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At least 523 records · Page 29Linked to original sources

PubMed2006

Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term.

Human placentation entails the remarkable integration of fetal and maternal cells into a single functional unit. In the basal plate region (the maternal-fetal interface) of the placenta, fetal cytotrophoblasts from the placenta invade the uterus and remodel the resident vasculature and avoid maternal immune rejection. Knowing the molecular bases for these unique cell-cell interactions is important for understanding how this specialized region functions during normal pregnancy with implications for tumor biology and transplantation immunology. Therefore, we undertook a global analysis of the gene expression profiles at the maternal-fetal interface. Basal plate biopsy specimens were obtained from 36 placentas (14-40 wk) at the conclusion of normal pregnancies. RNA was isolated, processed, and hybridized to HG-U133A&B Affymetrix GeneChips. Surprisingly, there was little change in gene expression during the 14- to 24-wk interval. In contrast, 418 genes were differentially expressed at term (37-40 wk) as compared with midgestation (14-24 wk). Subsequent analyses using quantitative PCR and immunolocalization approaches validated a portion of these results. Many of the differentially expressed genes are known in other contexts to be involved in differentiation, motility, transcription, immunity, angiogenesis, extracellular matrix dissolution, or lipid metabolism. One sixth were nonannotated or encoded hypothetical proteins. Modeling based on structural homology revealed potential functions for 31 of these proteins. These data provide a reference set for understanding the molecular components of the dialogue taking place between maternal and fetal cells in the basal plate as well as for future comparisons of alterations in this region that occur in obstetric complications.

Female↗

PubMed1997

Structure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug.

Triabin, a 142-residue protein from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis, is a potent and selective thrombin inhibitor. Its stoichiometric complex with bovine alpha-thrombin was crystallized, and its crystal structure was solved by Patterson search methods and refined at 2.6-A resolution to an R value of 0.184. The analysis revealed that triabin is a compact one-domain molecule essentially consisting of an eight-stranded beta-barrel. The eight strands A to H are arranged in the order A-C-B-D-E-F-G-H, with the first four strands exhibiting a hitherto unobserved up-up-down-down topology. Except for the B-C inversion, the triabin fold exhibits the regular up-and-down topology of lipocalins. In contrast to the typical ligand-binding lipocalins, however, the triabin barrel encloses a hydrophobic core intersected by a unique salt-bridge cluster. Triabin interacts with thrombin exclusively via its fibrinogen-recognition exosite. Surprisingly, most of the interface interactions are hydrophobic. A prominent exception represents thrombin's Arg-77A side chain, which extends into a hydrophobic triabin pocket forming partially buried salt bridges with Glu-128 and Asp-135 of the inhibitor. The fully accessible active site of thrombin in this complex is in agreement with its retained hydrolytic activity toward small chromogenic substrates. Impairment of thrombin's fibrinogen converting activity or of its thrombomodulin-mediated protein C activation capacity upon triabin binding is explained by usage of overlapping interaction sites of fibrinogen, thrombomodulin, and triabin on thrombin. These data demonstrate that triabin inhibits thrombin via a novel and unique mechanism that might be of interest in the context of potential therapeutic applications.

Amino Acid Sequence↗

PubMed2006

Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface.

Glutathione is the major cellular thiol present in mammalian cells and is critical for maintenance of redox homeostasis. However, current assay systems for glutathione lack application to intact animal tissues. To map the levels of glutathione in intact brain with cellular resolution (acute tissue slices and live animals), we have used two-photon imaging of monochlorobimane fluorescence, a selective enzyme-mediated marker for reduced glutathione. Previously, in vitro experiments using purified components and cultured glial cells attributed cellular monochlorobimane fluorescence to a glutathione S-transferase-dependent reaction with GSH. Our results indicate that cells at the cerebrospinal fluid or blood-brain interface, such as lateral ventricle ependymal cells (2.73 +/- 0.56 mm; glutathione), meningeal cells (1.45 +/- 0.09 mm), and astroglia (0.91 +/- 0.08 mm), contain high levels of glutathione. In comparison, layer II cortical neurons contained 20% (0.21 +/- 0.02 mm) the glutathione content of nearby astrocytes. Neuronal glutathione labeling increased 250% by the addition of the cell-permeable glutathione precursor N-acetylcysteine indicating that the monochlorobimane level or glutathione S-transferase activity within neurons was not limiting. Regional mapping showed that glutathione was highest in cells lining the lateral ventricles, specifically ependymal cells and the subventricular zone, suggesting a possible function for glutathione in oxidant homeostasis of developing neuronal progenitors. Consistently, developing neurons in the subgranular zone of dentate gyrus contained 3-fold more glutathione than older neurons found in the neighboring granular layer. In conclusion, mapping of glutathione levels in intact brain demonstrates a unique role for enhanced redox potential in developing neurons and cells at the cerebrospinal fluid and blood-brain interface.

