bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA
Authors: Chitty Lyn S. , Khalil Asma , Barrett Angela N. , Pajkrt Eva , Griffin David R. , Cole Tim J. 
Published: February 2013

ABSTRACTObjectiveTo improve the prenatal diagnosis of thanatophoric dysplasia by defining the change in fetal size across gestation and the frequency of sonographic features, and developing non‐invasive molecular genetic diagnosis based on cell‐free fetal DNA (cffDNA) in maternal plasma.MethodsFetuses with a confirmed diagnosis of thanatophoric dysplasia were ascertained, records reviewed, sonographic features and measurements determined. Charts of fetal size were then constructed using the LMS (lambda‐mu‐sigma) method and compared with charts used in normal pregnancies and those complicated by achondroplasia. Cases in this cohort referred to our Regional Genetics Laboratory for molecular diagnosis using cffDNA were identified and results reviewed.ResultsForty‐two cases were scanned in our units. Commonly reported sonographic features were very short and sometimes bowed femora, frontal bossing, cloverleaf skull, short fingers, a small chest and polyhydramnios. Limb shortening was obvious from as early as 13 weeks' gestation, with minimal growth after 20 weeks. Analysis of cffDNA in three of these pregnancies confirmed the presence of the c.742C>CT (p.Arg248Cys) or the c.1948A>AG (p.Lys650Glu) mutation in the fibroblast growth factor receptor 3 gene.ConclusionThese data should improve the accuracy of the sonographic diagnosis of thanatophoric dysplasia and have implications for reliable and safe targeted molecular confirmation using cffDNA. © 2013 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
Propoxyphene and the risk of out‐of‐hospital death
Authors: Ray Wayne A. , Murray Katherine T. , Kawai Vivian , Graham David J. , Cooper William O. , Hall Kathi , Michael Stein Charles 
Published: February 2013

ABSTRACTPurposeThe opioid analgesic propoxyphene was withdrawn from the US market in 2010, motivated by concerns regarding fatality in overdose and adverse cardiac effects, including prolongation of the QT interval. These concerns were based on case reports, summary vital statistics, and surrogate endpoint studies.MethodsUsing the linked Tennessee Medicaid database (1992–2007), we conducted a retrospective cohort study that compared risk of sudden cardiac, medication toxicity, and total out‐of‐hospital death for propoxyphene users with that for comparable nonusers of any prescribed opioid analgesic and users of hydrocodone, an opioid with similar indications. Cohort members had 1 873 500 propoxyphene prescriptions, 1 873 500 matched nonuser control periods, and 936 750 matched hydrocodone prescriptions.ResultsCurrent propoxyphene users had no increased risk for sudden cardiac death (versus nonusers: hazard ratio [HR] = 1.00 [0.81–1.23]; versus current hydrocodone users: HR = 0.91 [0.68–1.21]) but did have increased risk for medication toxicity deaths (versus nonusers: HR = 1.85 [1.07–3.19], p = 0.027; versus current hydrocodone users: HR = 2.10 [0.87–5.10], p = 0.100). Because toxicity deaths were a small proportion of study deaths, total out‐of‐hospital mortality differed by less than 10% between the study groups and was not significantly elevated for propoxyphene (versus nonusers: HR = 1.09 [0.95–1.25]; versus current hydrocodone users: HR = 1.06 [0.87–1.29] ).ConclusionsOur findings support the concern that propoxyphene has greater toxicity in overdose but do not provide evidence that it increases the risk of sudden cardiac death. Copyright © 2013 John Wiley & Sons, Ltd.
Poly(ethylene glycol)‐modulated cellular biocompatibility of polyhydroxyalkanoate films
Authors: Chan Rodman TH , Marçal Helder , Ahmed Tania , Russell Robert A , Holden Peter J , Foster L John R 
Published: February 2013

