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Lung damage and airway remodelling in severe asthma

CLINICAL AND EXPERIMENTAL ALLERGY 2012年第5期42卷 638-649页

作者： Brightling, C. E. Gupta, S. Gonem, S. Siddiqui, S. Univ Leicester Inst Lung Hlth Dept Infect Inflammat & Immun Leicester LE3 9QP Leics England Glenfield Hosp Leicester Leics England

Severe asthma is a heterogeneous disease with substantial unmet clinical need. Airway damage and remodelling is a consequence of complex hostenvironment interactions and is considered to be the cardinal feature leading onto the development and persistence of airflow obstruction. In this review, we shall bring together recent insights into the causes of airway damage and remodelling that propose key roles for pathogens and mechanical damage in addition to allergens, underlying genetic susceptibility, inflammatory and structural cell interactions, and impaired resolution of damage. We shall consider the consequences of airway remodelling in terms of airway geometry, mechanics and clinical expression of disease. Understanding the causes and consequences of airway damage and remodelling will shed light upon the structurefunction relationships required to begin to unravel the complexity of severe asthma and will enable us to target current and novel therapies as we begin to move towards realizing personalized medicine.

关键词： severe asthma Lung Injury structure-function relationships Remodeling Cell interactions Precision Medicine Airway Remodeling Airway Obstruction

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Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites

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HUMAN MOLECULAR GENETICS 2012年第12期21卷 2768-2778页

作者： Hannan, Fadil M. Nesbit, M. Andrew Zhang, Chen Cranston, Treena Curley, Alan J. Harding, Brian Fratter, Carl Rust, Nigel Christie, Paul T. Turner, Jeremy J. O. Lemos, Manuel C. Bowl, Michael R. Bouillon, Roger Brain, Caroline Bridges, Nicola Burren, Christine Connell, John M. Jung, Heike Marks, Eileen McCredie, David Mughal, Zulf Rodda, Christine Tollefsen, Sherida Brown, Edward M. Yang, Jenny J. Thakker, Rajesh V. Univ Oxford Nuffield Dept Clin Med Oxford Ctr Diabet Endocrinol & Metab Acad Endocrine Unit Oxford OX3 7LJ England Georgia State Univ Ctr Biotechnol & Drug Design Dept Chem Atlanta GA 30303 USA Churchill Hosp Oxford Mol Genet Lab Oxford OX3 7LJ England Univ Oxford Sir William Dunn Sch Pathol Oxford OX1 3RE England Katholieke Univ Leuven Clin & Lab Expt Med & Endocrinol Louvain Belgium Great Ormond St Hosp Sick Children Dept Paediat Endocrinol London WC1N 3JH England Chelsea & Westminster Hosp Paediat Endocrine Clin London SW10 9NH England Bristol Royal Hosp Children Dept Paediat Endocrinol & Diabet Bristol BS2 8BJ Avon England Univ Dundee Sch Med Ninewells Hosp & Med Sch Dundee DD1 4HN Scotland Univ Hosp Eppendorf Clin Children & Adolescent Med D-20246 Hamburg Germany Lilly Deutschland GmbH D-61352 Bad Homburg Germany Royal Liverpool Univ Hosp Dept Clin Chem Liverpool L7 8XP Merseyside England Royal Childrens Hosp Dept Nephrol Parkville Vic 3052 Australia Royal Manchester Childrens Hosp Dept Paediat Endocrinol Manchester M13 9WL Lancs England Monash Univ Monash Med Ctr Dept Paediat Clayton Vic 3168 Australia St Louis Univ Sch Med Cardinal Glennon Childrens Med Ctr Dept PediatDiv Endocrinol St Louis MO 63104 USA Harvard Univ Brigham & Womens Hosp Sch Med Div Endocrinol Diabet & HypertensDept Med Boston MA 02115 USA

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca-2)-binding sites. To elucidate the structurefunction relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 of one or more of the predicted Ca-2-binding sites, particularly at the VFTD cleft, which is the principal site of Ca-2 binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca-2 by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca-2 binding and the function of the CaSR.

