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At least 343 records · Page 19Linked to original sources

PubMed1996

Regulation of T-cell activation in the lung: alveolar macrophages induce reversible T-cell anergy in vitro associated with inhibition of interleukin-2 receptor signal transduction.

Alveolar macrophages (AM) are recognized as archetypal 'activated' macrophages with respect to their capacity to suppress T-cell responses to antigen or mitogen, and this function has been ascribed an important role in the maintenance of local immunological homeostasis at the delicate blood:air interface. The present study demonstrates that this suppression involves a unique form of T-cell anergy, in which 'AM-suppressed' T cells proceed normally through virtually all phases of the activation sequence including Ca2+ flux, T-cell receptor (TCR) modulation, cytokine [including interleukin-2 (IL-2)] secretion and IL-2 receptor (IL-2R) expression. However, the 'suppressed' T cells fail to up-regulate CD2, and do not re-express normal levels of TCR-associated molecules after initial down-modulation; moreover, they are unable to transduce IL-2 signals leading to phosphorylation of IL-2R-associated proteins, and remained locked in G0/G1. The induction of this form of anergy is blocked by an NO-synthase inhibitor, and is reversible upon removal of AM from the T cells, which then proliferate in the absence of further stimulation. We hypothesize that this mechanism provides the means to limit the magnitude of local immune responses in this fragile tissue microenvironment, while preserving the capacity for generation of immunological memory against locally encountered antigens via clonal expansion of activated T cells after their subsequent migration to regional lymphoid organs. In an accompanying paper, we demonstrate that a significant proportion of T cells freshly isolated from lung exhibit a comparable surface phenotype.

Animals↗

PubMed2006

Structure of the calmodulin alphaII-spectrin complex provides insight into the regulation of cell plasticity.

AlphaII-spectrin is a major cortical cytoskeletal protein contributing to membrane organization and integrity. The Ca2+-activated binding of calmodulin to an unstructured insert in the 11th repeat unit of alphaII-spectrin enhances the susceptibility of spectrin to calpain cleavage but abolishes its sensitivity to several caspases and to at least one bacterially derived pathologic protease. Other regulatory inputs including phosphorylation by c-Src also modulate the proteolytic susceptibility of alphaII-spectrin. These pathways, acting through spectrin, appear to control membrane plasticity and integrity in several cell types. To provide a structural basis for understanding these crucial biological events, we have solved the crystal structure of a complex between bovine calmodulin and the calmodulin-binding domain of human alphaII-spectrin (Protein Data Bank ID code 2FOT). The structure revealed that the entire calmodulin-spectrin-binding interface is hydrophobic in nature. The spectrin domain is also unique in folding into an amphiphilic helix once positioned within the calmodulin-binding groove. The structure of this complex provides insight into the mechanisms by which calmodulin, calpain, caspase, and tyrosine phosphorylation act on spectrin to regulate essential cellular processes.

Amino Acid Sequence↗

PubMed2004

Toward an optimal healing environment in pediatric rehabilitation.

Although recent scientific advances have enabled us to minimize disability and improve the quality of life for people with disabilities and their families, cure is still not possible for many rehabilitation patients. This inability to cure renders the field of rehabilitation medicine particularly well-suited to the philosophy of healing. In contrast to curing, which is aimed at removing or reversing a disease process, both rehabilitation and healing are meant to enhance all aspects of well-being, restore integrity to the person, and facilitate the creation of meaning. Pediatric rehabilitation represents the interface of rehabilitation medicine and pediatrics, and is associated with unique characteristics that provide a natural context for exploring the optimal healing environment. This paper describes those characteristics and argues for the systematic integration and evaluation of healing interventions among children with developmental disabilities and their caregivers (parents, health care practitioners, and teachers). The ultimate aim of these interventions would be to improve all levels of the children's functioning in their homes, schools, and community environments by reducing impairment and increasing activity and participation. The paper concludes with a discussion of research priorities and the challenges imposed by different research strategies.

Child↗

PubMed2005

X-ray structure of glutathione S-transferase from Schistosoma japonicum in a new crystal form reveals flexibility of the substrate-binding site.