Animals↗

PubMed2000

Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure.

The pentametric assembly of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of receptor structure.

Animals↗

PubMed2001

Flexible polyimide-based intracortical electrode arrays with bioactive capability.

The promise of advanced neuroprosthetic systems to significantly improve the quality of life for a segment of the deaf, blind, or paralyzed population hinges on the development of an efficacious, and safe, multichannel neural interface for the central nervous system. The candidate implantable device that is to provide such an interface must exceed a host of exacting design parameters. We present a thin-film, polyimide-based, multichannel intracortical Bio-MEMS interface manufactured with standard planar photo-lithographic CMOS-compatible techniques on 4-in silicon wafers. The use of polyimide provides a mechanically flexible substrate which can be manipulated into unique three-dimensional designs. Polyimide also provides an ideal surface for the selective attachment of various important bioactive species onto the device in order to encourage favorable long-term reactions at the tissue-electrode interface. Structures have an integrated polyimide cable providing efficient contact points for a high-density connector. This report details in vivo and in vitro device characterization of the biological, electrical and mechanical properties of these arrays. Results suggest that these arrays could be a candidate device for long-term neural implants.

Animals↗

PubMed1997

Word frequency analysis of dictated clinical data: a user-centered approach to the design of a structured data entry interface.

The design of a functional interface for direct entry of physical exam data by physicians remains a formidable challenge for developers of clinical information systems. Many developers use a theoretical approach, basing the interface on a model of the structure of the information and of the user-system interaction that is developed with one or more clinical domain expert(s). We explored the use of empirical analysis as a basis for the design of a structured data entry (SDE) interface. A collection of physical examination data from actual trauma patients, dictated by trauma surgeons, was used for the analysis. Using simple parsers written in Visual BASIC, we used word frequency analysis (WFA) and manual editing to identify the frequencies of unique terms used by physicians in recording 688 HEENT and 712 LUNG physical exams. A second-pass WFA was used to determine associated descriptive terms. A simple SDE interface was created based on the results of these analyses. The interface was then evaluated by assessing the extent to which the HEENT and LUNG segments of similar physical exams could be fully recorded using the empirically-based SDE interface. Using this interface, 68% of 200 trial HEENT exams, and 85% of 200 trial LUNG exams could be fully recorded. The interface was also considered helpful in recording substantial portions of the remainder of the exams. We believe that WFA can be a useful tool for finding empirical basis for SDE design.

Humans↗

PubMed1990

A novel mechanism of heme-heme interaction in the homodimeric hemoglobin from Scapharca inaequivalvis as manifested upon cleavage of the proximal Fe-N epsilon bond at low pH.

The CO-binding kinetics and the optical spectra of the NO derivative of the homodimeric hemoglobin from Scapharca inaequivalvis have been investigated over the range between pH 7.0 and 2.0. In the deoxygenated derivative, protonation of the proximal imidazole at very low pH values and the consequent cleavage of the Fe-N epsilon bond result in a approximately 50-fold enhancement of the rate constant for CO binding, as found in other hemoproteins. However, in the case of the hemoglobin from S. inaequivalvis, the pH profile displays a cooperative behavior (n = 1.8 +/- 0.1), a unique feature that differentiates this protein from any other hemoprotein investigated thus far. Cleavage of the proximal bond in the NO derivative of S. inaequivalvis hemoglobin likewise displays a very steep pH transition. The mode of assembly of the homodimer, in which the heme-carrying E and F helices provide the subunit interface and bring the hemes at a much shorter distance (18.4 A) than in vertebrate hemoglobins, is likely to provide the structural basis for this unique behavior.