关键词： structure-function relationships Mutation CASR gene Cleft

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Biaxial Tensile Testing and Constitutive Modeling of Human Supraspinatus Tendon

Biaxial Tensile Testing and Constitutive Modeling of Human S...

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38th Annual Northeast Bioengineering Conference (NEBEC)

作者： Szczesny, S. E. Peloquin, J. M. Cortes, D. H. Kadlowec, J. Soslowsky, L. J. Elliott, D. M. Univ Penn Dept Orthopaed Surg 424 Stemmler Hall Philadelphia PA 19104 USA Univ Penn Dept Bioengn Philadelphia PA 19104 USA Rowan Univ Dept Mech Engn Glassboro NJ 08028 USA

ISBN: (纸本)9781467311427

The heterogeneous composition, collagen fiber organization and mechanical properties of the supraspinatus tendon (SST) offer an opportunity for studying the structure-function relationships of fibrous musculoskeletal connective tissues. The objective of this study was to evaluate the contribution of collagen fiber organization to the planar tensile mechanics of the human SST. This was accomplished by fitting biaxial tensile data with a structural constitutive model that incorporates a sample-specific angular distribution of nonlinear fibers. Biaxial testing was employed to avoid the limitation of non-physiologic traction-free boundary conditions present during uniaxial testing. Samples were tested under a range of boundary conditions with simultaneous monitoring of collagen fiber orientation via polarized light imaging. The experimental data were input into a hyperelastic constitutive model incorporating the contributions of the uncrimped fibers. The model fit the longitudinal stresses well and was successfully validated. The transverse stresses were fit less well with greater errors observed for less aligned samples. Additional strain energy terms representing fiber-fiber interactions are likely necessary to provide closer approximation of the transverse stresses. This approach demonstrated that the longitudinal tensile mechanics of the SST are primarily dependent on the moduli, crimp, and angular distribution of its collagen fibers.

关键词： Constitutive models collagen fiber biaxial tensile test Tendon of supraspinatus Biaxial structure-function relationships Transverse Polarized light Boundary conditions extension tests

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Analysis of system structure-function relationships

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CHEMMEDCHEM 2007年第12期2卷 1774-1782页

作者： Fliri, Anton F. Loging, William T. Volkmann, Robert A. Pfizer Global Res & Dev Neurosci Med Chem Eastern Point Rd Groton CT 06340 USA

Preclinical pharmacology studies conducted with experimental medicines currently focus on assessments of drug effects attributed to a drug's putative mechanism of action. The high failure rate of medicines in clinical trials, however, underscores that the information gathered from these studies is insufficient for forecasting drug effect profiles actually observed in patients. Improving drug effect predictions and increasing success rates of new medicines in clinical trials are some of the key challenges currently faced by the pharmaceutical industry. Addressing these challenges requires development of new methods for capturing and comparing "system-wide" structure-effect information for medicines at the cellular and organism levels. The current investigation describes a strategy for moving in this direction by using six different descriptor sets for examining the relationship between molecular structure and broad effect information of 1064 medicines at the cellular and the organism level. To compare broad drug effect information between different medicines, information spectra for each of the 1064 medicines were created, and the similarity between information spectra was determined through hierarchical clustering. The structure-effect relationships ascertained through these comparisons indicate that information spectra similarity obtained through preclinical ligand binding experiments using a model proteome provide useful estimates for the broad drug effect profiles of these 1064 medicines in orgonisms. This premise is illustrated using the ligand binding profiles of selected medicines in the dataset as biomarkers for forecasting system-wide effect observations of medicines that were not included in the incipient 1064-medicine analysis.

