catalytic efficiency. Apparently, Arg91, His126, Asp156, and Glu241 are important catalytic residues of MCR. The importance of these residues for catalysis can be rationalized by the 1.8 A resolution crystal structure of MCR, which shows that the catalytic site is at the interface between the large and small domain of two different subunits of the dimeric enzyme. This crystal structure is the first structure of a complete enzyme of the bile acid synthesis pathway. It shows that MCR has unique structural features, not seen in the structures of the sequence related formyl-CoA transferases, suggesting that the family III CoA transferases can be subdivided in at least two classes, being racemases and CoA transferases.

Alanine↗

PubMed2003

HaploBlockFinder: haplotype block analyses.

UNLABELLED: Recent studies have unveiled discrete block-like structures of linkage disequilibrium (LD) in the human genome. We have developed a set of computer programs to analyze the block-like LD structures (haplotype blocks) based on haplotype data. Three definitions of haplotype block are supported, including minimal LD range, no historic recombination, and chromosome coverage. Tagged SNPs that uniquely distinguish common haplotypes are identified. A greedy algorithm was used to improve the efficiency. Two separate utilities were also provided to assist visual inspection of haplotype block structure and pattern of linkage disequilibrium. AVAILABILITY: A web interface for the HaploBlockFinder is available at http://cgi.uc.edu/cgi-bin/kzhang/haploBlockFinder.cgi the source codes are also freely available on the web site.

Algorithms↗

PubMed1975

A morphological study of anaerobic bacteria from the hypolimnia of two Michigan lakes.

Dense populations of anaerobic bacteria were found sequentially layered below the thermocline in two eutrophic lakes in southwest Michigan. Phase and electron microscopy of whole cells and thin sections were used to reveal the in situ morphology of the dominant members of the community. The predominant chlorophyll-containing bacteria were identified on the basis of their morphology to be members of the genera Pelodictyon, Prosthecochloris, Clathrochloris, Chlorochromatium, Pelochromatium, Thiopedia, Thiocystis, Thiospirillum, and Chromatium. The natural morphology of these organisms is described and compared with the morphology of reported isolates, the morphology of unisolated genera was compared with previous descriptions of natural samples. Most of the organisms near the sediment-water interface and two from the upper hypolimnion have not been previously described. They have been divided into six distinct groups based on morphology; the morphological features of each group are presented. This approach, based on the morphological uniqueness of the procaryotes present, provides a satisfactory method for grouping members of the hypolimnetic community for ecological studies.

Anaerobiosis↗

PubMed2006

Evanescent-wave-excited quasi-two-dimensional random lasing.

We report on random lasing from a dye-scatterer system directly excited by evanescent modes formed over a dielectric-dielectric interface. The system is quasi-two-dimensional because of the subwavelength exponential decay of the excitation energy. Spectral narrowing by a factor of approximately 13 was obtained under diffusive scattering conditions. The peak intensity exhibited a unique dual-saturation behavior due to the localized nature of the excitation. We observed a reduction of threshold for samples with a higher dye concentration because of a larger excitation-state occupation number within the same interaction volume.

Journal Article↗

PubMedDate not supplied

New knowledge for and about primary care: a view through the looking glass of the Annals of Family Medicine.

PURPOSE: At this second anniversary of the Annals of Family Medicine, we sought to characterize primary care research and to identify opportunities for new directions by analyzing the content of the first and second volumes of the Annals. METHODS: Using an a priori classification scheme, 2 editors independently categorized each research article and essay published in 2003 and 2004, excluding supplements. We categorized the domain of knowledge, methods, topical content, whether articles represented core values of primary care, and looked for articles that studied health/illness/symptoms from a uniquely primary care experience. We reconciled differences by discussion. RESULTS: Among 110 articles, knowledge domains reflected the 4 quadrants of the clinician (n = 6), patient, family, or community (10), health care system (32), disease (22), or the interface (39) between these quadrants. The most frequent methods were cross-sectional studies (23), cohorts (15), randomized clinical trials (13), qualitative interviews (11), analyses of secondary data (11), systematic reviews (11), methods/theory development (10), self-reflections (8), and mixed methods (5). The most common topical areas were chronic disease and prevention. Core primary care values were represented in 75% of articles. Only 2 articles represented an integrative illness/healing perspective. CONCLUSIONS: Despite contemporary forces driving a reductionistic approach, primary care research, as reflected by articles published in the Annals of Family Medicine, addresses the domains of knowledge that contribute to comprehensive, relationship-centered health care. More work is needed to understand the nature of health and illness in whole people and ways to integrate diverse knowledge, methods and fragmented health care.

Health Knowledge, Attitudes, Practice↗