AbstractPolyhydroxybutyrate (PHB) and its copolymer with hydroxyvalerate, P(HB‐co‐HV), are widely used biomaterials. In this study, improvements of their biological properties of degradability and compatibility were achieved by blending with low‐molecular‐weight poly(ethylene glycol) (PEG106) approved for medical use. Surface morphology and chemistry are known to support cell attachment. Attachment and proliferation of neural olfactory ensheathing cells increased by 17.0 and 32.2% for PHB and P(HB‐co‐HV) composite films. Cell attachment was facilitated by increases in surface hydrophilicity, water contact angles decreased by 26 ± 2° and water uptake increased by 23.3% depending upon biopolymer and PEG loading. Cells maintained high viability (>95%) on the composite films with no evidence of cytotoxic effects. Assays of mitochondrial function and cell leakage showed improved cell health as a consequence of PEG loading. The PEG component was readily solubilised from composite films, allowing control of degradation profiles in the cell growth medium. Promotion of biopolymer compatibility and degradability was not at the expense of material properties, with the extension to break of the composites increasing by 5.83 ± 1.06%. Similarly, crystallinity decreased by 36%. The results show that blending of common polyhydroxyalkanoate biomaterials with low‐molecular‐weight PEG can be used to promote biocompatibility and manipulate physiochemical and material properties as well as degradation.© 2013 Society of Chemical Industry
GSAFold: A new application of GSA to protein structure prediction
Authors: Melo Marcelo C. R. , Bernardi Rafael C. , Fernandes Tácio V. A. , Pascutti Pedro G. 
Published: February 2013

AbstractThe folding process defines three‐dimensional protein structures from their amino acid chains. A protein's structure determines its activity and properties; thus knowing such conformation on an atomic level is essential for both basic and applied studies of protein function and dynamics. However, the acquisition of such structures by experimental methods is slow and expensive, and current computational methods mostly depend on previously known structures to determine new ones. Here we present a new software called GSAFold that applies the generalized simulated annealing (GSA) algorithm on ab initio protein structure prediction. The GSA is a stochastic search algorithm employed in energy minimization and used in global optimization problems, especially those that depend on long‐range interactions, such as gravity models and conformation optimization of small molecules. This new implementation applies, for the first time in ab initio protein structure prediction, an analytical inverse for the Visitation function of GSA. It also employs the broadly used NAMD Molecular Dynamics package to carry out energy calculations, allowing the user to select different force fields and parameterizations. Moreover, the software also allows the execution of several simulations simultaneously. Applications that depend on protein structures include rational drug design and structure‐based protein function prediction. Applying GSAFold in a test peptide, it was possible to predict the structure of mastoparan‐X to a root mean square deviation of 3.00 Å. Proteins 2012; © 2012 Wiley Periodicals, Inc.
Peptide binding to the PDZ3 domain by conformational selection
Authors: Steiner Sandra , Caflisch Amedeo 
Published: February 2013

AbstractThe PDZ domains, a large family of peptide recognition proteins, bind to the C‐terminal segment of membrane ion channels and receptors thereby mediating their localization. The peptide binding process is not known in detail and seems to differ among different PDZ domains. For the third PDZ domain of the synaptic protein PSD‐95 (PDZ3), a lock‐and‐key mechanism was postulated on the basis of the almost perfect overlap of the crystal structures in the presence and absence of its peptide ligand. Here, peptide binding to PDZ3 is investigated by explicit solvent molecular dynamics (MD) simulations (for a total of 1.3 μs) and the cut‐based free energy profile method for determining free energy barriers and basins. The free energy landscape of apo PDZ3 indicates that there are multiple basins within the native state. These basins differ by the relative orientation of the α2 helix and β2 strand, the two secondary structure elements that make up the peptide binding site. Only the structure with the smallest aperture of the binding site is populated in the MD simulations of the complex whose analysis reveals that the peptide ligand binds to PDZ3 by selecting one of three conformations. Thus, the dynamical information obtained by the atomistic simulations increment the static, that is, partial, picture of the PDZ3 binding mechanism based on the X‐ray crystallography data. Importantly, the simulation results show for the first time that conformational selection is a possible mechanism of peptide binding by PDZ domains in general. Proteins 2012. © 2012 Wiley Periodicals, Inc.
Identification, structural, and biochemical characterization of a group of large Csn2 proteins involved in CRISPR‐mediated bacterial immunity
Authors: Lee Kwang‐Hoon , Lee Seong‐Gyu , Eun Lee Kyung , Jeon Hyesung , Robinson Howard , Oh Byung‐Ha 
Published: February 2013

