bluuebunny/crossref_metadata_2025_split huggingface dataset:
The accumulation of versican in the nodules of benign prostatic hyperplasia
Authors: True Lawrence D. , Hawley Sarah , Norwood Thomas H. , Braun Kathleen R. , Evanko Stephen P. , Chan Christina K. , LeBaron Richard C. , Wight Thomas N. 
Published: September 2008

AbstractBACKGROUNDProteoglycans, a complex group of extracellular matrix (ECM) molecules, are elevated in benign prostatic hyperplasia (BPH). Versican is a stromal proteoglycan present in prostate tissue. Versican expression is elevated in tissues with increased proliferation. Based on these observations, we determined the extent and distribution of versican expression in prostates with BPH.METHODSThe involvement of versican in BPH nodules was compared with levels in non‐nodular transition (TZ) and peripheral zone (PZ) tissues from 18 human prostate glands using immunohistochemistry, Northern blots and/or QRTPCR to localize versican and quantify versican mRNA transcript levels, and Western blots to assess gene product levels.RESULTSIncreased versican immunoreactivity was observed in the stroma of BPH nodules. Higher steady state levels of versican variants V0, V1, and V3 mRNA transcript and gene product were detected in the nodular tissues than in the non‐nodular TZ or PZ parenchyma.CONCLUSIONSThese results suggest that versican may play a role in nodule formation in BPH. Prostate 69: 149–158, 2009. © 2008 Wiley–Liss, Inc.
Inflammatory processes of prostate tissue microenvironment drive rat prostate carcinogenesis: Preventive effects of celecoxib
Authors: Narayanan Narayanan K. , Nargi Dominick , Horton Lori , Reddy Bandaru S. , Bosland Maarten C. , Narayanan Bhagavathi A. 
Published: September 2008

AbstractBACKGROUNDProstate tissue microenvironment is susceptible to several risk factors including carcinogens, dietary factors, hormones, cytokines and growth factors that could induce chronic inflammation. Because of the difference in the serum levels and the intrinsic ability of monocytes/macrophages to cause harm, the transcriptional responses triggered by inflammatory stimuli must be controlled. Unfortunately, an in‐depth association between prostate cancer and potential mediators of inflammation has not been completely investigated.METHODSTo determine whether activated macrophage (infiltrating monocytes), iNOS and NF‐κB are primary mediators of inflammation, besides COX‐2, in prostate carcinogenesis, we examined tissue sections of rat prostate tumor induced by N‐methyl‐N‐nitrosourea (MNU) plus testosterone in a follow‐up study. We performed H&E and immunohsitochemical staining of the prostate tissue to detect specific markers of inflammation.RESULTSWe report an increase in infiltrating monocyte, iNOS, NF‐κBp65, VEGF and TNF‐α at the early and advanced stages of tumor growth in MNU plus testosterone treated rats. Monocyte infiltration was often found in the stromal and perivascular regions of the DL prostate. We conclude for the first time that prostate cancer induced by MNU plus testosterone partly involves mediators of inflammation which could trigger the process of carcinogenesis and cause loss of apoptosis. Selective COX‐2 inhibitor celecoxib at a dose of 500 mg/kg/bw administered for 52 weeks reduced infiltrating monocytes, inhibited iNOS, NF‐κB p65 expression, induced apoptosis and tumor growth inhibition.CONCLUSIONCarcinogen plus testosterone induced prostate carcinogenesis showing activation of macrophage, iNOS and NF‐κBp65 could be prevented by celecoxib or related anti‐inflammatory agents. Prostate 69: 133–141, 2009. © 2008 Wiley–Liss, Inc.
Trapping open and closed forms of FitE—A group III periplasmic binding protein
Authors: Shi Rong , Proteau Ariane , Wagner John , Cui Qizhi , Purisima Enrico O. , Matte Allan , Cygler Miroslaw 
Published: September 2008