The crystal structure of the 26 kDa glutathione S-transferase from Schistosoma japonicum (SjGST) was determined at 3 A resolution in the new space group P2(1)2(1)2(1). The structure of orthorhombic SjGST reveals unique features of the ligand-binding site and dimer interface when compared with previously reported structures. SjGST is recognized as the major detoxification enzyme of S. japonicum, a pathogenic helminth causing schistosomiasis. As resistance against the established inhibitor of SjGST, praziquantel, has been reported these results might prove to be valuable for the development of novel drugs.

Animals↗

PubMed1995

Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein.

Relative to other noncollagenous, extracellular matrix proteins in mineralized tissues, colloidal-gold immunocytochemistry has demonstrated that the ultrastructural distribution of osteopontin (OPN) is unique in that this protein preferentially accumulates at mineralized tissue interfaces. In bone, this protein is present as a major component of cell-matrix and matrix-matrix interfacial structures called cement lines and laminae limitantes. In the present article, the implications of this distinct tissue distribution are discussed in terms of the bone remodeling sequence, and a detailed account of the secretion, accumulation and potential role of OPN is presented and related to current theory on the cellular and extracellular matrix events associated with basic multicellular unit (BMU)-based bone remodeling. In this context, a proposal is made describing the production of this protein as one of the earliest, and latest, secretory activities of the osteoblastic lineage, and that this activity manifests itself morphologically as a cement line ('plane') and a lamina limitans, respectively, at bone matrix interfaces. When integrated with other, known functional characteristics of this protein, the present morphological and compositional data indicate that OPN in cement lines and laminae limitantes may participate in initial and late extracellular matrix organization and mineralization, matrix-matrix/mineral adhesion and/or cell adhesion at bone interfaces.

Animals↗

PubMed2004

IgA response in serum and gut secretion in sensitized mice fed with the dust mite Dermatophagoides pteronyssinus extract.

Induced oral tolerance to mucosal-exposed antigens in immunized animals is of particular interest for the development of immunotherapeutic approaches to human allergic diseases. This is a unique feature of mucosal surfaces which represent the main contact interface with the external environment. However, the influence of oral tolerance on specific and natural polyreactive IgA antibodies, the major defense mechanism of the mucosa, is unknown. We have shown that oral administration of an extract of the dust mite Dermatophagoides pteronyssinus (Dp) to primed mice caused down-regulation of IgE responses and an increase in tumor growth factor-beta secretion. In the present study, we observed that primed inbred female A/Sn mice (8 to 10 weeks old) fed by gavage a total weight of 1.0-mg Dp extract on the 6th, 7th and 8th days post-immunization presented normal secretion of IL-4 and IL-10 in gut-associated lymphoid tissue and a decreased production of interferon gamma induced by Dp in the draining lymph nodes (13,340 +/- 3,519 vs 29,280 +/- 2,971 pg/ml). Mice fed the Dp extract also showed higher levels of serum anti-Dp IgA antibodies and an increase of IgA-secreting cells in mesenteric lymph nodes (N = 10), reflecting an increase in total fecal IgA antibodies (N = 10). The levels of secretory anti-Dp IgA antibodies increased after re-immunization regardless of Dp extract feeding. Oral tolerance did not interfere with serum or secretory IgA antibody reactivity related to self and non-self antigens. These results suggest that induction of oral tolerance to a Dp extract in sensitized mice triggered different regulatory mechanisms which inhibited the IgE response and stimulated systemic and secretory IgA responses, preserving the natural polyreactive IgA antibody production.

Administration, Oral↗

PubMed2003

Generic design of Web-based clinical databases.