AbstractMany prokaryotic organisms acquire immunity against foreign genetic material by incorporating a short segment of foreign DNA called spacer into chromosomal loci, termed clustered regularly interspaced short palindromic repeats (CRISPRs). The encoded RNAs are processed into small fragments that guide the silencing of the invading genetic elements. The CRISPR‐associated (Cas) proteins are the main executioners of these processes. Herein, we report the crystal structure of Stu0660 of Streptococcus thermophilus, a Cas protein involved in the acquisition of new spacers. By homotetramerization, Stu0660 forms a central channel which is decorated with basic amino acids and binds linear double‐stranded DNA (dsDNA), but not circular dsDNA. Despite undetectably low sequence similarity, two N‐terminal domains of Stu0660 are similar to the entire structure of an Enterococcus faecalis Csn2 protein, which also forms a homotetramer and binds dsDNA. Thus, this work identifies a previously unknown group of Stu0660‐like Csn2 proteins (∼350 residues), which are larger than the known canonical Csn2 proteins (∼220 residues) by containing an extra C‐terminal domain. The commonly present central channel in the two subgroups appears as a design to selectively interact with linear dsDNA. Proteins 2012. © 2012 Wiley Periodicals, Inc.
The catalytic domain of the germination‐specific lytic transglycosylase SleB from Bacillus anthracis displays a unique active site topology
Authors: Jing Xing , Robinson Howard R. , Heffron Jared D. , Popham David L. , Schubot Florian D. 
Published: February 2013

AbstractBacillus anthracis produces metabolically inactive spores. Germination of these spores requires germination‐specific lytic enzymes (GSLEs) that degrade the unique cortex peptidoglycan to permit resumption of metabolic activity and outgrowth. We report the first crystal structure of the catalytic domain of a GSLE, SleB. The structure revealed a transglycosylase fold with unique active site topology and permitted identification of the catalytic glutamate residue. Moreover, the structure provided insights into the molecular basis for the specificity of the enzyme for muramic‐δ‐lactam‐containing cortex peptidoglycan. The protein also contains a metal‐binding site that is positioned directly at the entrance of the substrate‐binding cleft. Proteins 2012;. © 2012 Wiley Periodicals, Inc.
Analysis of the movements of helices in EF‐hands
Authors: Kawasaki Hiroshi , Kretsinger Robert H. 
Published: February 2013

AbstractWe have developed a method to place an EF‐lobe in a coordinate system that recognizes the similarity of its two EF‐hand domains as well as their relationship by a pseudo‐two fold axis, z. The x‐axis connects the center of mass, calculated from α‐carbons of helices E1 and F1, with the center of mass of E2 and F2. The resulting coordinate system is intrinsic to each EF‐lobe and requires no comparison with other EF‐lobes. It has provided an intuitive and informative way to compare EF‐lobes and especially those changes associated with calcium and/or target binding. We analyzed the EF‐lobes of calmodulin and of other subfamilies with four EF‐hands. We have rationalized a complex pattern of changes of conformation associated with calcium coordination and effector binding as observed in different subfamilies of EF‐hand proteins. Proteins 2012. © 2012 Wiley Periodicals, Inc.
Characterizing the morphology of protein binding patches
Authors: Malod‐Dognin Noël , Bansal Achin , Cazals Frédéric 
Published: February 2013

