bluuebunny/crossref_metadata_2025_split huggingface dataset:
A regularized XFEM model for the transition from continuous to discontinuous displacements
Authors: Benvenuti E. , Tralli A. , Ventura G. 
Published: October 2007

AbstractThis work focuses on the modelling through the extended finite element method of structural problems characterized by discontinuous displacement. As a model problem, an elastic isotropic domain characterized by a displacement discontinuity across a surface is studied. A regularization of the displacement field is introduced depending on a scalar parameter. The regularized solution is defined in a layer. The emerging strain and stress fields are independently modelled using specific constitutive assumptions. In particular, it is shown that the mechanical work spent within the regularization layer can be interpreted as an interface work provided that a spring‐like constitutive law is adopted. The accuracy of the integration procedures adopted for the stiffness matrix is assessed, as highly non‐linear terms appear. Standard Gauss quadrature is compared with adaptive quadrature and with a new technique, based on an equivalent polynomial approach. One‐ and two‐dimensional results are reported for varying discretization size, regularization parameter, and constitutive parameters. Copyright © 2007 John Wiley & Sons, Ltd.
Simulating deformation of objects with multi‐materials using boundary element method
Authors: Zhou Aifang , Hui Kinchuen , Lai Yuenhoo 
Published: October 2007

AbstractIn this paper, an algorithm for simulating the elastostatic deformation of multiple objects with different material properties using boundary element method is introduced. By tessellating the surface of a geometric model into elements and classifying all the element nodes into different groups with different attributes, and partitioning the stiffness matrix into several sub‐matrices according to these attributes, a compact expression for the unknown variables is obtained. Comparing with the direct matrix inversion method, the dimension of the system matrix in the expression has been effectively reduced. Besides, this expression shows that the deformation of a multi‐component object can be simulated in a way similar to that of a single‐component object. The capacitance method is adopted for evaluating the deformation of the object. Experimental results illustrate that the proposed method is practical and efficient. Copyright © 2007 John Wiley & Sons, Ltd.
Antibiotics in Dutch general practice: nationwide electronic GP database and national reimbursement rates
Authors: Akkerman Annemiek E. , Kuyvenhoven Marijke M. , Verheij Theo J.M. , van Dijk Liset 
Published: October 2007

AbstractPurposeIn order to assess whether different databases generate information which can be reliable compared with each other, this study aimed to assess to which degree prescribing rates for systemic antibiotics from a nationwide electronic general practitioner (GP) database correspond with national reimbursement rates, and to investigate for which indications antibiotics are prescribed.MethodsNationwide GP prescribing data were collected from the Second Dutch National Survey of General Practice (DNSGP‐2) based on 90 general practices serving 358 008 patients in 2001. Dutch national reimbursement rates for GPs were derived from claims data of the Dutch Drug Information System/Health Care Insurance Board (GIP/CVZ) from 2001. We calculated antibiotic prescribing rates per 1000 patients/inhabitants for each database, and these rates were compared for the total rates and according to antibiotic subgroups. Indications for which GPs prescribed antibiotics were described.ResultsIn national reimbursement data, 339 antibiotic prescriptions per 1000 inhabitants were prescribed by GPs, while the nationwide GP database showed 255 prescriptions per 1000 patients (75% coverage with reimbursement rates). The nationwide GP database showed high volumes of sulphonamides & trimethoprim, and small volumes of macrolides and quinolones. Half of the prescriptions (48%) were prescribed for respiratory diseases, a quarter (26%) for urinary diseases and 7% for ear diseases.ConclusionsGPs voluntarily participating in a research network prescribe less antibiotics than Dutch GPs in general, and are cautious in prescribing newer and more broad‐spectrum antibiotics. This point has to be taken into account when databases will be compared with each other. Copyright © 2007 John Wiley & Sons, Ltd.
Neuroproteomics and its applications in research on nicotine and other drugs of abuse
Authors: Li Ming D. , Wang Ju 
Published: October 2007