BACKGROUND: The complexity and the rapid evolution and expansion of the domain of clinical information make development and maintenance of clinical databases difficult. Whenever new data types are introduced or existing types are modified in a conventional relational database system, the physical design of the database must be changed accordingly. For this reason, it is desirable that a clinical database be flexible and allow for modifications and for addition of new types of data without having to change the physical database schema. The ideal clinical database would therefore implement a highly-detailed logical database schema in a completely-generic physical schema that stores the wide variety of clinical data in a small and constant number of tables. OBJECTIVE: The objective was to review the medical literature regarding generic design of clinical databases. METHODS: A search strategy was devised for PubMed and Google to get the best match of peer-reviewed articles and free Web resources on the subject. RESULTS: Eight peer reviewed articles and a Web tutorial were found. All the resources described the so-called Entity-Attribute-Value (EAV) design as a means of simplifying the physical layout of data tables in a clinical database. In Entity-Attribute-Value design all data can be stored in a single generic table with conceptually 3 columns: 1 for entity (eg, patient identification), 1 for attribute (eg, name), and 1 for value (eg, "Jens Hansen"). To add more descriptive fields to the entity class, all that is necessary is to add attribute values to be stored in the attribute field. The main advantages of the Entity-Attribute-Value design are flexibility and effective entity-centered data retrieval. The main disadvantages are complicated front-end programming needed to display data in a conventional layout that the user understands and less-efficient attribute-centered queries. The Internet offers unique opportunities for database deployment, eliminating problems of user-interface deployment. Furthermore, Web forms may be generated in a completely-generic fashion during run time from metadata describing the semantic structure of clinical information stored in the database. CONCLUSIONS: The Entity-Attribute-Value model is useful for generic design of clinical databases. Depending on the specific requirements of the application, more or less complex metadata models may be applied.

Databases, Factual↗

PubMed1996

Confocal imaging of the keratocyte network in porcine cornea using the fixable vital dye 5-chloromethylfluorescein diacetate.

This study reports on the combined use of an aldehyde fixable, cell viability fluoroprobe, 5-chloromethylfluorescein diacetate (CMFDA), confocal laser scanning microscopy and digital image reconstruction, to produce high resolution images of corneal keratocyte preparations in situ. The central region of freshly enucleated porcine corneae were removed and stained overnight at 4 degrees C with CMFDA. The tissue was washed, fixed, and frozen for cryosectioning in either a horizontal or antero-posterior orientation. Sections from anterior, central and posterior stroma were examined with a confocal microscope, and the digital images rendered as three-dimensional stereo reconstructions. Fluorescent CMFDA which completely permeated the cell bodies and extremes of the finest ramifying cell processes of all keratocytes provided exceptional high resolution images of the three morphologically distinct cell subpopulations at different levels of the stroma, and enabled improved characterisation of each cell type. Anteriorly was a thin, dense, non-lamellar network of keratocytes subjacent Bowman's membrane. In the central stroma, keratocytes were arranged in layers, the cell bodies had a flattened pyramidal or stellate shape, and the fine cell processes formed extensive distal ramifications. Immediately anterior to Descemet's membrane a small subpopulation of keratocytes with large cell bodies and short branched processes was identified. Extensive and diverse cell-to-cell contacts were orientated in all stromal planes, including ramping cell bridges between keratocyte lamellae in the central stroma. The use of the cell viability dye CMFDA is feasible and valuable for enhancing the visibility of entire keratocyte population in the intact cornea. Diverse multi-directional cell processes and intercellular contacts throughout the keratocyte network suggest a strong capacity for direct communication and cohesion in the maintenance and repair of the stromal matrix. Keratocytes closely related to the epithelium and endothelium have unique morphologies which may relate to specialised functions of these interface cells.

Animals↗

PubMed1991

Tubal pregnancy. Associated histopathology.

Endometrial histologic characteristics are of little value in predicting ectopic pregnancy. The growing tubal gestation does not have any unique characteristics as far as the maternal-fetal tissue interface is concerned. The placentation is relatively superficial, and the growth is intraluminal. Tubal rupture occurs as a result of progressive tubal distention with focal hemorrhagic necrosis. Persistence is a reflection of incomplete evacuation combined with the noncyclic shedding of the tubal epithelium. The evacuated implantation site and conservative surgical incisions are not directly related to the recurrence of ipsilateral tubal pregnancies. The most common histologic finding related to tubal pregnancy is that of prior tubal disease.

Embryo Implantation↗

PubMed2005

Differential gene expression of collagen-binding small leucine-rich proteoglycans and lysyl hydroxylases, during mineralization by MC3T3-E1 cells cultured on titanium implant material.