AbstractLet the patch of a partner in a protein complex be the collection of atoms accounting for the interaction. To improve our understanding of the structure–function relationship, we present a patch model decoupling the topological and geometric properties. While the geometry is classically encoded by the atomic positions, the topology is recorded in a graph encoding the relative position of concentric shells partitioning the interface atoms. The topological–geometric duality provides the basis of a generic dynamic programming‐based algorithm comparing patches at the shell level, which may favor topological or geometric features. On the biological side, we address four questions, using 249 cocrystallized heterodimers organized in biological families. First, we dissect the morphology of binding patches and show that Nature enjoyed the topological and geometric degrees of freedom independently while retaining a finite set of qualitatively distinct topological signatures. Second, we argue that our shell‐based comparison is effective to perform atomic‐level comparisons and show that topological similarity is a less stringent than geometric similarity. We also use the topological versus geometric duality to exhibit topo‐rigid patches, whose topology (but not geometry) remains stable upon docking. Third, we use our comparison algorithms to infer specificity‐related information amidst a database of complexes. Finally, we exhibit a descriptor outperforming its contenders to predict the binding affinities of the affinity benchmark. The softwares developed with this article are available from http://team.inria.fr/abs/vorpatch_compatch/. Proteins 2012; © 2012 Wiley Periodicals, Inc.
Solution structure and siRNA‐mediated knockdown analysis of the mitochondrial disease‐related protein C12orf65
Authors: Kogure Hiroyuki , Hikawa Yusuke , Hagihara Mamoru , Tochio Naoya , Koshiba Seizo , Inoue Yusuke , Güntert Peter , Kigawa Takanori , Yokoyama Shigeyuki , Nameki Nobukazu 
Published: February 2013

AbstractLoss of function of the c12orf65 gene causes a mitochondrial translation defect, leading to encephalomyopathy. The C12orf65 protein is thought to play a role similar to that of ICT1 in rescuing stalled mitoribosomes during translation. Both proteins belong to a family of Class I peptide release factors (RFs), all characterized by the presence of a GGQ motif. Here, we determined the solution structure of the GGQ‐containing domain (GGQ domain) of C12orf65 from mouse by NMR spectroscopy, and examined the effect of siRNA‐mediated knockdown of C12orf65 on mitochondria in HeLa cells using flow cytometry. The GGQ domain, comprising residues 60–124 of the 184‐residue full‐length protein, forms a structure with a 310‐β1‐β2‐β3‐α1 topology that resembles the GGQ domain structure of RF more closely than that of ICT1. Thus, the GGQ domain structures of this protein family can be divided into two types, depending on the region linking β2 and β3; the C12orf65/RF type having a 6‐residue π‐HB turn and the ICT1 type having an α‐helix. Knockdown of C12orf65 resulted in increased ROS production and apoptosis, leading to inhibition of cell proliferation. Substantial changes in mitochondrial membrane potential and mass in the C12orf65‐knockdown cells were observed compared with the control cells. These results indicate that the function of C12orf65 is essential for cell vitality and mitochondrial function. Although similar effects were observed in ICT1‐downregulated cells, there were significant differences in the range and pattern of the effects between C12orf65‐ and ICT1‐knockdown cells, suggesting different roles of C12orf65 and ICT1 in rescuing stalled mitoribosomes. Proteins 2012. © 2012 Wiley Periodicals, Inc.
Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes
Authors: Romanowska Julia , Reuter Nathalie , Trylska Joanna 
Published: February 2013

AbstractAminoglycoside antibiotics are used against severe bacterial infections. They bind to the bacterial ribosomal RNA and interfere with the translation process. However, bacteria produce aminoglycoside modifying enzymes (AME) to resist aminoglycoside actions. AMEs form a variable group and yet they specifically recognize and efficiently bind aminoglycosides, which are also diverse in terms of total net charge and the number of pseudo‐sugar rings. Here, we present the results of 25 molecular dynamics simulations of three AME representatives and aminoglycoside ribosomal RNA binding site, unliganded and complexed with an aminoglycoside, kanamycin A. A comparison of the aminoglycoside binding sites in these different receptors revealed that the enzymes efficiently mimic the nucleic acid environment of the ribosomal RNA binding cleft. Although internal dynamics of AMEs and their interaction patterns with aminoglycosides differ, the energetical analysis showed that the most favorable sites are virtually the same in the enzymes and RNA. The most copied interactions were of electrostatic nature, but stacking was also replicated in one AME:kanamycin complex. In addition, we found that some water‐mediated interactions were very stable in the simulations of the complexes. We show that our simulations reproduce well findings from NMR or X‐ray structural studies, as well as results from directed mutagenesis. The outcomes of our analyses provide new insight into aminoglycoside resistance mechanism that is related to the enzymatic modification of these drugs. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Combining coarse‐grained nonbonded and atomistic bonded interactions for protein modeling
Authors: Zacharias Martin 
Published: February 2013