AbstractPeriplasmic binding proteins (PBPs) are essential components of bacterial transport systems, necessary for bacterial growth and survival. The two‐domain structures of PBPs are topologically classified into three groups based on the number of crossovers or hinges between the globular domains: group I PBPs have three connections, group II have two, and group III have only one. Although a large number of structures for group I or II PBPs are known, fewer group III PBPs have been structurally characterized. Group I and II PBPs exhibit significant domain motions during transition from the unbound to ligand‐bound form, however, no large conformational changes have been observed to date in group III PBPs. We have solved the crystal structure of a periplasmic binding protein FitE, part of an iron transport system, fit, recently identified in a clinical E. coli isolate. The structure, determined at 1.8 Å resolution, shows that FitE is a group III PBP containing a single α‐helix bridging the two domains. Among the individual FitE molecules present in two crystal forms we observed three different conformations (open, closed, intermediate). Our crystallographic and molecular dynamics results strongly support the notion that group III PBPs also adopt the same Venus flytrap mechanism as do groups I and II PBPs. Unlike other group III PBPs, FitE forms dimers both in solution and in the crystals. The putative siderophore binding pocket is lined with arginine residues, suggesting an anionic nature of the iron‐containing siderophore. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Unifying mechanical and thermodynamic descriptions across the thioredoxin protein family
Authors: Mottonen James M. , Xu Minli , Jacobs Donald J. , Livesay Dennis R. 
Published: September 2008

AbstractWe compare various predicted mechanical and thermodynamic properties of nine oxidized thioredoxins (TRX) using a Distance Constraint Model (DCM). The DCM is based on a nonadditive free energy decomposition scheme, where entropic contributions are determined from rigidity and flexibility of structure based on distance constraints. We perform averages over an ensemble of constraint topologies to calculate several thermodynamic and mechanical response functions that together yield quantitative stability/flexibility relationships (QSFR). Applied to the TRX protein family, QSFR metrics display a rich variety of similarities and differences. In particular, backbone flexibility is well conserved across the family, whereas cooperativity correlation describing mechanical and thermodynamic couplings between the residue pairs exhibit distinctive features that readily standout. The diversity in predicted QSFR metrics that describe cooperativity correlation between pairs of residues is largely explained by a global flexibility order parameter describing the amount of intrinsic flexibility within the protein. A free energy landscape is calculated as a function of the flexibility order parameter, and key values are determined where the native‐state, transition‐state, and unfolded‐state are located. Another key value identifies a mechanical transition where the global nature of the protein changes from flexible to rigid. The key values of the flexibility order parameter help characterize how mechanical and thermodynamic response is linked. Variation in QSFR metrics and key characteristics of global flexibility are related to the native state X‐ray crystal structure primarily through the hydrogen bond network. Furthermore, comparison of three TRX redox pairs reveals differences in thermodynamic response (i.e., relative melting point) and mechanical properties (i.e., backbone flexibility and cooperativity correlation) that are consistent with experimental data on thermal stabilities and NMR dynamical profiles. The results taken together demonstrate that small‐scale structural variations are amplified into discernible global differences by propagating mechanical couplings through the H‐bond network. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Structure of the S1S2 glutamate binding domain of GLuR3
Authors: Ahmed Ahmed H. , Wang Qi , Sondermann Holger , Oswald Robert E. 
Published: September 2008

AbstractGlutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system. Determining the structural differences between the binding sites of different subtypes is crucial to our understanding of neuronal circuits and to the development of subtype specific drugs. The structures of the binding domain (S1S2) of the GluR3 (flip) AMPA receptor subunit bound to glutamate and AMPA and the GluR2 (flop) subunit bound to glutamate were determined by X‐ray crystallography to 1.9, 2.1, and 1.55 Å, respectively. Overall, the structure of GluR3 (flip) S1S2 is very similar to GluR2 (flop) S1S2 (backbone RMSD of 0.30 ± 0.05 for glutamate‐bound and 0.26 ± 0.01 for AMPA‐bound). The differences in the flip and flop isoforms are subtle and largely arise from one hydrogen bond across the dimer interface and associated water molecules. Comparison of the binding affinity for various agonists and partial agonists suggest that the S1S2 domains of GluR2 and GluR3 show only small differences in affinity, unlike what is found for the intact receptors (with the exception of one ligand, Cl‐HIBO, which has a 10‐fold difference in affinity for GluR2 vs. GluR3). Proteins 2009. © 2008 Wiley‐Liss, Inc.
Backbone conformations and side chain flexibility of two somatostatin mimics investigated by molecular dynamics simulations
Authors: Interlandi Gianluca 
Published: September 2008