Titanium implants create a unique ultrastructure (composed of a collagenous zone with relatively disorganized fibril morphology) at the bone-implant interface. The objective of this study was to investigate the temporal mRNA expression patterns, using real-time polymerase chain reaction, of type I collagen (COLI) and regulators for collagen fibrillogenesis, collagen-binding small leucine-rich proteoglycans (SLRPs) and lysyl hydroxylases (LHs), during mineralization, by MC3T3-E1 cells cultured on titanium (Ti). Lysates of the cultures on Ti and on plastic wells (Pl) for 10-50 d were used for the quantification of calcium and mRNA. Although the onset of calcium accumulation in the cultures on Ti (30-40 d) was slower than that of cultures on Pl (20-30 d), the gene expression patterns during mineralization were similar in cells cultured on either material. COLI and fibromodulin were up-regulated just before the onset of mineralization and then down-regulated. Lumican and LH1 were up-regulated just before the onset of mineralization and then returned to the baseline level. Decorin and LH2 were up-regulated at the late mineralization stage. Biglycan was down-regulated once at the early mineralization stage and then returned to the original level. LH3 was maintained at a steady level throughout. This study suggests actual but distinct roles of SLRPs and LHs in the formation of a unique ultrastructure at the bone-implant interface.

3T3 Cells↗

PubMed1993

Human nonpancreatic secreted phospholipase A2: interfacial parameters, substrate specificities, and competitive inhibitors.

The rate and equilibrium parameters for the interfacial catalysis by recombinant human nonpancreatic secreted phospholipase A2 were determined. Results show that the enzyme binds to anionic interfaces with considerably higher affinity than to zwitterionic interfaces. The extent of hydrolysis per enzyme on anionic vesicles in the processive scooting mode shows that the enzyme is fully catalytically active as a monomer. Among several secreted phospholipases A2 tested, the human nonpancreatic secreted enzyme is unique in its ability to undergo slow intervesicle exchange either by dissociation from the interface followed by binding to a different vesicle or by promoting the fusion of vesicles. The equilibrium dissociation constants for calcium, substrate analogs, reaction products, and several competitive inhibitors bound to the enzyme at the interface were determined by monitoring the ligand-conferred protection of the active site histidine residue from alkylation by phenacyl bromide. The interfacial Michaelis-Menten parameters were determined from the analysis of the entire reaction progress curve and also by monitoring the effect of competitive inhibitors on the initial rate of hydrolysis in the scooting mode. The interfacial Michaelis constant (KM*) for the substrate 1,2-dimyristoylglycero-sn-3-phosphomethanol was determined to be considerably above the maximal attainable mole fraction of unity for the substrate in the bilayer. Substrate specificity studies show that the enzyme does not significantly discriminate between phospholipids that differ in the type of polar head group or in the degree of unsaturation of the fatty acyl chains. Competitive inhibitors are described that display a high degree of selectivity for binding to the nonpancreatic versus pancreatic phospholipase A2. The kinetic properties of the human nonpancreatic secreted phospholipase A2 suggest that the enzyme has evolved to hydrolyze substrates at anionic interfaces and at high calcium concentrations.

Catalysis↗

PubMed2004

ESTIMA, a tool for EST management in a multi-project environment.

BACKGROUND: Single-pass, partial sequencing of complementary DNA (cDNA) libraries generates thousands of chromatograms that are processed into high quality expressed sequence tags (ESTs), and then assembled into contigs representative of putative genes. Usually, to be of value, ESTs and contigs must be associated with meaningful annotations, and made available to end-users. RESULTS: A web application, Expressed Sequence Tag Information Management and Annotation (ESTIMA), has been created to meet the EST annotation and data management requirements of multiple high-throughput EST sequencing projects. It is anchored on individual ESTs and organized around different properties of ESTs including chromatograms, base-calling quality scores, structure of assembled transcripts, and multiple sources of comparison to infer functional annotation, Gene Ontology associations, and cDNA library information. ESTIMA consists of a relational database schema and a set of interactive query interfaces. These are integrated with a suite of web-based tools that allow a user to query and retrieve information. Further, query results are interconnected among the various EST properties. ESTIMA has several unique features. Users may run their own EST processing pipeline, search against preferred reference genomes, and use any clustering and assembly algorithm. The ESTIMA database schema is very flexible and accepts output from any EST processing and assembly pipeline. ESTIMA has been used for the management of EST projects of many species, including honeybee (Apis mellifera), cattle (Bos taurus), songbird (Taeniopygia guttata), corn rootworm (Diabrotica vergifera), catfish (Ictalurus punctatus, Ictalurus furcatus), and apple (Malus x domestica). The entire resource may be downloaded and used as is, or readily adapted to fit the unique needs of other cDNA sequencing projects. CONCLUSIONS: The scripts used to create the ESTIMA interface are freely available to academic users in an archived format from http://titan.biotec.uiuc.edu/ESTIMA/. The entity-relationship (E-R) diagrams and the programs used to generate the Oracle database tables are also available. We have also provided detailed installation instructions and a tutorial at the same website. Presently the chromatograms, EST databases and their annotations have been made available for cattle and honeybee brain EST projects. Non-academic users need to contact the W.M. Keck Center for Functional and Comparative Genomics, University of Illinois at Urbana-Champaign, Urbana, IL, for licensing information.

