ProTSAV: A protein tertiary structure analysis and validation server.

PubMed

Singh, Ankita; Kaushik, Rahul; Mishra, Avinash; Shanker, Asheesh; Jayaram, B

2016-01-01

Quality assessment of predicted model structures of proteins is as important as the protein tertiary structure prediction. A highly efficient quality assessment of predicted model structures directs further research on function. Here we present a new server ProTSAV, capable of evaluating predicted model structures based on some popular online servers and standalone tools. ProTSAV furnishes the user with a single quality score in case of individual protein structure along with a graphical representation and ranking in case of multiple protein structure assessment. The server is validated on ~64,446 protein structures including experimental structures from RCSB and predicted model structures for CASP targets and from public decoy sets. ProTSAV succeeds in predicting quality of protein structures with a specificity of 100% and a sensitivity of 98% on experimentally solved structures and achieves a specificity of 88%and a sensitivity of 91% on predicted protein structures of CASP11 targets under 2Å.The server overcomes the limitations of any single server/method and is seen to be robust in helping in quality assessment. ProTSAV is freely available at http://www.scfbio-iitd.res.in/software/proteomics/protsav.jsp. Copyright © 2015 Elsevier B.V. All rights reserved.

Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure.

PubMed

Meitinger, T; Meindl, A; Bork, P; Rost, B; Sander, C; Haasemann, M; Murken, J

1993-12-01

The X-lined gene for Norrie disease, which is characterized by blindness, deafness and mental retardation has been cloned recently. This gene has been thought to code for a putative extracellular factor; its predicted amino acid sequence is homologous to the C-terminal domain of diverse extracellular proteins. Sequence pattern searches and three-dimensional modelling now suggest that the Norrie disease protein (NDP) has a tertiary structure similar to that of transforming growth factor beta (TGF beta). Our model identifies NDP as a member of an emerging family of growth factors containing a cystine knot motif, with direct implications for the physiological role of NDP. The model also sheds light on sequence related domains such as the C-terminal domain of mucins and of von Willebrand factor.

Quantification of the Thermodynamically Linked Quaternary and Tertiary Structural Stabilities of Transthyretin and its Disease-Associated Variants–the Relationship between Stability and Amyloidosis†

PubMed Central

Hurshman Babbes, Amy R.; Powers, Evan T.; Kelly, Jeffery W.

2009-01-01

Urea denaturation studies were carried out as a function of transthyretin (TTR) concentration to quantify the thermodynamically linked quaternary and tertiary structural stability and to better understand the relationship between mutant folding energetics and amyloid disease phenotype. Urea denaturation of TTR involves at least two equilibria—dissociation of tetramers into folded monomers, and monomer unfolding. To deal with the thermodynamic linkage of these equilibria, we analyzed concentration-dependent denaturation data by global fitting to an equation that simultaneously accounts for the two-step denaturation process. Using this method, the quaternary and tertiary structural stabilities of well-behaved TTR sequences, wild type (WT) TTR and the disease-associated variant V122I, were scrutinized. The V122I variant is linked to late onset familial amyloid cardiomyopathy, the most common familial TTR amyloid disease. V122I TTR exhibits a destabilized quaternary structure and a stable tertiary structure relative to WT TTR. Three other variants of TTR were also examined, L55P, V30M, and A25T TTR. The L55P mutation is associated with the most aggressive familial TTR amyloid disease. L55P TTR has a complicated denaturation pathway that includes dimers and trimers, and so globally fitting its concentration-dependent urea denaturation data yielded error-laden estimates of stability parameters. Nevertheless, it is clear that L55P TTR is substantially less stable than WT TTR, primarily because its tertiary structure is unstable, although its quaternary structure is destabilized as well. V30M is the most common mutation associated with neuropathic forms of TTR amyloid disease. V30M TTR is certainly destabilized relative to WT TTR, but like L55P TTR it has a complex denaturation pathway that cannot be fit to the aforementioned two-step denaturation model. Literature data suggest that V30M TTR has stable quaternary structure but unstable tertiary structure. The A25T mutant, associated with central nervous system amyloidosis, is highly aggregation-prone and exhibits drastically reduced quaternary and tertiary structural stability. The observed differences in stability amongst the disease-associated TTR variants highlight the complexity and the heterogeneity of TTR amyloid disease, an observation having important implications for the treatment of these diseases. PMID:18537267

Massive integration of diverse protein quality assessment methods to improve template based modeling in CASP11

PubMed Central

Cao, Renzhi; Bhattacharya, Debswapna; Adhikari, Badri; Li, Jilong; Cheng, Jianlin

2015-01-01

Model evaluation and selection is an important step and a big challenge in template-based protein structure prediction. Individual model quality assessment methods designed for recognizing some specific properties of protein structures often fail to consistently select good models from a model pool because of their limitations. Therefore, combining multiple complimentary quality assessment methods is useful for improving model ranking and consequently tertiary structure prediction. Here, we report the performance and analysis of our human tertiary structure predictor (MULTICOM) based on the massive integration of 14 diverse complementary quality assessment methods that was successfully benchmarked in the 11th Critical Assessment of Techniques of Protein Structure prediction (CASP11). The predictions of MULTICOM for 39 template-based domains were rigorously assessed by six scoring metrics covering global topology of Cα trace, local all-atom fitness, side chain quality, and physical reasonableness of the model. The results show that the massive integration of complementary, diverse single-model and multi-model quality assessment methods can effectively leverage the strength of single-model methods in distinguishing quality variation among similar good models and the advantage of multi-model quality assessment methods of identifying reasonable average-quality models. The overall excellent performance of the MULTICOM predictor demonstrates that integrating a large number of model quality assessment methods in conjunction with model clustering is a useful approach to improve the accuracy, diversity, and consequently robustness of template-based protein structure prediction. PMID:26369671

Principles of protein folding--a perspective from simple exact models.

PubMed Central

Dill, K. A.; Bromberg, S.; Yue, K.; Fiebig, K. M.; Yee, D. P.; Thomas, P. D.; Chan, H. S.

1995-01-01

General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics--fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse. PMID:7613459

Computational study of stability of an H-H-type pseudoknot motif.