AbstractMolecular dynamics simulations with two designed somatostatin mimics, SOM230 and SMS 201‐995, were performed in explicit water for a total aggregated time of 208 ns. Analysis of the runs with SOM230 revealed the presence of two clusters of conformations. Strikingly, the two sampled conformers correspond to the two main X‐ray structures in the asymmetric unit of SMS 201‐995. Structural comparison between the residues of SOM230 and SMS 201‐995 provides an explanation for the high binding affinity of SOM230 to four of five somatostatin receptors. Similarly, cluster analysis of the simulations with SMS 201‐995 shows that the backbone of the peptide interconverts between its two main crystallographic conformers. The conformations of SMS 201‐995 sampled in the two clusters violated two different sets of NOE distance constraints in agreement with a previous NMR study. Differences in side chain fluctuations between SOM230 and SMS 201‐995 observed in the simulations may contribute to the relatively higher binding affinity of SOM230 to most somatostatin receptors. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Accurate prediction for atomic‐level protein design and its application in diversifying the near‐optimal sequence space
Authors: Fromer Menachem , Yanover Chen 
Published: September 2008

AbstractThe task of engineering a protein to assume a target three‐dimensional structure is known as protein design. Computational search algorithms are devised to predict a minimal energy amino acid sequence for a particular structure. In practice, however, an ensemble of low‐energy sequences is often sought. Primarily, this is performed because an individual predicted low‐energy sequence may not necessarily fold to the target structure because of both inaccuracies in modeling protein energetics and the nonoptimal nature of search algorithms employed. Additionally, some low‐energy sequences may be overly stable and thus lack the dynamic flexibility required for biological functionality. Furthermore, the investigation of low‐energy sequence ensembles will provide crucial insights into the pseudo‐physical energy force fields that have been derived to describe structural energetics for protein design. Significantly, numerous studies have predicted low‐energy sequences, which were subsequently synthesized and demonstrated to fold to desired structures. However, the characterization of the sequence space defined by such energy functions as compatible with a target structure has not been performed in full detail. This issue is critical for protein design scientists to successfully continue using these force fields at an ever‐increasing pace and scale. In this paper, we present a conceptually novel algorithm that rapidly predicts the set of lowest energy sequences for a given structure. Based on the theory of probabilistic graphical models, it performs efficient inspection and partitioning of the near‐optimal sequence space, without making any assumptions of positional independence. We benchmark its performance on a diverse set of relevant protein design examples and show that it consistently yields sequences of lower energy than those derived from state‐of‐the‐art techniques. Thus, we find that previously presented search techniques do not fully depict the low‐energy space as precisely. Examination of the predicted ensembles indicates that, for each structure, the amino acid identity at a majority of positions must be chosen extremely selectively so as to not incur significant energetic penalties. We investigate this high degree of similarity and demonstrate how more diverse near‐optimal sequences can be predicted in order to systematically overcome this bottleneck for computational design. Finally, we exploit this in‐depth analysis of a collection of the lowest energy sequences to suggest an explanation for previously observed experimental design results. The novel methodologies introduced here accurately portray the sequence space compatible with a protein structure and further supply a scheme to yield heterogeneous low‐energy sequences, thus providing a powerful instrument for future work on protein design. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Mechanical stability and differentially conserved physical–chemical properties of titin Ig‐domains
Authors: Garcia Tzintzuni I. , Oberhauser Andres F. , Braun Werner 
Published: September 2008