Animals↗

PubMed2005

Behaviour and design considerations for continuous flow closed-open-closed liquid microchannels.

This paper introduces a method of combining open and closed microchannels in a single component in a novel way which couples the benefits of both open and closed microfluidic systems and introduces interesting on-chip microfluidic behaviour. Fluid behaviour in such a component, based on continuous pressure driven flow and surface tension, is discussed in terms of cross sectional flow behaviour, robustness, flow-pressure performance, and its application to microfluidic interfacing. The closed-open-closed microchannel possesses the versatility of upstream and downstream closed microfluidics along with open fluidic direct access. The device has the advantage of eliminating gas bubbles present upstream when these enter the open channel section. The unique behaviour of this device opens the door to applications including direct liquid sample interfacing without the need for additional and bulky sample tubing.

Equipment Design↗

PubMed2001

Solution conformation of alpha-conotoxin EI, a neuromuscular toxin specific for the alpha 1/delta subunit interface of torpedo nicotinic acetylcholine receptor.

A high resolution structure of alpha-conotoxin EI has been determined by (1)H NMR spectroscopy and molecular modeling. alpha-Conotoxin EI has the same disulfide framework as alpha 4/7 conotoxins targeting neuronal nicotinic acetylcholine receptors but antagonizes the neuromuscular receptor as do the alpha 3/5 and alpha A conotoxins. The unique binding preference of alpha-conotoxin EI to the alpha(1)/delta subunit interface of Torpedo neuromuscular receptor makes it a valuable structural template for superposition of various alpha-conotoxins possessing distinct receptor subtype specificities. Structural comparison of alpha-conotoxin EI with the gamma-subunit favoring alpha-conotoxin GI suggests that the Torpedo delta-subunit preference of the former originates from its second loop. Superposition of three-dimensional structures of seven alpha-conotoxins reveals that the estimated size of the toxin-binding pocket in nicotinic acetylcholine receptor is approximately 20 A (height) x 20 A (width) x 15 A (thickness).

Amino Acid Sequence↗

PubMed2005

Transmetalation reaction between hydrophobic silver nanoparticles and aqueous chloroaurate ions at the air-water interface.

The transmetalation reaction between a sacrificial nanoparticle and more noble metal ions in solution has emerged as a novel method for creating unique hollow and bimetallic nanostructures. In this report, we investigate the possibility of carrying out the transmetalation reaction between hydrophobic silver nanoparticles assembled and constrained at the air-water interface and subphase gold ions. We observe that facile reduction of the subphase gold ions by the sacrificial silver nanoparticles occurs resulting in the formation of elongated gold nanostructures that appear to cross-link the sacrificial silver particles. This transmetalation reaction may be modulated by the insertion of an electrostatic barrier in the form of an ionizable lipid monolayer between the silver nanoparticles and the aqueous gold ions that impacts the gold nanoparticle assembly. Transmetalation reactions between nanoparticles constrained into a close-packed structure and appropriate metal ions could lead to a new strategy for metallic cross-linking of nanoparticles and generation of coatings with promising optoelectonic behavior.

Journal Article↗

PubMed2000

Scanning tunneling microscopy: a unique tool in the study of chirality, dynamics, and reactivity in physisorbed organic monolayers.