PubMed

Wang, Jun; Zhao, Yunjie; Wang, Jian; Xiao, Yi

2015-12-01

Motifs in RNA tertiary structures are important to their structural organizations and biological functions. Here we consider an H-H-type pseudoknot (HHpk) motif that consists of two hairpins connected by a junction loop and with kissing interactions between the two hairpin loops. Such a tertiary structural motif is recurrently found in RNA tertiary structures, but is difficult to predict computationally. So it is important to understand the mechanism of its formation and stability. Here we investigate the stability of the HHpk tertiary structure by using an all-atom molecular dynamics simulation. The results indicate that the HHpk tertiary structure is stable. However, it is found that this stability is not due to the helix-helix packing, as is usually expected, but is maintained by the combined action of the kissing hairpin loops and junctions, although the former plays the main role. Stable HHpk motifs may form structural platforms for the molecules to realize their biological functions. These results are useful for understanding the construction principle of RNA tertiary structures and structure prediction.

An Amino Acid Code to Define a Protein’s Tertiary Packing Surface

PubMed Central

Fraga, Keith J.; Joo, Hyun; Tsai, Jerry

2015-01-01

One difficult aspect of the protein-folding problem is characterizing the non-specific interactions that define packing in protein tertiary structure. To better understand tertiary structure, this work extends the knob-socket model by classifying the interactions of a single knob residue packed into a set of contiguous sockets, or a pocket made up of 4 or more residues. The knob-socket construct allows for a symbolic two-dimensional mapping of pockets. The two-dimensional mapping of pockets provides a simple method to investigate the variety of pocket shapes in order to understand the geometry of protein tertiary surfaces. The diversity of pocket geometries can be organized into groups of pockets that share a common core, which suggests that some interactions in pockets are ancillary to packing. Further analysis of pocket geometries displays a preferred configuration that is right-handed in α-helices and left-handed in β-sheets. The amino acid composition of pockets illustrates the importance of non-polar amino acids in packing as well as position specificity. As expected, all pocket shapes prefer to pack with hydrophobic knobs; however, knobs are not selective for the pockets they pack. Investigating side-chain rotamer preferences for certain pocket shapes uncovers no strong correlations. These findings allow a simple vocabulary based on knobs and sockets to describe protein tertiary packing that supports improved analysis, design and prediction of protein structure. PMID:26575337

Analysis of Management Practices in Lagos State Tertiary Institutions through Total Quality Management Structural Framework

ERIC Educational Resources Information Center

AbdulAzeez, Abbas Tunde

2016-01-01

This research investigated total quality management practices and quality teacher education in public tertiary institutions in Lagos State. The study was therefore designed to analyse management practices in Lagos state tertiary institutions through total quality management structural framework. The selected public tertiary institutions in Lagos…

Massive integration of diverse protein quality assessment methods to improve template based modeling in CASP11.

PubMed

Cao, Renzhi; Bhattacharya, Debswapna; Adhikari, Badri; Li, Jilong; Cheng, Jianlin

2016-09-01

Model evaluation and selection is an important step and a big challenge in template-based protein structure prediction. Individual model quality assessment methods designed for recognizing some specific properties of protein structures often fail to consistently select good models from a model pool because of their limitations. Therefore, combining multiple complimentary quality assessment methods is useful for improving model ranking and consequently tertiary structure prediction. Here, we report the performance and analysis of our human tertiary structure predictor (MULTICOM) based on the massive integration of 14 diverse complementary quality assessment methods that was successfully benchmarked in the 11th Critical Assessment of Techniques of Protein Structure prediction (CASP11). The predictions of MULTICOM for 39 template-based domains were rigorously assessed by six scoring metrics covering global topology of Cα trace, local all-atom fitness, side chain quality, and physical reasonableness of the model. The results show that the massive integration of complementary, diverse single-model and multi-model quality assessment methods can effectively leverage the strength of single-model methods in distinguishing quality variation among similar good models and the advantage of multi-model quality assessment methods of identifying reasonable average-quality models. The overall excellent performance of the MULTICOM predictor demonstrates that integrating a large number of model quality assessment methods in conjunction with model clustering is a useful approach to improve the accuracy, diversity, and consequently robustness of template-based protein structure prediction. Proteins 2016; 84(Suppl 1):247-259. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Modeling Human Serum Albumin Tertiary Structure to Teach Upper-Division Chemistry Students Bioinformatics and Homology Modeling Basics

ERIC Educational Resources Information Center

Petrovic, Dus?an; Zlatovic´, Mario

2015-01-01

A homology modeling laboratory experiment has been developed for an introductory molecular modeling course for upper-division undergraduate chemistry students. With this experiment, students gain practical experience in homology model preparation and assessment as well as in protein visualization using the educational version of PyMOL…

RNA secondary structure prediction with pseudoknots: Contribution of algorithm versus energy model.

PubMed

Jabbari, Hosna; Wark, Ian; Montemagno, Carlo

2018-01-01

RNA is a biopolymer with various applications inside the cell and in biotechnology. Structure of an RNA molecule mainly determines its function and is essential to guide nanostructure design. Since experimental structure determination is time-consuming and expensive, accurate computational prediction of RNA structure is of great importance. Prediction of RNA secondary structure is relatively simpler than its tertiary structure and provides information about its tertiary structure, therefore, RNA secondary structure prediction has received attention in the past decades. Numerous methods with different folding approaches have been developed for RNA secondary structure prediction. While methods for prediction of RNA pseudoknot-free structure (structures with no crossing base pairs) have greatly improved in terms of their accuracy, methods for prediction of RNA pseudoknotted secondary structure (structures with crossing base pairs) still have room for improvement. A long-standing question for improving the prediction accuracy of RNA pseudoknotted secondary structure is whether to focus on the prediction algorithm or the underlying energy model, as there is a trade-off on computational cost of the prediction algorithm versus the generality of the method. The aim of this work is to argue when comparing different methods for RNA pseudoknotted structure prediction, the combination of algorithm and energy model should be considered and a method should not be considered superior or inferior to others if they do not use the same scoring model. We demonstrate that while the folding approach is important in structure prediction, it is not the only important factor in prediction accuracy of a given method as the underlying energy model is also as of great value. Therefore we encourage researchers to pay particular attention in comparing methods with different energy models.