AbstractThe rapidly growing field of neuroproteomics is able to track changes in protein expression and protein modifications underlying various physiological conditions, including the neural diseases related to drug addiction. Thus, it presents great promise in characterizing protein function, biochemical pathways, and networks to understand the mechanisms underlying drug dependence. In this article, we first provide an overview of proteomics technologies and bioinformatics tools available to analyze proteomics data. Then we summarize the recent applications of proteomics to profile the protein expression pattern in animal or human brain tissues after the administration of nicotine, alcohol, amphetamine, butorphanol, cocaine, and morphine. By comparing the protein expression profiles in response to chronic nicotine exposure with those appearing in response to treatment with other drugs of abuse, we identified three biological processes that appears to be regulated by multiple drugs of abuse: energy metabolism, oxidative stress response, and protein degradation and modification. Such similarity indicates that despite the obvious differences among their chemical properties and the receptors with which they interact, different substances of abuse may cause some similar changes in cellular activities and biological processes in neurons.
Clinical proteomics in neurodegenerative diseases
Authors: Zhou Jian‐Ying , Hanfelt John , Peng Junmin 
Published: October 2007

AbstractInvestigation of the human specimens is an essential element for understanding the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The studies hold promise for identifying biomarkers for diagnosis and prognosis, elucidating disease mechanisms, and accelerating the development of new strategies for therapeutic intervention. Here, we review proteomics studies of human brain samples in light of recent advances of mass spectrometry, focusing on the general strategies for experimental design and analysis (e.g., sample pooling and replication, selection of proteomics platforms, and false discovery rate in data processing), because quantitative analysis of clinical samples is confounded by a number of variables, including genetic differences, antemortem and postmortem factors, and experimental errors. Diverse proteomics platforms are also discussed with respect to sensitivity, throughput, and accuracy. Regarding the enormous complexity of the human brain and the limitation of current proteomics technologies, it may be more practical to analyze a subset of proteome in a functional context, in order to facilitate the identification of important disease‐related proteins in the substantial noise reflecting biological and technical variances.
Predicting the order in which contacts are broken during single molecule protein stretching experiments
Authors: Sułkowska Joanna I. , Kloczkowski Andrzej , Sen Taner Z. , Cieplak Marek , Jernigan Robert L. 
Published: October 2007

AbstractWe combine two methods to enable the prediction of the order in which contacts are broken under external stretching forces in single molecule experiments. These two methods are Gō‐like models and elastic network models. The Gō‐like models have shown remarkable success in representing many aspects of protein behavior, including the reproduction of experimental data obtained from atomic force microscopy. The simple elastic network models are often used successfully to predict the fluctuations of residues around their mean positions, comparing favorably with the experimentally measured crystallographic B‐factors. The behavior of biomolecules under external forces has been demonstrated to depend principally on their elastic properties and the overall shape of their structure. We have studied in detail the muscle protein titin and green fluorescent protein and tested for ten other proteins. First, we stretch the proteins computationally by performing stochastic dynamics simulations with the Gō‐like model. We obtain the force–displacement curves and unfolding scenarios of possible mechanical unfolding. We then use the elastic network model to calculate temperature factors (B‐factors) and compare the slowest modes of motion for the stretched proteins and compare them with the predicted order of breaking contacts between residues in the Gō‐like model. Our results show that a simple Gaussian network model is able to predict contacts that break in the next time stage of stretching. Additionally, we have found that the contact disruption is strictly correlated with the highest force exerted by the backbone on these residues. Our prediction of bond‐breaking agrees well with the unfolding scenario obtained with the Gō‐like model. We anticipate that this method will be a useful new tool for interpreting stretching experiments. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Assessing secondary structure assignment of protein structures by using pairwise sequence‐alignment benchmarks
Authors: Zhang Wei , Dunker A. Keith , Zhou Yaoqi 
Published: October 2007