关键词： biospectra cellular response drug design proteins structure-function relationships

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structure-function relationship in an archaebacterial methionine sulphoxide reductase B

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MOLECULAR MICROBIOLOGY 2011年第2期79卷 342-358页

作者： Carella, Michela Becher, Juliane Ohlenschlaeger, Oliver Ramachandran, Ramadurai Guehrs, Karl-Heinz Wellenreuther, Gerd Meyer-Klaucke, Wolfram Heinemann, Stefan H. Goerlach, Matthias Fritz Lipmann Inst Leibniz Inst Altersforsch D-07745 Jena Germany EMBL Hamburg DESY D-22603 Hamburg Germany Univ Jena Zentrum Mol Biomed Inst Biochem & Biophys D-07745 Jena Germany

P>Oxidation of methionine to methionine sulphoxide (MetSO) may lead to loss of molecular integrity and function. This oxidation can be 'repaired' by methionine sulphoxide reductases (MSRs), which reduce MetSO back to methionine. Two structurally unrelated classes of MSRs, MSRA and MSRB, show stereoselectivity towards the S and the R enantiomer of the sulphoxide respectively. Interestingly, these enzymes were even maintained throughout evolution in anaerobic organisms. Here, the activity and the nuclear magnetic resonance (NMR) structure of MTH711, a zinc containing MSRB from the thermophilic, methanogenic archaebacterium Methanothermobacter thermoautotrophicus, are described. The structure appears more rigid as compared with similar MSRBs from aerobic and mesophilic organisms. No significant structural differences between the oxidized and the reduced MTH711 state can be deduced from our NMR data. A stable sulphenic acid is formed at the catalytic Cys residue upon oxidation of the enzyme with MetSO. The two non-zinc-binding cysteines outside the catalytic centre are not necessary for activity of MTH711 and are not situated close enough to the active-site cysteine to serve in regenerating the active centre via the formation of an intramolecular disulphide bond. These findings imply a reaction cycle that differs from that observed for other MSRBs.

关键词： Methionine Oxidation structure-function relationships Reductase Stereoselectivity Cysteine Sulfoxides

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FROM MOLECULAR PHYLOGENETICS TO QUANTUM CHEMISTRY: DISCOVERING ENZYME DESIGN PRINCIPLES THROUGH COMPUTATION

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COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL 2012年第3期2卷 e201209018页

作者： Wymore, Troy Brooks, Charles L., III Pittsburgh Supercomp Ctr 300 South Craig St Pittsburgh PA 15213 USA Univ Michigan Dept Chem & Biophys Ann Arbor MI 48109 USA

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Analysis of sintered polymer scaffolds using concomitant synchrotron computed tomography and in situ mechanical testing

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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE 2011年第12期22卷 2599-2605页

作者： Dhillon, A. Schneider, P. Kuhn, G. Reinwald, Y. White, L. J. Levchuk, A. Rose, F. R. A. J. Mueller, R. Shakesheff, K. M. Rahman, C. V. Univ Nottingham Div Drug Delivery & Tissue Engn Ctr Biomol Sci Nottingham NG7 2RD England ETH Inst Biomech CH-8093 Zurich Switzerland

The mechanical behaviour of polymer scaffolds plays a vital role in their successful use in bone tissue engineering. The present study utilised novel sintered polymer scaffolds prepared using temperature-sensitive poly(dl-lactic acid-co-glycolic acid)/poly(ethylene glycol) particles. The microstructure of these scaffolds was monitored under compressive strain by image-guided failure assessment (IGFA), which combined synchrotron radiation computed tomography (SR CT) and in situ micro-compression. Three-dimensional CT data sets of scaffolds subjected to a strain rate of 0.01%/s illustrated particle movement within the scaffolds with no deformation or cracking. When compressed using a higher strain rate of 0.02%/s particle movement was more pronounced and cracks between sintered particles were observed. The results from this study demonstrate that IGFA based on simultaneous SR CT imaging and micro-compression testing is a useful tool for assessing structural and mechanical scaffold properties, leading to further insight into structure-function relationships in scaffolds for bone tissue engineering applications.