Is the Conformational Ensemble of Alzheimer’s Aβ10-40 Peptide Force Field Dependent?

PubMed Central

Siwy, Christopher M.

2017-01-01

By applying REMD simulations we have performed comparative analysis of the conformational ensembles of amino-truncated Aβ10-40 peptide produced with five force fields, which combine four protein parameterizations (CHARMM36, CHARMM22*, CHARMM22/cmap, and OPLS-AA) and two water models (standard and modified TIP3P). Aβ10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated Aβ10-40 3JHNHα-coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length Aβ1-40 peptide. Our study led us to several conclusions. First, all force fields predict that Aβ adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary Aβ10-40 structure, albeit standard TIP3P model favors slightly more compact states. Third, although the secondary structures observed in CHARMM36 and CHARMM22/cmap simulations are qualitatively similar, their tertiary interactions show little consistency. Fourth, two force fields, OPLS-AA and CHARMM22* have unique features setting them apart from CHARMM36 or CHARMM22/cmap. OPLS-AA reveals moderate β-structure propensity coupled with extensive, but weak long-range tertiary interactions leading to Aβ collapsed conformations. CHARMM22* exhibits moderate helix propensity and generates multiple exceptionally stable long- and short-range interactions. Our investigation suggests that among all force fields CHARMM22* differs the most from CHARMM36. Fifth, the analysis of 3JHNHα-coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico Aβ10-40 and experimental Aβ1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as Aβ1-40 or Aβ1-42. This observation suggests that the differences in the conformational ensembles of Aβ10-40 and Aβ1-40 are small and the former can be used as proxy of the full-length peptide. Based on this argument, we concluded that CHARMM36 force field with standard TIP3P model produces the most accurate representation of Aβ10-40 conformational ensemble. PMID:28085875

Acyl carrier protein structural classification and normal mode analysis

PubMed Central

Cantu, David C; Forrester, Michael J; Charov, Katherine; Reilly, Peter J

2012-01-01

All acyl carrier protein primary and tertiary structures were gathered into the ThYme database. They are classified into 16 families by amino acid sequence similarity, with members of the different families having sequences with statistically highly significant differences. These classifications are supported by tertiary structure superposition analysis. Tertiary structures from a number of families are very similar, suggesting that these families may come from a single distant ancestor. Normal vibrational mode analysis was conducted on experimentally determined freestanding structures, showing greater fluctuations at chain termini and loops than in most helices. Their modes overlap more so within families than between different families. The tertiary structures of three acyl carrier protein families that lacked any known structures were predicted as well. PMID:22374859

A new way to see RNA

PubMed Central

Keating, Kevin S.; Humphris, Elisabeth L.; Pyle, Anna Marie

2015-01-01

Unlike proteins, the RNA backbone has numerous degrees of freedom (eight, if one counts the sugar pucker), making RNA modeling, structure building and prediction a multidimensional problem of exceptionally high complexity. And yet RNA tertiary structures are not infinite in their structural morphology; rather, they are built from a limited set of discrete units. In order to reduce the dimensionality of the RNA backbone in a physically reasonable way, a shorthand notation was created that reduced the RNA backbone torsion angles to two (η and θ, analogous to ϕ and ψ in proteins). When these torsion angles are calculated for nucleotides in a crystallographic database and plotted against one another, one obtains a plot analogous to a Ramachandran plot (the η/θ plot), with highly populated and unpopulated regions. Nucleotides that occupy proximal positions on the plot have identical structures and are found in the same units of tertiary structure. In this review, we describe the statistical validation of the η/θ formalism and the exploration of features within the η/θ plot. We also describe the application of the η/θ formalism in RNA motif discovery, structural comparison, RNA structure building and tertiary structure prediction. More than a tool, however, the η/θ formalism has provided new insights into RNA structure itself, revealing its fundamental components and the factors underlying RNA architectural form. PMID:21729350

Tertiary structural propensities reveal fundamental sequence/structure relationships.

PubMed

Zheng, Fan; Zhang, Jian; Grigoryan, Gevorg

2015-05-05

Extracting useful generalizations from the continually growing Protein Data Bank (PDB) is of central importance. We hypothesize that the PDB contains valuable quantitative information on the level of local tertiary structural motifs (TERMs). We show that by breaking a protein structure into its constituent TERMs, and querying the PDB to characterize the natural ensemble matching each, we can estimate the compatibility of the structure with a given amino acid sequence through a metric we term "structure score." Considering submissions from recent Critical Assessment of Structure Prediction (CASP) experiments, we found a strong correlation (R = 0.69) between structure score and model accuracy, with poorly predicted regions readily identifiable. This performance exceeds that of leading atomistic statistical energy functions. Furthermore, TERM-based analysis of two prototypical multi-state proteins rapidly produced structural insights fully consistent with prior extensive experimental studies. We thus find that TERM-based analysis should have considerable utility for protein structural biology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Automated and fast building of three-dimensional RNA structures.

PubMed

Zhao, Yunjie; Huang, Yangyu; Gong, Zhou; Wang, Yanjie; Man, Jianfen; Xiao, Yi

2012-01-01

Building tertiary structures of non-coding RNA is required to understand their functions and design new molecules. Current algorithms of RNA tertiary structure prediction give satisfactory accuracy only for small size and simple topology and many of them need manual manipulation. Here, we present an automated and fast program, 3dRNA, for RNA tertiary structure prediction with reasonable accuracy for RNAs of larger size and complex topology.

Model for an RNA tertiary interaction from the structure of an intermolecular complex between a GAAA tetraloop and an RNA helix.