AbstractHow to make an objective assignment of secondary structures based on a protein structure is an unsolved problem. Defining the boundaries between helix, sheet, and coil structures is arbitrary, and commonly accepted standard assignments do not exist. Here, we propose a criterion that assesses secondary structure assignment based on the similarity of the secondary structures assigned to pairwise sequence‐alignment benchmarks, where these benchmarks are determined by prior structural alignments of the protein pairs. This criterion is used to rank six secondary structure assignment methods: STRIDE, DSSP, SECSTR, KAKSI, P‐SEA, and SEGNO with three established sequence‐alignment benchmarks (PREFAB, SABmark, and SALIGN). STRIDE and KAKSI achieve comparable success rates in assigning the same secondary structure elements to structurally aligned residues in the three benchmarks. Their success rates are between 1–4% higher than those of the other four methods. The consensus of STRIDE, KAKSI, SECSTR, and P‐SEA, called SKSP, improves assignments over the best single method in each benchmark by an additional 1%. These results support the usefulness of the sequence‐alignment benchmarks as a means to evaluate secondary structure assignment. The SKSP server and the benchmarks can be accessed at http://sparks.informatics.iupui.edu Proteins 2008. © 2007 Wiley‐Liss, Inc.
Common occurrence of internal repeat symmetry in membrane proteins
Authors: Choi Sungwon , Jeon Jouhyun , Yang Jae‐Seong , Kim Sanguk 
Published: October 2007

AbstractSymmetry plays significant roles in protein structure and function. Particularly, symmetric interfaces are known to act as switches for two‐state conformational change. Membrane proteins often undergo two‐state conformational change during the transport process of ion channels or the active/inactive transitions in receptors. Here, we provide the first comprehensive analyses of internal repeat symmetry in membrane proteins. We examined the known membrane protein structures and found that, remarkably, nearly half of them have internal repeat symmetry. Moreover, we found that the conserved cores of these internal repeats are positioned at the interface of symmetric units when they are mapped on structures. Because of the large sequence divergence that occurs between internal repeats, the inherent symmetry present in protein sequences often has only been detected after structure determination. We therefore developed a sensitive procedure to predict the internal repeat symmetry from sequence information and identified 4653 proteins that are likely to have internal repeat symmetry. Proteins 2008. © 2007 Wiley‐Liss, Inc.
In silico local structure approach: A case study on Outer Membrane Proteins
Authors: Martin Juliette , de Brevern Alexandre G. , Camproux Anne‐Claude 
Published: October 2007

AbstractThe detection of Outer Membrane Proteins (OMP) in whole genomes is an actual question, their sequence characteristics have thus been intensively studied. This class of protein displays a common β‐barrel architecture, formed by adjacent antiparallel strands. However, due to the lack of available structures, few structural studies have been made on this class of proteins. Here we propose a novel OMP local structure investigation, based on a structural alphabet approach, i.e., the decomposition of 3D structures using a library of four‐residue protein fragments. The optimal decomposition of structures using hidden Markov model results in a specific structural alphabet of 20 fragments, six of them dedicated to the decomposition of β‐strands. This optimal alphabet, called SA20‐OMP, is analyzed in details, in terms of local structures and transitions between fragments. It highlights a particular and strong organization of β‐strands as series of regular canonical structural fragments. The comparison with alphabets learned on globular structures indicates that the internal organization of OMP structures is more constrained than in globular structures. The analysis of OMP structures using SA20‐OMP reveals some recurrent structural patterns. The preferred location of fragments in the distinct regions of the membrane is investigated. The study of pairwise specificity of fragments reveals that some contacts between structural fragments in β‐sheets are clearly favored whereas others are avoided. This contact specificity is stronger in OMP than in globular structures. Moreover, SA20‐OMP also captured sequential information. This can be integrated in a scoring function for structural model ranking with very promising results. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Shark IgNAR antibody mimotopes target a murine immunoglobulin through extended CDR3 loop structures
Authors: Simmons David P. , Streltsov Victor A. , Dolezal Olan , Hudson Peter J. , Coley Andrew M. , Foley Michael , Proll David F. , Nuttall Stewart D. 
Published: October 2007