AbstractA hybrid coarse‐grained (CG) and atomistic (AT) model for protein simulations and rapid searching and refinement of peptide–protein complexes has been developed. In contrast to other hybrid models that typically represent spatially separate parts of a protein by either a CG or an AT force field model, the present approach simultaneously represents the protein by an AT (united atom) and a CG model. The interactions of the protein main chain are described based on the united atom force field allowing a realistic representation of protein secondary structures. In addition, the AT description of all other bonded interactions keeps the protein compatible with a realistic bonded geometry. Nonbonded interactions between side chains and side chains and main chain are calculated at the level of a CG model using a knowledge‐based potential. Unrestrained molecular dynamics simulations on several test proteins resulted in trajectories in reasonable agreement with the corresponding experimental structures. Applications to the refinement of docked peptide–protein complexes resulted in improved complex structures. Application to the rapid refinement of docked protein–protein complex is also possible but requires further optimization of force field parameters. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Critical analysis of the successes and failures of homology models of G protein‐coupled receptors
Authors: Bhattacharya Supriyo , Lam Alfonso Ramon , Li Hubert , Balaraman Gouthaman , Niesen Michiel Jacobus Maria , Vaidehi Nagarajan 
Published: February 2013

AbstractWe present a critical assessment of the performance of our homology model refinement method for G protein‐coupled receptors (GPCRs), called LITICon that led to top ranking structures in a recent structure prediction assessment GPCRDOCK2010. GPCRs form the largest class of drug targets for which only a few crystal structures are currently available. Therefore, accurate homology models are essential for drug design in these receptors. We submitted five models each for human chemokine CXCR4 (bound to small molecule IT1t and peptide CVX15) and dopamine D3DR (bound to small molecule eticlopride) before the crystal structures were published. Our models in both CXCR4/IT1t and D3/eticlopride assessments were ranked first and second, respectively, by ligand RMSD to the crystal structures. For both receptors, we developed two types of protein models: homology models based on known GPCR crystal structures, and ab initio models based on the prediction method MembStruk. The homology‐based models compared better to the crystal structures than the ab initio models. However, a robust refinement procedure for obtaining high accuracy structures is needed. We demonstrate that optimization of the helical tilt, rotation, and translation is vital for GPCR homology model refinement. As a proof of concept, our in‐house refinement program LITiCon captured the distinct orientation of TM2 in CXCR4, which differs from that of adrenoreceptors. These findings would be critical for refining GPCR homology models in future. Proteins 2013. © 2012 Wiley Periodicals, Inc.
High resolution crystal structure of Sco5413, a widespread actinomycete MarR family transcriptional regulator of unknown function
Authors: Holley Tracey A. , Stevenson Clare E. M. , Bibb Mervyn J. , Lawson David M. 
Published: February 2013

AbstractThe crystal structure of Sco5413 from Streptomyces coelicolor A3(2) has been determined at 1.25 Å resolution, the highest resolution reported for a MarR family transcriptional regulator. Putative orthologs are encoded by the majority of sequenced actinomycete genomes, and may play roles in regulating growth and antibiotic production, but they have yet to be assigned a precise function. Sco5413 forms a homodimer and, through comparisons with other MarR family protein structures, we postulate that it adopts a conformation compatible with DNA binding, and that a channel at the dimer interface, lined by well‐conserved residues, is the binding site of an unidentified effector ligand. Proteins 2013. © 2012 Wiley Periodicals, Inc.