PubMed

Pley, H W; Flaherty, K M; McKay, D B

1994-11-03

In large structured RNAs, RNA hairpins in which the strands of the duplex stem are connected by a tetraloop of the consensus sequence 5'-GNRA (where N is any nucleotide, and R is either G or A) are unusually frequent. In group I introns there is a covariation in sequence between nucleotides in the third and fourth positions of the loop with specific distant base pairs in putative RNA duplex stems: GNAA loops correlate with successive 5'-C-C.G-C base pairs in stems, whereas GNGA loops correlate with 5'-C-U.G-A. This has led to the suggestion that GNRA tetraloops may be involved in specific long-range tertiary interactions, with each A in position 3 or 4 of the loop interacting with a C-G base pair in the duplex, and G in position 3 interacting with a U-A base pair. This idea is supported experimentally for the GAAA loop of the P5b extension of the group I intron of Tetrahymena thermophila and the L9 GUGA terminal loop of the td intron of bacteriophage T4 (ref. 4). NMR has revealed the overall structure of the tetraloop for 12-nucleotide hairpins with GCAA and GAAA loops and models have been proposed for the interaction of GNRA tetraloops with base pairs in the minor groove of A-form RNA. Here we describe the crystal structure of an intermolecular complex between a GAAA tetraloop and an RNA helix. The interactions we observe correlate with the specificity of GNRA tetraloops inferred from phylogenetic studies, suggesting that this complex is a legitimate model for intramolecular tertiary interactions mediated by GNRA tetraloops in large structured RNAs.

A Stochastic Evolutionary Model for Protein Structure Alignment and Phylogeny

PubMed Central

Challis, Christopher J.; Schmidler, Scott C.

2012-01-01

We present a stochastic process model for the joint evolution of protein primary and tertiary structure, suitable for use in alignment and estimation of phylogeny. Indels arise from a classic Links model, and mutations follow a standard substitution matrix, whereas backbone atoms diffuse in three-dimensional space according to an Ornstein–Uhlenbeck process. The model allows for simultaneous estimation of evolutionary distances, indel rates, structural drift rates, and alignments, while fully accounting for uncertainty. The inclusion of structural information enables phylogenetic inference on time scales not previously attainable with sequence evolution models. The model also provides a tool for testing evolutionary hypotheses and improving our understanding of protein structural evolution. PMID:22723302

Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes.

PubMed

Borghoff, Susan J; Ring, Caroline; Banton, Marcy I; Leavens, Teresa L

2017-05-01

In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC 0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC 0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Bhageerath-H: A homology/ab initio hybrid server for predicting tertiary structures of monomeric soluble proteins

PubMed Central

2014-01-01

Background The advent of human genome sequencing project has led to a spurt in the number of protein sequences in the databanks. Success of structure based drug discovery severely hinges on the availability of structures. Despite significant progresses in the area of experimental protein structure determination, the sequence-structure gap is continually widening. Data driven homology based computational methods have proved successful in predicting tertiary structures for sequences sharing medium to high sequence similarities. With dwindling similarities of query sequences, advanced homology/ ab initio hybrid approaches are being explored to solve structure prediction problem. Here we describe Bhageerath-H, a homology/ ab initio hybrid software/server for predicting protein tertiary structures with advancing drug design attempts as one of the goals. Results Bhageerath-H web-server was validated on 75 CASP10 targets which showed TM-scores ≥0.5 in 91% of the cases and Cα RMSDs ≤5Å from the native in 58% of the targets, which is well above the CASP10 water mark. Comparison with some leading servers demonstrated the uniqueness of the hybrid methodology in effectively sampling conformational space, scoring best decoys and refining low resolution models to high and medium resolution. Conclusion Bhageerath-H methodology is web enabled for the scientific community as a freely accessible web server. The methodology is fielded in the on-going CASP11 experiment. PMID:25521245

A Hydrostratigraphic Model and Alternatives for the Groundwater Flow and Contaminant Transport Model of Corrective Action Unit 97: Yucca Flat-Climax Mine, Lincoln and Nye Counties, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geotechnical Sciences Group Bechtel Nevada

2006-01-01

A new three-dimensional hydrostratigraphic framework model for the Yucca Flat-Climax Mine Corrective Action Unit was completed in 2005. The model area includes Yucca Flat and Climax Mine, former nuclear testing areas at the Nevada Test Site, and proximal areas. The model area is approximately 1,250 square kilometers in size and is geologically complex. Yucca Flat is a topographically closed basin typical of many valleys in the Basin and Range province. Faulted and tilted blocks of Tertiary-age volcanic rocks and underlying Proterozoic and Paleozoic sedimentary rocks form low ranges around the structural basin. During the Cretaceous Period a granitic intrusive wasmore » emplaced at the north end of Yucca Flat. A diverse set of geological and geophysical data collected over the past 50 years was used to develop a structural model and hydrostratigraphic system for the basin. These were integrated using EarthVision? software to develop the 3-dimensional hydrostratigraphic framework model. Fifty-six stratigraphic units in the model area were grouped into 25 hydrostratigraphic units based on each unit's propensity toward aquifer or aquitard characteristics. The authors organized the alluvial section into 3 hydrostratigraphic units including 2 aquifers and 1 confining unit. The volcanic units in the model area are organized into 13 hydrostratigraphic units that include 8 aquifers and 5 confining units. The underlying pre-Tertiary rocks are divided into 7 hydrostratigraphic units, including 3 aquifers and 4 confining units. Other units include 1 Tertiary-age sedimentary confining unit and 1 Mesozoic-age granitic confining unit. The model depicts the thickness, extent, and geometric relationships of these hydrostratigraphic units (''layers'' in the model) along with the major structural features (i.e., faults). The model incorporates 178 high-angle normal faults of Tertiary age and 2 low-angle thrust faults of Mesozoic age. The complexity of the model area and the non-uniqueness of some of the interpretations incorporated into the base model made it necessary to formulate alternative interpretations for some of the major features in the model. Five of these alternatives were developed so they could be modeled in the same fashion as the base model. This work was done for the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office in support of the Underground Test Area subproject of the Environmental Restoration Project.« less

Consistent global structures of complex RNA states through multidimensional chemical mapping

PubMed Central

Cheng, Clarence Yu; Chou, Fang-Chieh; Kladwang, Wipapat; Tian, Siqi; Cordero, Pablo; Das, Rhiju