AbstractMimotopes mimic the three‐dimensional topology of an antigen epitope, and are frequently recognized by antibodies with affinities comparable to those obtained for the original antibody–antigen interaction. Peptides and anti‐idiotypic antibodies are two classes of protein mimotopes that mimic the topology (but not necessarily the sequence) of the parental antigen. In this study, we combine these two classes by selecting mimotopes based on single domain IgNAR antibodies, which display exceptionally long CDR3 loop regions (analogous to a constrained peptide library) presented in the context of an immunoglobulin framework with adjacent and supporting CDR1 loops. By screening an in vitro phage‐display library of IgNAR variable domains (VNARs) against the target antigen monoclonal antibody MAb5G8, we obtained four potential mimotopes. MAb5G8 targets a linear tripeptide epitope (AYP) in the flexible signal sequence of the Plasmodium falciparum Apical Membrane Antigen—1 (AMA1), and this or similar motifs were detected in the CDR loops of all four VNARs. The VNARs, 1‐A‐2, −7, −11, and −14, were demonstrated to bind specifically to this paratope by competition studies with an artificial peptide and all showed enhanced affinities (3–46 nM) compared to the parental antigen (175 nM). Crystallographic studies of recombinant proteins 1‐A‐7 and 1‐A‐11 showed that the SYP motifs on these VNARs presented at the tip of the exposed CDR3 loops, ideally positioned within bulge‐like structures to make contact with the MAb5G8 antibody. These loops, in particular in 1‐A‐11, were further stabilized by inter‐ and intra‐ loop disulphide bridges, hydrogen bonds, electrostatic interactions, and aromatic residue packing. We rationalize the higher affinity of the VNARs compared to the parental antigen by suggesting that adjacent CDR1 and framework residues contribute to binding affinity, through interactions with other CDR regions on the antibody, though of course definitive support of this hypothesis will rely on co‐crystallographic studies. Alternatively, the selection of mimotopes from a large (<4 × 108) constrained library may have allowed selection of variants with even more favorable epitope topologies than present in the original antigenic structure, illustrating the power of in vivo selection of mimotopes from phage‐displayed molecular libraries. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Molecular dynamics simulations of domain motions of substrate‐free S‐adenosyl‐ L‐homocysteine hydrolase in solution
Authors: Hu Chen , Fang Jianwen , Borchardt Ronald T. , Schowen Richard L. , Kuczera Krzysztof 
Published: October 2007

AbstractS‐Adenosyl‐L‐homocysteine hydrolase (SAHH) is an enzyme regulating intracellular methylation reactions. The homotetrameric SAHH exists in an open conformation in absence of substrate, while enzyme:inhibitor complexes crystallize in the closed conformation, in which the ligands are engulfed by the protein due to an 18° domain reorientation within each of the four subunits. We present a microscopic description of the structure and dynamics of the substrate‐free, NAD+‐bound SAHH in solution, based on a 15‐ns molecular dynamics simulation in explicit solvent. In the trajectory, the four cofactor‐binding domains formed a relatively rigid core with structure very similar to the crystal conformation. The four substrate‐binding domains, located at the protein exterior, also retained internal structures similar to the crystal, while undergoing large amplitude rigid‐body reorientations. The trajectory domain motions exhibited two interesting properties. First, within each subunit the domains fluctuated between open and closed conformations, while at the tetramer level 80% of the domain motions were perpendicular to the direction of the open‐to‐closed structural transition. Second, the domain reorientations in solution could be represented as a sum of two components, faster, with 20–50 ps correlation time and 3–4° amplitude, and slower, with 8–23 ns correlation time and amplitude of 14–22°. The faster motion is similar to the 1.5 cm−1 frequency hinge‐bending vibrations found in our recent normal mode analysis (Wang et al., Biochemistry 2005;44:7228–7239). The slower motion agrees with fluorescence anisotropy decay measurements, which detected a 10–20 ns domain reorientation of ca. 26° amplitude in the substrate‐free enzyme (Wang et al., Biochemistry 2006;45:7778–7786). Our simulations are thus in excellent agreement with experimental data. The simulations allow us to assign the observed nanosecond fluorescence anisotropy signal to fluctuations in domain orientations, and indicate that the microscopic mechanism of the motion involves rotational diffusion within a cone of 10–20°. Overall, our simulation results complement the existing experimental data and provide important new insights into SAHH domain motions in solution, which play a crucial role in the catalytic mechanism of SAHH. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Electrostatic rate enhancement and transient complex of protein–protein association
Authors: Alsallaq Ramzi , Zhou Huan‐Xiang 
Published: October 2007