Animals↗

PubMed2005

The response regulator OmpR oligomerizes via beta-sheets to form head-to-head dimers.

In Escherichia coli, the EnvZ/OmpR two-component regulatory system regulates expression of the porin genes ompF and ompC in response to changes in osmolarity. It has recently become apparent that OmpR functions as a global regulator, by regulating the expression of many genes in addition to the porin genes. OmpR consists of two domains; phosphorylation of the N-terminal receiver domain increases DNA binding affinity of the C-terminal domain and vice versa. Many response regulators including PhoB and FixJ dimerize upon phosphorylation. Here, we demonstrate that OmpR dimerization is stimulated by phosphorylation or by DNA binding. The dimerization interface revealed here was unanticipated and had previously not been predicted. Using the accepted head-to-tail tandem-binding model as a guide, we set out to examine the intermolecular interactions between OmpR dimers bound to DNA by protein-protein cross-linking methods. Surprisingly, amino acid positions that we expected to form cross-linked dimers did not. Conversely, positions predicted not to form dimers did. Because of these results, we designed a series of 23 cysteine-substituted OmpR mutants that were used to investigate dimer interfaces formed via the beta-sheet region. This four-stranded beta-sheet is a unique feature of the OmpR group of winged helix-turn-helix proteins. Many of the cysteine-substituted mutants are dominant to wild-type OmpR, are phosphorylated by acetyl phosphate as well as the cognate kinase EnvZ, and the cross-linked proteins are capable of binding to DNA. Our results are consistent with a model in which OmpR binds to DNA in a head-to-head orientation, in contrast to the previously proposed asymmetric head-to-tail model. They also raise the possibility that OmpR may be capable of adopting more than one orientation as it binds to a vast array of genes to activate or repress transcription.

Bacterial Proteins↗

PubMed2001

Backbone dynamics of the calcium-signaling protein apo-S100B as determined by 15N NMR relaxation.

Backbone dynamics of homodimeric apo-S100B were studied by (15)N nuclear magnetic resonance relaxation at 9.4 and 14.1 T. Longitudinal relaxation (T(1)), transverse relaxation (T(2)), and the (15)N-[(1)H] NOE were measured for 80 of 91 backbone amide groups. Internal motional parameters were determined from the relaxation data using the model-free formalism while accounting for diffusion anisotropy. Rotational diffusion of the symmetric homodimer has moderate but statistically significant prolate axial anisotropy (D( parallel)/D( perpendicular) = 1.15 +/- 0.02), a global correlation time of tau(m) = 7.80 +/- 0.03 ns, and a unique axis in the plane normal to the molecular symmetry axis. Of 29 residues at the dimer interface (helices 1 and 4), only one has measurable internal motion (Q71), and the order parameters of the remaining 28 were the highest in the protein (S(2) = 0.80 to 0.91). Order parameters in the typical EF hand calcium-binding loop (S(2) = 0.73 to 0.87) were slightly lower than in the pseudo-EF hand (S(2) = 0.75 to 0.89), and effective internal correlation times, tau(e), distinct from global tumbling, were detected in the calcium-binding loops. Helix 3, which undergoes a large, calcium-induced conformational change necessary for target-protein binding, does not show evidence of interchanging between the apo and Ca(2+)-bound orientations in the absence of calcium but has rapid motion in several residues throughout the helix (S(2) = 0.78 to 0.88; 10 < or = tau(e) < or = 30 ps). The lowest order parameters were found in the C-terminal tail (S(2) = 0.62 to 0.83). Large values for chemical exchange also occur in this loop and in regions nearby in space to the highly mobile C-terminal loop, consistent with exchange broadening effects observed.

Amino Acid Sequence↗

PubMed1989

Intermediates on the reassociation pathway of phosphofructokinase I from Escherichia coli.