2015-01-01

Accelerating discoveries of non-coding RNA (ncRNA) in myriad biological processes pose major challenges to structural and functional analysis. Despite progress in secondary structure modeling, high-throughput methods have generally failed to determine ncRNA tertiary structures, even at the 1-nm resolution that enables visualization of how helices and functional motifs are positioned in three dimensions. We report that integrating a new method called MOHCA-seq (Multiplexed •OH Cleavage Analysis with paired-end sequencing) with mutate-and-map secondary structure inference guides Rosetta 3D modeling to consistent 1-nm accuracy for intricately folded ncRNAs with lengths up to 188 nucleotides, including a blind RNA-puzzle challenge, the lariat-capping ribozyme. This multidimensional chemical mapping (MCM) pipeline resolves unexpected tertiary proximities for cyclic-di-GMP, glycine, and adenosylcobalamin riboswitch aptamers without their ligands and a loose structure for the recently discovered human HoxA9D internal ribosome entry site regulon. MCM offers a sequencing-based route to uncovering ncRNA 3D structure, applicable to functionally important but potentially heterogeneous states. DOI: http://dx.doi.org/10.7554/eLife.07600.001 PMID:26035425

Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme

PubMed Central

Mustoe, Anthony M.; Al-Hashimi, Hashim M.; Brooks, Charles L.

2016-01-01

A requirement for specific RNA folding is that the free-energy landscape discriminate against non-native folds. While tertiary interactions are critical for stabilizing the native fold, they are relatively non-specific, suggesting additional mechanisms contribute to tertiary folding specificity. In this study, we use coarse-grained molecular dynamics simulations to explore how secondary structure shapes the tertiary free-energy landscape of the Azoarcus ribozyme. We show that steric and connectivity constraints posed by secondary structure strongly limit the accessible conformational space of the ribozyme, and that these so-called topological constraints in turn pose strong free-energy penalties on forming different tertiary contacts. Notably, native A-minor and base-triple interactions form with low conformational free energy, while non-native tetraloop/tetraloop–receptor interactions are penalized by high conformational free energies. Topological constraints also give rise to strong cooperativity between distal tertiary interactions, quantitatively matching prior experimental measurements. The specificity of the folding landscape is further enhanced as tertiary contacts place additional constraints on the conformational space, progressively funneling the molecule to the native state. These results indicate that secondary structure assists the ribozyme in navigating the otherwise rugged tertiary folding landscape, and further emphasize topological constraints as a key force in RNA folding. PMID:26481360

Thioesterases: A new perspective based on their primary and tertiary structures

PubMed Central

Cantu, David C; Chen, Yingfei; Reilly, Peter J

2010-01-01

Thioesterases (TEs) are classified into EC 3.1.2.1 through EC 3.1.2.27 based on their activities on different substrates, with many remaining unclassified (EC 3.1.2.–). Analysis of primary and tertiary structures of known TEs casts a new light on this enzyme group. We used strong primary sequence conservation based on experimentally proved proteins as the main criterion, followed by verification with tertiary structure superpositions, mechanisms, and catalytic residue positions, to accurately define TE families. At present, TEs fall into 23 families almost completely unrelated to each other by primary structure. It is assumed that all members of the same family have essentially the same tertiary structure; however, TEs in different families can have markedly different folds and mechanisms. Conversely, the latter sometimes have very similar tertiary structures and catalytic mechanisms despite being only slightly or not at all related by primary structure, indicating that they have common distant ancestors and can be grouped into clans. At present, four clans encompass 12 TE families. The new constantly updated ThYme (Thioester-active enzYmes) database contains TE primary and tertiary structures, classified into families and clans that are different from those currently found in the literature or in other databases. We review all types of TEs, including those cleaving CoA, ACP, glutathione, and other protein molecules, and we discuss their structures, functions, and mechanisms. PMID:20506386

The geology and mechanics of formation of the Fort Rock Dome, Yavapai County, Arizona

USGS Publications Warehouse

Fuis, Gary S.

1996-01-01

The Fort Rock Dome, a craterlike structure in northern Arizona, is the erosional product of a circular domal uplift associated with a Precambrian shear zone exposed within the crater and with Tertiary volcanism. A section of Precambrian to Quaternary rocks is described, and two Tertiary units, the Crater Pasture Formation and the Fort Rock Creek Rhyodacite, are named. A mathematical model of the doming process is developed that is consistent with the history of the Fort Rock Dome.

Improvement on a simplified model for protein folding simulation.

PubMed

Zhang, Ming; Chen, Changjun; He, Yi; Xiao, Yi

2005-11-01

Improvements were made on a simplified protein model--the Ramachandran model-to achieve better computer simulation of protein folding. To check the validity of such improvements, we chose the ultrafast folding protein Engrailed Homeodomain as an example and explored several aspects of its folding. The engrailed homeodomain is a mainly alpha-helical protein of 61 residues from Drosophila melanogaster. We found that the simplified model of Engrailed Homeodomain can fold into a global minimum state with a tertiary structure in good agreement with its native structure.

Automated extraction and classification of RNA tertiary structure cyclic motifs

PubMed Central

Lemieux, Sébastien; Major, François

2006-01-01

A minimum cycle basis of the tertiary structure of a large ribosomal subunit (LSU) X-ray crystal structure was analyzed. Most cycles are small, as they are composed of 3- to 5 nt, and repeated across the LSU tertiary structure. We used hierarchical clustering to quantify and classify the 4 nt cycles. One class is defined by the GNRA tetraloop motif. The inspection of the GNRA class revealed peculiar instances in sequence. First is the presence of UA, CA, UC and CC base pairs that substitute the usual sheared GA base pair. Second is the revelation of GNR(Xn)A tetraloops, where Xn is bulged out of the classical GNRA structure, and of GN/RA formed by the two strands of interior-loops. We were able to unambiguously characterize the cycle classes using base stacking and base pairing annotations. The cycles identified correspond to small and cyclic motifs that compose most of the LSU RNA tertiary structure and contribute to its thermodynamic stability. Consequently, the RNA minimum cycles could well be used as the basic elements of RNA tertiary structure prediction methods. PMID:16679452

Exploration of Novel Chemical Space: Synthesis and in vitro Evaluation of N-Functionalized Tertiary Sulfonimidamides.

PubMed

Izzo, Flavia; Schäfer, Martina; Lienau, Philip; Ganzer, Ursula; Stockman, Robert; Lücking, Ulrich

2018-05-04

An unprecedented set of structurally diverse sulfonimidamides (47 compounds) has been prepared by various N-functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N-functionalization reactions of model compound 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X-ray analyses of selected N-functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N-functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formation mechanism of NDMA from ranitidine, trimethylamine, and other tertiary amines during chloramination: a computational study.