Scanning tunneling microscopy (STM) is applied to study organic monolayers, physisorbed at the liquid-graphite interface. Due to the very local nature of the probing, the structure of these adlayers has been imaged with very high detail. The high resolution allowed us to investigate the effect of molecular chirality on the monolayer formation and provided a unique way to study chemical reactions at the liquid-graphite interface. Making use of a fast scanning mode, dynamic processes in these adlayers have been visualized.

Absorption↗

PubMed1995

A novel low oxygen affinity recombinant hemoglobin (alpha96val--> Trp): switching quaternary structure without changing the ligation state.

Using our Escherichia coli expression plasmid (pHE2) in which synthetic human alpha and beta-globin genes are coexpressed with the E. coli methionine aminopeptidase gene under the control of separate tac promoters, we have constructed a new artificial hemoglobin in which the valine residue at position 96 of the alpha chain, located in the alpha 1 beta 2 subunit interface, has been replaced by a tryptophan residue using site-directed mutagenesis. We have determined the oxygen-binding properties of this recombinant hemoglobin, r Hb (alpha 96Val-->Trp), and have used proton nuclear magnetic resonance spectroscopy to investigate its tertiary structure around the heme group and the quaternary structure in the alpha 1 beta 2 subunit interface. This artificial hemoglobin shows a low oxygen affinity, but high cooperativity in oxygen binding, and exhibits no unusual subunit dissociation when ligated. Molecular dynamics simulations suggest that the unique oxygen-binding property of r Hb (alpha 96Val-->Trp) may be due to an extra hydrogen bond between alpha 96Trp and beta 99Asp in the alpha 1 beta 2 subunit interface in the deoxy form. Despite the replacement of a small amino acid residue, valine, by a large tryptophan residue in the alpha 1 beta 2 subunit interface, this artificial hemoglobin shows very similar tertiary structure around the heme pockets and quaternary structure in the alpha 1 beta 2 subunit interface compared to those of human normal adult hemoglobin. Another unique feature of this artificial hemoglobin is that the ligated form, e.g. carbonmonoxy form, of this hemoglobin in the oxy-quaternary structure can be converted to the deoxy-like quaternary structure by the addition of an allosteric effector, inositol hexaphosphate, as well as by lowering the temperature in the absence of inositol hexaphosphate, without changing its ligation state. Thus, this recombinant hemoglobin can be used to gain new insights regarding the nature of subunit interactions in the alpha 1 beta 2 interface and the molecular basis for the allosteric mechanism of hemoglobin.

Base Sequence↗

PubMed2002

Conformational change coupling the dimerization and activation of KSHV protease.

The mechanism of herpesviral protease activation upon dimerization was studied using two independent spectroscopic assays augmented by directed mutagenesis. Spectroscopic changes, attributable to dimer interface conformational plasticity, were observed upon dimerization of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr). KSHV Pr's dissociation constant of 585 +/- 135 nM at 37 degrees C was measured by a concentration-dependent, 100-fold increase in specific activity to a value of 0.275 +/- 0.023 microM product min(-1) (microM enzyme)(-1). A 4 nm blue-shifted fluorescence emission spectrum and a 25% increase in ellipticity at 222 nm were detected by circular dichroism upon dimer association. This suggested enhanced hydrophobic packing within the dimer interface and/or core, as well as altered secondary structures. To better understand the structure-activity relationship between the monomer and the dimer, KSHV Pr molecules were engineered to remain monomeric via substitution of two separate residues within the dimer interface, L196 and M197. These mutants were proteolytically inactive while exhibiting the spectroscopic signature and thermal stability of wild type, dissociated monomers (T(M) = 75 degrees C). KSHV Pr conformational changes were found to be relevant in vivo, as the autoproteolytic inactivation of KSHV Pr at its dimer disruption site [Pray et al. (1999) J. Mol. Biol. 289, 197-203] was detected in viral particles from KSHV-infected cells. This characterization of structural plasticity suggests that the structure of the KSHV Pr monomer is stable and significantly different from its structure in the dimer. This structural uniqueness should be considered in the development of compounds targeting the dimer interface of KSHV Pr monomers.

Cell Line↗