关键词： structure-function relationships X-Ray Computed Tomography SCAFFOLD POLYMER Bone Tissue Compression tests strain rate Mechanical testing Mechanical properties

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Hydraulic efficiency compromises compression strength perpendicular to the grain in Norway spruce trunkwood

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TREES-structure AND function 2011年第2期25卷 289-299页

作者： Rosner, Sabine Karlsson, Bo Univ Nat Resources & Life Sci Dept Integrat Biol Inst Bot BOKU Vienna A-1180 Vienna Austria Forestry Res Inst Sweden Skogforsk S-26890 Svalov Sweden

The aim of this study was to investigate bending stiffness and compression strength perpendicular to the grain of Norway spruce (Picea abies (L.) Karst.) trunkwood with different anatomical and hydraulic properties. Hydraulically less safe mature sapwood had bigger hydraulic lumen diameters and higher specific hydraulic conductivities than hydraulically safer juvenile wood. Bending stiffness (MOE) was higher, whereas radial compression strength lower in mature than in juvenile wood. A density-based tradeoff between MOE and hydraulic efficiency was apparent in mature wood only. Across cambial age, bending stiffness did not compromise hydraulic efficiency due to variation in latewood percent and because of the structural demands of the tree top (e.g. high flexibility). Radial compression strength compromised, however, hydraulic efficiency because it was extremely dependent on the characteristics of the "weakest" wood part, the highly conductive earlywood. An increase in conduit wall reinforcement of earlywood tracheids would be too costly for the tree. Increasing radial compression strength by modification of microfibril angles or ray cell number could result in a decrease of MOE, which would negatively affect the trunk's capability to support the crown. We propose that radial compression strength could be an easily assessable and highly predictive parameter for the resistance against implosion or vulnerability to cavitation across conifer species, which should be topic of further studies.

关键词： Compression strength perpendicular to the grain Conduit wall reinforcement Hydraulic efficiency Modulus of elasticity in bending Norway spruce structure-function relationships Vulnerability to cavitation Wood shrinkage

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A Mechanism for Evolving Novel Plant Sesquiterpene Synthase function

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MOLECULAR INFORMATICS 2011年第10期30卷 896-906页

作者： Wymore, Troy Chen, Brian Y. Nicholas, Hugh B., Jr. Ropelewski, Alexander J. Brooks, Charles L., III Pittsburgh Supercomp Ctr Pittsburgh PA 15213 USA Univ Michigan Dept Chem & Biophys Ann Arbor MI 48109 USA

Plant sesquiterpene synthases, a subset of the terpene synthase superfamily, are a mechanistically diverse family of enzymes capable of synthesizing hundreds of complex compounds with high regio- and stereospecificity and are of biological importance due to their role in plant defense mechanisms. In the current report we describe a large-scale, high-resolution phylogenetic analysis of similar to 200 plant sesquiterpene synthases integrated with structural and experimental data that address these issues. We observe that all sequences that cluster together on the phylogenetic tree into well-defined groups share at least the first reaction in the catalytic mechanism subsequent to the initial ionization step and many share steps beyond this down to proton transfers between the enzyme and substrate. Most significant is the previously unreported high conservation of an Asp-Tyr-Asp triad. Due to its high conservation, patterns in the phylogenetic tree as well as experimental and modeling results, we suggest that this Asp-Tyr-Asp triad is an important functional element responsible for many proton transfers to and from the substrate and intermediates along the plant sesquiterpene synthase catalytic cycle and whose position can be tuned by residues outside the active site that can lead to the evolution of novel enzyme function.

关键词： Sesquiterpene synthases Molecular evolution Phylogenetics Enzymes structure-function relationships

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Rheological Investigation of Prunus Sp. Gums in Aqueous Medium

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INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH 2011年第24期50卷 14148-14154页

作者： Amarioarei, Gina Spiridon, Iuliana Lungu, Maria Bercea, Maria Petru Poni Inst Macromol Chem Iasi 700487 Romania Gheorghe Asachi Tech Univ Fac Chem Engn & Environm Protect Dept Nat & Synthet Polymers Iasi 700050 Romania

The paper presents the preparation and rheological behavior of exudate gum obtained from tree gum cherry (Prunus cerasus) in aqueous medium. The shear and oscillatory flow experiments as well as creep-recovery tests, performed in different conditions of shear at 37 degrees C, show peculiar behavior of the samples as a function of their composition. Rheological parameters are very sensitive to variations in molecular structure or intermolecular interactions, and they are useful in developing structure-function relationships for polysaccharide-based systems.

关键词： structure-function relationships Prunus Oscillatory flow recovery test molecular structure aqueous media Gums Creep recovery

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