PubMed

Liu, Yong Dong; Selbes, Meric; Zeng, Chengchu; Zhong, Rugang; Karanfil, Tanju

2014-01-01

Chloramination of drinking waters has been associated with N-nitrosodimethylamine (NDMA) formation as a disinfection byproduct. NDMA is classified as a probable carcinogen and thus its formation during chloramination has recently become the focus of considerable research interest. In this study, the formation mechanisms of NDMA from ranitidine and trimethylamine (TMA), as models of tertiary amines, during chloramination were investigated by using density functional theory (DFT). A new four-step formation pathway of NDMA was proposed involving nucleophilic substitution by chloramine, oxidation, and dehydration followed by nitrosation. The results suggested that nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines. When 45 other tertiary amines were examined, the proposed mechanism was found to be more applicable to aromatic tertiary amines, and there may be still some additional factors or pathways that need to be considered for aliphatic tertiary amines. The heterolytic ONN(Me)2-R(+) bond dissociation energy to release NDMA and carbocation R(+) was found to be a criterion for evaluating the reactivity of aromatic tertiary amines. A structure-activity study indicates that tertiary amines with benzyl, aromatic heterocyclic ring, and diene-substituted methenyl adjacent to the DMA moiety are potentially significant NDMA precursors. The findings of this study are helpful for understanding NDMA formation mechanism and predicting NDMA yield of a precursor.

Visualizing the global secondary structure of a viral RNA genome with cryo-electron microscopy

PubMed Central

Garmann, Rees F.; Gopal, Ajaykumar; Athavale, Shreyas S.; Knobler, Charles M.; Gelbart, William M.; Harvey, Stephen C.

2015-01-01

The lifecycle, and therefore the virulence, of single-stranded (ss)-RNA viruses is regulated not only by their particular protein gene products, but also by the secondary and tertiary structure of their genomes. The secondary structure of the entire genomic RNA of satellite tobacco mosaic virus (STMV) was recently determined by selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE). The SHAPE analysis suggested a single highly extended secondary structure with much less branching than occurs in the ensemble of structures predicted by purely thermodynamic algorithms. Here we examine the solution-equilibrated STMV genome by direct visualization with cryo-electron microscopy (cryo-EM), using an RNA of similar length transcribed from the yeast genome as a control. The cryo-EM data reveal an ensemble of branching patterns that are collectively consistent with the SHAPE-derived secondary structure model. Thus, our results both elucidate the statistical nature of the secondary structure of large ss-RNAs and give visual support for modern RNA structure determination methods. Additionally, this work introduces cryo-EM as a means to distinguish between competing secondary structure models if the models differ significantly in terms of the number and/or length of branches. Furthermore, with the latest advances in cryo-EM technology, we suggest the possibility of developing methods that incorporate restraints from cryo-EM into the next generation of algorithms for the determination of RNA secondary and tertiary structures. PMID:25752599

Denaturation of RNA secondary and tertiary structure by urea: simple unfolded state models and free energy parameters account for measured m-values

PubMed Central

Lambert, Dominic; Draper, David E.

2012-01-01

To investigate the mechanism by which urea destabilizes RNA structure, urea-induced unfolding of four different RNA secondary and tertiary structures was quantified in terms of an m-value, the rate at which the free energy of unfolding changes with urea molality. From literature data and our osmometric study of a backbone analog, we derived average interaction potentials (per Å2 of solvent accessible surface) between urea and three kinds of RNA surfaces: phosphate, ribose, and base. Estimates of the increases in solvent accessible surface areas upon RNA denaturation were based on a simple model of unfolded RNA as a combination of helical and single strand segments. These estimates, combined with the three interaction potentials and a term to account for urea interactions with released ions, yield calculated m-values in good agreement with experimental values (200 mm monovalent salt). Agreement was obtained only if single-stranded RNAs were modeled in a highly stacked, A form conformation. The primary driving force for urea induced denaturation is the strong interaction of urea with the large surface areas of bases that become exposed upon denaturation of either RNA secondary or tertiary structure, though urea interactions with backbone and released ions may account for up to a third of the m-value. Urea m-values for all four RNA are salt-dependent, which we attribute to an increased extension (or decreased charge density) of unfolded RNAs with increased urea concentration. The sensitivity of the urea m-value to base surface exposure makes it a potentially useful probe of the conformations of RNA unfolded states. PMID:23088364

Sub-crop geologic map of pre-Tertiary rocks in the Yucca Flat and northern Frenchman Flat areas, Nevada Test Site, southern Nevada

USGS Publications Warehouse

Cole, James C.; Harris, Anita G.; Wahl, Ronald R.