AbstractThe association of two proteins is bounded by the rate at which they, via diffusion, find each other while in appropriate relative orientations. Orientational constraints restrict this rate to ∼105–106 M−1 s−1. Proteins with higher association rates generally have complementary electrostatic surfaces; proteins with lower association rates generally are slowed down by conformational changes upon complex formation. Previous studies (Zhou, Biophys J 1997;73:2441–2445) have shown that electrostatic enhancement of the diffusion‐limited association rate can be accurately modeled by
$k_{\bf D}$
= $k_{D}0\ {exp} ( - \langle U_{el} \rangle^{\star}/k_{B} T),$
where kD and kD0 are the rates in the presence and absence of electrostatic interactions, respectively, 〈Uel〉☆ is the average electrostatic interaction energy in a “transient‐complex” ensemble, and kBT is the thermal energy. The transient‐complex ensemble separates the bound state from the unbound state. Predictions of the transient‐complex theory on four protein complexes were found to agree well with the experiment when the electrostatic interaction energy was calculated with the linearized Poisson–Boltzmann (PB) equation (Alsallaq and Zhou, Structure 2007;15:215–224). Here we show that the agreement is further improved when the nonlinear PB equation is used. These predictions are obtained with the dielectric boundary defined as the protein van der Waals surface. When the dielectric boundary is instead specified as the molecular surface, electrostatic interactions in the transient complex become repulsive and are thus predicted to retard association. Together these results demonstrate that the transient‐complex theory is predictive of electrostatic rate enhancement and can help parameterize PB calculations. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Improved model building and assessment of the Calcium‐sensing receptor transmembrane domain
Authors: Bu Lintao , Michino Mayako , Wolf Romain M. , Brooks Charles L. 
Published: October 2007

AbstractA three‐dimensional model of the human Calcium‐sensing receptor (CaSR) seven transmembrane domain was built via a novel sequence alignment method based on the conserved contacts in proteins using the crystal structure of bovine rhodopsin as the template. This model was tested by docking NPS 2143, the first identified allosteric antagonist of CaSR. In our model, Glu837 plays a critical role in anchoring the protonated nitrogen atom and hydroxy oxygen atom of NPS 2143. The phenyl moiety of the ligand contacts residues Phe668, Pro672, and Ile841. The naphthalene moiety is surrounded by several hydrophobic residues, including Phe684, Phe688, and Phe821. Our model appears to be consistent with all six residues that have been demonstrated to be critical for NPS 2143 binding, in contrast with existing homology models based on traditional sequence alignment of CaSR to rhodopsin. This provides validation of our sequence alignment method and the use of the rhodopsin backbone as the initial structure in homology modeling of other G protein‐coupled receptors that are not members of the rhodopsin family. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Do collagenases unwind triple‐helical collagen before peptide bond hydrolysis? Reinterpreting experimental observations with mathematical models
Authors: Nerenberg Paul S. , Salsas‐Escat Ramon , Stultz Collin M. 
Published: October 2007

AbstractIt has been postulated that triple‐helical collagen is actively unwound by collagenases before peptide bond hydrolysis—a supposition that explains the small catalytic rate constant associated with collagenolysis. We propose an alternate model of collagen degradation that does not require active unwinding by collagenases, but instead suggests that the regions of collagen near the collagenase cleavage site can adopt either a native triple‐helical or a partially unfolded conformation. In this model, collagenases preferentially bind to and stabilize partially unfolded conformers before cleaving the scissile bond. Existing experimental observations (which were previously taken to support active unwinding models) are reinterpreted using corroborative evidence from numerical simulations and found to be consistent with this framework. These data support the notion that collagen, like all other biological heteropolymers, undergoes thermal fluctuations that cause it to sample distinct structures in the neighborhood of the native state, and collagenolysis occurs when collagenases recognize the appropriate unwound conformers. Proteins 2008. © 2007 Wiley‐Liss, Inc.