The folding and association pathway of the allosteric phosphofructokinase from Escherichia coli has been investigated after complete denaturation of the protein in guanidine hydrochloride by spectroscopical methods, fluorescence and circular dichroism. Three successive processes can be observed during the renaturation of this protein. First, a fast reaction, detected by fluorescence, results in the formation of a (partially) structured monomer. Second, two monomers associate into a dimeric species. This step involves the shielding of the unique tryptophan residue, Trp 311, from the aqueous solvent, and it corresponds to the formation of the interface containing the effector binding site. The presence of ATP during renaturation increases the rate of formation of this dimeric species. The other ligands of the enzyme have no effect on this reaction as well as on the whole reactivation. Finally, the enzymatic activity is regained during the third slowest step. This last reaction is due to the association of two dimers into the native tetrameric structure. The presence of fructose 6-phosphate does not increase the rate of reactivation, even though this ligand strongly stabilizes the native enzyme against denaturation by bridging the interface corresponding to the active site. The self-assembly of phosphofructokinase from E. coli from its unfolded and separated chains follows a specific order in the formation of the interactions between subunits and involves a dimeric intermediate with a defined geometry.

Allosteric Regulation↗

PubMed2005

Refinement of multidomain protein structures by combination of solution small-angle X-ray scattering and NMR data.

Determination of the 3D structures of multidomain proteins by solution NMR methods presents a number of unique challenges related to their larger molecular size and the usual scarcity of constraints at the interdomain interface, often resulting in a decrease in structural accuracy. In this respect, experimental information from small-angle scattering of X-ray radiation in solution (SAXS) presents a suitable complement to the NMR data, as it provides an independent constraint on the overall molecular shape. A computational procedure is described that allows incorporation of such SAXS data into the mainstream high-resolution macromolecular structure refinement. The method is illustrated for a two-domain 177-amino-acid protein, gammaS crystallin, using an experimental SAXS data set fitted at resolutions from approximately 200 A to approximately 30 A. Inclusion of these data during structure refinement decreases the backbone coordinate root-mean-square difference between the derived model and the high-resolution crystal structure of a 54% homologous gammaB crystallin from 1.96 +/- 0.07 A to 1.31 +/- 0.04 A. Combining SAXS data with NMR restraints can be accomplished at a moderate computational expense and is expected to become useful for multidomain proteins, multimeric assemblies, and tight macromolecular complexes.

Computational Biology↗

PubMed2006

Absolute orientation of molecules at interfaces.

A method to determine the absolute orientation of molecules at liquid interfaces by sum frequency generation (SFG) is reported. It is based on measurements of the orientations of two nonparallel vibrationally active chromophores in the molecule of interest combined with a rotation matrix formulation to obtain the absolute molecular orientation. We chose m-tolunitrile, a planar molecule adsorbed to the air/water interface, as a proof-of-method experiment. Quantitative analysis of different polarization sum frequency intensities facilitate unique peak assignments of the methyl and nitrile groups of m-tolunitrile. The SFG analysis of the measurement yields a nitrile group tilting at 53 degrees to the surface normal, and the C3 axis of the methyl group is almost upright at 23 degrees with respect to the surface normal. Using a rotation matrix formulation, we found that the angle between the surface plane and the m-tolunitrile molecular plane is 70 degrees.

Journal Article↗

PubMed2006

Piezoelectric and semiconducting coupled power generating process of a single ZnO belt/wire. A technology for harvesting electricity from the environment.

This paper presents the experimental observation of piezoelectric generation from a single ZnO wire/belt for illustrating a fundamental process of converting mechanical energy into electricity at nanoscale. By deflecting a wire/belt using a conductive atomic force microscope tip in contact mode, the energy is first created by the deflection force and stored by piezoelectric potential, and later converts into piezoelectric energy. The mechanism of the generator is a result of coupled semiconducting and piezoelectric properties of ZnO. A piezoelectric effect is required to create electric potential of ionic charges from elastic deformation; semiconducting property is necessary to separate and maintain the charges and then release the potential via the rectifying behavior of the Schottky barrier at the metal-ZnO interface, which serves as a switch in the entire process. The good conductivity of ZnO is rather unique because it makes the current flow possible. This paper demonstrates a principle for harvesting energy from the environment. The technology has the potential of converting mechanical movement energy (such as body movement, muscle stretching, blood pressure), vibration energy (such as acoustic/ultrasonic wave), and hydraulic energy (such as flow of body fluid, blood flow, contraction of blood vessels) into electric energy that may be sufficient for self-powering nanodevices and nanosystems in applications such as in situ, real-time, and implantable biosensing, biomedical monitoring, and biodetection.