1997-01-01

This map displays interpreted structural and stratigraphic relations among the Paleozoic and older rocks of the Nevada Test Site region beneath the Miocene volcanic rocks and younger alluvium in the Yucca Flat and northern Frenchman Flat basins. These interpretations are based on a comprehensive examination and review of data for more than 77 drillholes that penetrated part of the pre-Tertiary basement beneath these post-middle Miocene structural basins. Biostratigraphic data from conodont fossils were newly obtained for 31 of these holes, and a thorough review of all prior microfossil paleontologic data is incorporated in the analysis. Subsurface relationships are interpreted in light of a revised regional geologic framework synthesized from detailed geologic mapping in the ranges surrounding Yucca Flat, from comprehensive stratigraphic studies in the region, and from additional detailed field studies on and around the Nevada Test Site.All available data indicate the subsurface geology of Yucca Flat is considerably more complicated than previous interpretations have suggested. The western part of the basin, in particular, is underlain by relics of the eastward-vergent Belted Range thrust system that are folded back toward the west and thrust by local, west-vergent contractional structures of the CP thrust system. Field evidence from the ranges surrounding the north end of Yucca Flat indicate that two significant strike-slip faults track southward beneath the post-middle Miocene basin fill, but their subsurface traces cannot be closely defined from the available evidence. In contrast, the eastern part of the Yucca Flat basin is interpreted to be underlain by a fairly simple north-trending, broad syncline in the pre-Tertiary units. Far fewer data are available for the northern Frenchman Flat basin, but regional analysis indicates the pre- Tertiary structure there should also be relatively simple and not affected by thrusting.This new interpretation has implications for ground water flow through pre-Tertiary rocks beneath the Yucca Flat and northern Frenchman Flat areas, and has consequences for ground water modeling and model validation. Our data indicate that the Mississippian Chainman Shale is not a laterally extensive confining unit in the western part of the basin because it is folded back onto itself by the convergent structures of the Belted Range and CP thrust systems. Early and Middle Paleozoic limestone and dolomite are present beneath most of both basins and, regardless of structural complications, are interpreted to form a laterally continuous and extensive carbonate aquifer. Structural culmination that marks the French Peak accommodation zone along the topographic divide between the two basins provides a lateral pathway through highly fractured rock between the volcanic aquifers of Yucca Flat and the regional carbonate aquifer. This pathway may accelerate the migration of ground-water contaminants introduced by underground nuclear testing toward discharge areas beyond the Nevada Test Site boundaries. Predictive three-dimensional models of hydrostratigraphic units and ground-water flow in the pre-Tertiary rocks of subsurface Yucca Flat are likely to be unrealistic due to the extreme structural complexities. The interpretation of hydrologic and geochemical data obtained from monitoring wells will be difficult to extrapolate through the flow system until more is known about the continuity of hydrostratigraphic units.

[Changes in the secondary and tertiary structure of serum albumin in interactions with ligands of various structures].

PubMed

Trinus, F P; Braver-Chernobul'skaia, B S; Luĭk, A I; Boldeskul, A E; Velichko, A N

1984-01-01

High affinity interactions between blood serum albumin and five substances of various chemical structure, exhibiting distinct physiological activity, were accompanied by alterations in the protein tertiary structure, while the albumin secondary structure was involved in conformational transformation after less effective affinity binding.

The complex folding pathways of protein A suggest a multiple-funnelled energy landscape

NASA Astrophysics Data System (ADS)

St-Pierre, Jean-Francois; Mousseau, Normand; Derreumaux, Philippe

2008-01-01

Folding proteins into their native states requires the formation of both secondary and tertiary structures. Many questions remain, however, as to whether these form into a precise order, and various pictures have been proposed that place the emphasis on the first or the second level of structure in describing folding. One of the favorite test models for studying this question is the B domain of protein A, which has been characterized by numerous experiments and simulations. Using the activation-relaxation technique coupled with a generic energy model (optimized potential for efficient peptide structure prediction), we generate more than 50 folding trajectories for this 60-residue protein. While the folding pathways to the native state are fully consistent with the funnel-like description of the free energy landscape, we find a wide range of mechanisms in which secondary and tertiary structures form in various orders. Our nonbiased simulations also reveal the presence of a significant number of non-native β and α conformations both on and off pathway, including the visit, for a non-negligible fraction of trajectories, of fully ordered structures resembling the native state of nonhomologous proteins.

Kaltag fault, northern Yukon, Canada: Constraints on evolution of Arctic Alaska

NASA Astrophysics Data System (ADS)

Lane, Larry S.

1992-07-01

The Kaltag fault has been linked to several strike-slip models of evolution of the western Arctic Ocean. Hundreds of kilometres of Cretaceous-Tertiary displacement have been hypothesized in models that emplace Arctic Alaska into its present position by either left- or right-lateral strike slip. However, regional-scale displacement is precluded by new potential-field data. Postulated transform emplacement of Arctic Alaska cannot be accommodated by motion on the Kaltag fault or adjacent structures. The Kaltag fault of the northern Yukon is an eastward extrapolation of its namesake in west-central Alaska; however, a connection cannot be demonstrated. Cretaceous-Tertiary displacement on the Alaskan Kaltag fault is probably accommodated elsewhere.

Tertiary model of a plant cellulose synthase

PubMed Central

Sethaphong, Latsavongsakda; Haigler, Candace H.; Kubicki, James D.; Zimmer, Jochen; Bonetta, Dario; DeBolt, Seth; Yingling, Yaroslava G.

2013-01-01

A 3D atomistic model of a plant cellulose synthase (CESA) has remained elusive despite over forty years of experimental effort. Here, we report a computationally predicted 3D structure of 506 amino acids of cotton CESA within the cytosolic region. Comparison of the predicted plant CESA structure with the solved structure of a bacterial cellulose-synthesizing protein validates the overall fold of the modeled glycosyltransferase (GT) domain. The coaligned plant and bacterial GT domains share a six-stranded β-sheet, five α-helices, and conserved motifs similar to those required for catalysis in other GT-2 glycosyltransferases. Extending beyond the cross-kingdom similarities related to cellulose polymerization, the predicted structure of cotton CESA reveals that plant-specific modules (plant-conserved region and class-specific region) fold into distinct subdomains on the periphery of the catalytic region. Computational results support the importance of the plant-conserved region and/or class-specific region in CESA oligomerization to form the multimeric cellulose–synthesis complexes that are characteristic of plants. Relatively high sequence conservation between plant CESAs allowed mapping of known mutations and two previously undescribed mutations that perturb cellulose synthesis in Arabidopsis thaliana to their analogous positions in the modeled structure. Most of these mutation sites are near the predicted catalytic region, and the confluence of other mutation sites supports the existence of previously undefined functional nodes within the catalytic core of CESA. Overall, the predicted tertiary structure provides a platform for the biochemical engineering of plant CESAs. PMID:23592721

A Model for Considering the Financial Sustainability of Learning and Teaching Programs: Concepts and Challenges

ERIC Educational Resources Information Center

De Bellis, David

2012-01-01

The expansion of tertiary education, an intensity of focus on accountability and performance, and the emergence of new governance and management structures drives an economic fiscal perspective of the value of learning and teaching. Accurate and meaningful models defining financial sustainability are therefore proposed as an imperative for…

Prediction of protein tertiary structure to low resolution: performance for a large and structurally diverse test set.