AbstractThe mechanisms that determine mechanical stabilities of protein folds remain elusive. Our understanding of these mechanisms is vital to both bioengineering efforts and to the better understanding and eventual treatment of pathogenic mutations affecting mechanically important proteins such as titin. We present a new approach to analyze data from single‐molecule force spectroscopy for different domains of the giant muscle protein titin. The region of titin found in the I‐band of a sarcomere is composed of about 40 Ig‐domains and is exposed to force under normal physiological conditions and connects the free‐hanging ends of the myosin filaments to the Z‐disc. Recent single‐molecule force spectroscopy data show a mechanical hierarchy in the I‐band domains. Domains near the C‐terminus in this region unfold at forces two to three times greater than domains near the beginning of the I‐band. Though all of these Ig‐domains are thought to share a fold and topology common to members of the Ig‐like fold family, the sequences of neighboring domains vary greatly with an average sequence identity of only 25%. We examine in this study the relation of these unique mechanical stabilities of each I‐band Ig domain to specific, conserved physical–chemical properties of amino acid sequences in related Ig domains. We find that the sequences of each individual titin Ig domain are very highly conserved, with an average sequence identity of 79% across species that are divergent as humans, chickens, and zebra fish. This indicates that the mechanical properties of each domain are well conserved and tailored to its unique position in the titin molecule. We used the PCPMer software to determine the conservation of amino acid properties in titin Ig domains grouped by unfolding forces into “strong” and “weak” families. We found two motifs unique to each family that may have some role in determining the mechanical properties of these Ig domains. A detailed statistical analysis of properties of individual residues revealed several positions that displayed differentially conserved properties in strong and weak families. In contrast to previous studies, we find evidence that suggests that the mechanical stability of Ig domains is determined by several residues scattered across the β‐sandwich fold, and force sensitive residues are not only confined to the A′‐G region. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Unusual role of the substrate in droplet‐induced GaAs/AlGaAs quantum‐dot pairs
Authors: Wang Zh. M. , Mazur Yu. I. , Sablon K. A. , Mishima T. D. , Johnson M. B. , Salamo G. J. 
Published: September 2008

AbstractThe structural complexity of GaAs quantum‐dot pairs has been revealed by cross‐sectional transmission electron microscopy. As a result of high‐temperature droplet epitaxy, the AlGaAs substrate beneath the quantum‐dot pairs is no longer immobile and its reconstruction is observed to define the crystallization of gallium droplets under an arsenic flux. The GaAs quantum‐dot pairs are immersed into the substrate and further confined by the re‐distributed AlGaAs materials above the substrate plane. There are two underlying mechanisms responsible for the final nanostructure configuration, melt‐back etching by the gallium droplets and preferential crystallization of gallium around reconstructed sidewalls. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
3D‐Quantitative Structure‐Activity Relationships: Nonlinear Dependence Described Directly from 3D Structures Using a Comparative Molecular Field Analysis (CoMFA) Approach
Authors: Kim Ki Hwan 
Published: September 2008

AbstractThe applicability of the comparative molecular field analysis (CoMFA) approach to describe the parabolic or bilinear dependence of biological activity on hydrophobicity in 3D quantitative structure‐activity relationships (QSAR) has been investigated. Molecular fields calculated with a H2O probe produced significant correlations with excellent cross‐validation. The results indicate that the CoMFA approach is an excellent methodology for describing nonlinear effects in 3D QSAR studies.
Fuzzy Adaptive Least Squares and Its Application to Structure‐Activity Studies
Authors: Moriguchi Ikuo , Hirono Shuichi , Liu Qian , Nakagome Izumi 
Published: September 2008

AbstractFuzzy adaptive least squares (FALS91), a pattern recognition method for analyzing structure‐activity rating data to generate QSAR models, has been developed. A novel feature of FALS91 is that the degree to which each sample belongs to its activity class is given using a fuzzy membership function. This paper first describes the algorithm and calculation procedure of FALS91, and then shows its application to the correlation of structure with the activity rating of 31 calmodulin inhibitors and 29 α‐methylene‐γ‐butyrolactones with allergenic activity. Considerably high reliability was shown in both recognition and leave‐one‐out prediction of the FALS91 analyses.
The Use of Computerized Molecular Structure Scanning and Principal Component Analysis to Calculate Molecular Descriptors for QSAR
Authors: Hemken Heinz G. , Lehmann F. Pedro A. 
Published: September 2008