Electric Conductivity↗

PubMed2001

Varieties of religion-family linkages.

The 4 articles in this special issue make important contributions to both family and religious studies as well as to their interface. This commentary begins by considering 4 unifying themes present across all of the articles, including meaningful religion-family linkages, the importance of gender differences in the faith-family interface, the significance of intergenerational relationships, and the need for better theory. The authors then discuss the unique major strength and secondary limitations of each study. Finally, the commentary focuses on two challenges inhibiting the contemporary study of religion and the family--a relative lack of racial and religious diversity in samples and the lack of a unifying theory of religion-family linkages--and suggests how to adjust the trajectory of future theory and research to address these issues.

Adult↗

PubMed2002

Novel domain packing in the crystal structure of a thiosulphate-oxidizing enzyme.

A key component of the oxidative biogeochemical sulphur cycle involves the utilization by bacteria of reduced inorganic sulphur compounds as electron donors to photosynthetic or respiratory electron transport chains. The SoxAX protein of the photosynthetic bacterium Rhodovulum sulfidophilum is a heterodimeric c-type cytochrome that is involved in the oxidation of thiosulphate and sulphide. The recently solved crystal structure of the SoxAX complex represents the first structurally characterized example of a productive electron transfer complex between haemoproteins where both partners adopt the c-type cytochrome fold. The packing of c-type cytochrome domains both within SoxA and at the interface between the subunits of the complex has been compared with other examples and found to be unique.

Bacterial Proteins↗

PubMed2006

Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis.

Ser/Thr phosphorylation has emerged as a critical regulatory mechanism in a number of bacteria, including Mycobacterium tuberculosis. This problematic pathogen encodes 11 eukaryotic-like Ser/Thr kinases, yet few substrates or signaling targets have been characterized. Here, we report the structure of EmbR (2.0 A), a putative transcriptional regulator of key arabinosyltransferases (EmbC, -A, and -B), and an endogenous substrate of the Ser/Thr-kinase PknH. EmbR presents a unique domain architecture: the N-terminal winged-helix DNA-binding domain forms an extensive interface with the all-helical central bacterial transcriptional activation domain and is positioned adjacent to the regulatory C-terminal forkhead-associated (FHA) domain, which mediates binding to a Thr-phosphorylated site in PknH. The structure in complex with a phospho-peptide (1.9 A) reveals a conserved mode of phospho-threonine recognition by the FHA domain and evidence for specific recognition of the cognate kinase. The present structures suggest hypotheses as to how EmbR might propagate the phospho-relay signal from its cognate kinase, while serving as a template for the structurally uncharacterized Streptomyces antibiotic regulatory protein family of transcription factors.

Bacterial Proteins↗

PubMed2005

Crack path prediction in anisotropic brittle materials.

A force balance condition to predict quasistatic crack paths in anisotropic brittle materials is derived from an analysis of diffuse interface continuum models that describe both short-scale failure and macroscopic linear elasticity. The path is uniquely determined by the directional anisotropy of the fracture energy, independent of details of the failure process. The derivation exploits the gradient dynamics and translation symmetry properties of this class of models to define a generalized energy-momentum tensor whose integral around an arbitrary closed path enclosing the crack tip yields all forces acting on this tip, including Eshelby's configurational forces, cohesive forces, and dissipative forces. Numerical simulations are in very good agreement with analytic predictions.

Journal Article↗

PubMed2004

Toward improved communication about wildland fire: mental models research to identify information needs for natural resource management.

The management of natural- and human-induced wildland fires is an intricate process that must balance two considerations: that of fire as a necessary natural disturbance and that of the risks that fire poses. Reconciling tradeoffs between these risks and benefits is contingent upon informed, directed, and two-way communication between wildland fire managers and stakeholders. In an effort to aid with the design of such a communication effort, this study used mental models research to determine the unique wildland fire information and decision-making needs of stakeholders living at the wildland-urban interface of a fire-prone area. While the analysis revealed many similarities in how stakeholders conceptualized the risks and benefits of wildland fire, many misconceptions and important gaps in understanding on the part of both expert and nonexpert respondents were identified.

Adolescent↗