AbstractA simple computerized molecular structure scanning method was developed for generating a large, fixed number of calculated structural variables based on model structures derived from force‐field and quantum mechanics methods. These were reduced to one or a few parameters for QSAR studies by means of principal component analysis. When analyzed by principal component regression, the resulting descriptors summarize such gross features as electron distribution and substituent shape and volume very well. For two data sets (some substituted amphetamine hallucinogens and some dihydropyridine vasodilators), these calculated parameters were at least equivalent in their ability to model drug potency to those commonly used in QSAR.
QSAR and Molecular Modelling Studies on Histamine H1‐Receptor Antagonists
Authors: Laak Anton M. Ter , van Drooge Marc J. , Timmerman Hendrik , den Kelder Gabrielle M. Donné‐Op 
Published: September 2008

AbstractIn this review article all relevant QSAR and molecular modelling studies that have been performed on both classical and non‐classical histamine H1‐antagonists are evaluated. Comparison of the results from these studies gives more insight into the physico‐chemical and conformational features that define receptor binding of H1‐antagonists. QSAR analyses indicate that at least seven classes of classical H1‐antagonists bind at the same receptor site. For these compounds a basic amino‐group, an aromatic ring (the so‐called “cis”‐ring) and a hydrophobic group (at the position of the so‐called “trans”‐ring) are essential for receptor binding. Similarities in the QSAR equations of diphenhydramines, mono‐phenyl analogues of diphenhydramines and benzimidazoles show that hydrophobic and steric factors are important for binding at the “trans”‐ring location. In literature it has been suggested that both aromatic rings of the non‐classical OPPI compounds can be superimposed in a folded conformation on the “cis”‐ and “trans”‐ring of the classical H1‐antagonist model. Although this idea remains interesting, QSAR data indicate that the proposed superimposition is probably not valid.Most molecular modelling studies performed on H1‐antagonists appear to have major draw‐backs: (1) e.g. only crystal structures were studied andor (2) antagonists were superimposed on the agonist histamine, whereas no experimental evidence is available that agonists and antagonists occupy similar receptor sites and/or (3) not all low energy conformations were considered. The most important conclusion that can be drawn from these modelling studies is that the optimal distance between the basic nitrogen atom and one of the aromatic rings is around 6 Å. Furthermore, two models of the H1‐antagonist binding site based on superimposition of antagonists on the classical semi‐rigid compound cyproheptadine are compared. It is concluded that cyproheptadine with the piperidylene ring in a boat conformation can be be used as a template for further modelling studies.
Development and validation of an analytical method for the simultaneous determination of cocaine and its main metabolite, benzoylecgonine, in human hair by gas chromatography/mass spectrometry
Authors: Barroso M. , Dias M. , Vieira D. N. , Queiroz J. A. , López‐Rivadulla M. 
Published: September 2008

AbstractA new, simple and rapid procedure has been developed and validated for the determination of cocaine and its main metabolite, benzoylecgonine, in human hair samples. After extraction from within the hair matrix by a mixture of methanol/hydrochloric acid (2:1) at 65°C for 3 h, and sample cleanup by mixed‐mode solid‐phase extraction (SPE), the extracts were analyzed by gas chromatography/mass spectrometry (GC/MS), after derivatization with N‐methyl‐N‐(trimethylsilyl)trifluoroacetamide with 5% chlorotrimethylsilane. Using a sample size of only 20 mg of hair, limits of detection (LODs) and quantitation (LOQs) were, respectively, 20 and 50 pg/mg for cocaine, and 15 and 50 pg/mg for benzoylecgonine, achieving the cut‐off values proposed by the Society of Hair Testing for the analysis of these compounds in hair. The method was found to be linear (weighing factor of 1/x) between the LOQ and 20 ng/mg for both compounds, with correlation coefficients ranging from 0.9974 to 0.9996 for cocaine; and from 0.9981 to 0.9994 for benzoylecgonine. Intra‐ and interday precision and accuracy were in conformity with the criteria normally accepted in bioanalytical method validation. The sample cleanup step presented a mean absolute recovery greater than 90% for both compounds. The developed method may be useful in forensic toxicology laboratories for the analysis of cocaine and benzoylecgonine in hair samples, taking into account its speed (only 3 h are required for the extraction of the analytes from within the matrix, whereas 5 h or even overnight extractions have been reported) and the low limits achieved (using a single quadrupole mass spectrometer, which is available in most laboratories). Copyright © 2008 John Wiley & Sons, Ltd.