PubMed

Eyrich, V A; Standley, D M; Friesner, R A

1999-05-14

We report the tertiary structure predictions for 95 proteins ranging in size from 17 to 160 residues starting from known secondary structure. Predictions are obtained from global minimization of an empirical potential function followed by the application of a refined atomic overlap potential. The minimization strategy employed represents a variant of the Monte Carlo plus minimization scheme of Li and Scheraga applied to a reduced model of the protein chain. For all of the cases except beta-proteins larger than 75 residues, a native-like structure, usually 4-6 A root-mean-square deviation from the native, is located. For beta-proteins larger than 75 residues, the energy gap between native-like structures and the lowest energy structures produced in the simulation is large, so that low RMSD structures are not generated starting from an unfolded state. This is attributed to the lack of an explicit hydrogen bond term in the potential function, which we hypothesize is necessary to stabilize large assemblies of beta-strands. Copyright 1999 Academic Press.

Analysis of the tertiary structure of the ribonuclease P ribozyme-substrate complex by site-specific photoaffinity crosslinking.

PubMed Central

Harris, M E; Kazantsev, A V; Chen, J L; Pace, N R

1997-01-01

Bacterial ribonuclease P (RNase P), an endonuclease involved in tRNA maturation, is a ribonucleoprotein containing a catalytic RNA. The secondary structure of this ribozyme is well-established, and a low-resolution model of the three-dimensional structure of the ribozyme-substrate complex has been proposed based on site-specific crosslinking and phylogenetic comparative data [Harris ME et al., 1994 EMBO J 13:3953-3963]. However, several substructures of that model were poorly constrained by the available data. In the present analysis, additional constraints between elements within the Escherichia coli RNase P RNA-pre-tRNA complex were determined by intra- and intermolecular crosslinking experiments. Circularly permuted RNase P RNAs were used to position an azidophenacyl photoactive crosslinking agent specifically at strategic sites within the ribozyme-substrate complex. Crosslink sites were mapped by primer extension and confirmed by analysis of the mobility of the crosslinked RNA lariats on denaturing acrylamide gels relative to circular and linear RNA standards. Crosslinked species generally retained significant catalytic activity, indicating that the results reflect the native ribozyme structure. The crosslinking results support the general configuration of the structure model and predicate new positions and orientations for helices that were previously poorly constrained by the data set. The expanded library of crosslinking constraints was used, together with secondary and tertiary structure identified by phylogenetic sequence comparisons, to refine significantly the model of RNase P RNA with bound substrate pre-tRNA. The crosslinking results and data from chemical-modification and mutational studies are discussed in the context of the current structural perspective on this ribozyme. PMID:9174092

Protein Folding and Structure Prediction from the Ground Up: The Atomistic Associative Memory, Water Mediated, Structure and Energy Model.

PubMed

Chen, Mingchen; Lin, Xingcheng; Zheng, Weihua; Onuchic, José N; Wolynes, Peter G

2016-08-25

The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained force field with transferable tertiary interactions that incorporates local in sequence energetic biases using bioinformatically derived structural information about peptide fragments with locally similar sequences that we call memories. The memory information from the protein data bank (PDB) database guides proper protein folding. The structural information about available sequences in the database varies in quality and can sometimes lead to frustrated free energy landscapes locally. One way out of this difficulty is to construct the input fragment memory information from all-atom simulations of portions of the complete polypeptide chain. In this paper, we investigate this approach first put forward by Kwac and Wolynes in a more complete way by studying the structure prediction capabilities of this approach for six α-helical proteins. This scheme which we call the atomistic associative memory, water mediated, structure and energy model (AAWSEM) amounts to an ab initio protein structure prediction method that starts from the ground up without using bioinformatic input. The free energy profiles from AAWSEM show that atomistic fragment memories are sufficient to guide the correct folding when tertiary forces are included. AAWSEM combines the efficiency of coarse-grained simulations on the full protein level with the local structural accuracy achievable from all-atom simulations of only parts of a large protein. The results suggest that a hybrid use of atomistic fragment memory and database memory in structural predictions may well be optimal for many practical applications.

Tertiary structure-related activity of tick defensin (persulcatusin) in the taiga tick, Ixodes persulcatus.

PubMed

Isogai, Emiko; Isogai, Hiroshi; Okumura, Kazuhiko; Hori, Hatsuhiro; Tsuruta, Hiroki; Kurebayashi, Yoichi

2011-01-01

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates constituting the front line of host innate immunity. To examine the importance of the tertiary structure of tick defensin in its antimicrobial activity, we synthesized two types of the peptides with tertiary structure or primary one on basis of the information of the sequence in the defensin originated from the taiga tick, Ixodes persulcatus. Chemically synthesized peptides were used to investigate the activity spectrum against Staphylococcus aureus, Borrelia garinii and flora-associated bacteria. Both synthetic peptides showed antimicrobial activity against S. aureus in short-time killing within 1 h, but they do not show the activity against B. garinii, Stenotrophomonas maltophila and Bacillus spp., which were frequently isolated from the midgut of I. persulcatus. The teriary structure brought more potent activity to S. aureus than primary one in short-time killing. We also examined its antimicrobial activity by evaluation of growth inhibition in the presence of the synthetic peptides. Minimum inhibitory concentration (MIC) was ranged from 1.2 to 5.0 μg/ml in tertiary peptide and from 10 to 40 μg/ml in primary peptide, when 10 strains of S. aureus were used. From the curve of cumulative inhibition rates, MIC50 (MIC which half of the strains showed) to S. aureus is about 1.2 μg/ml in the peptide with tertiary structure and about 10 μg/ml in the linear one. Corynebacterium renale is 10 times or more sensitive to tertiary peptide than primary one. In conclusion, the presence of 3 disulfide bridges, which stabilize the molecule and maintain the tertiary structure, is considered to have an effect on their antimicrobial activities against Gram-positive bacteria such as S. aureus.

Interpretation of Gravimetric and Aeromagnetic Data of the Tecoripa Chart in Southeast Sonora, Mexico.

NASA Astrophysics Data System (ADS)

Martínez-Retama, S.; Montaño-Del Cid, M. A.

2015-12-01

The Tecoripa chart H12-D64 is located southeast of the state of Sonora, México, south of Arizona. The geology is represented by sedimentary rocks of the Ordovician and Triassic, volcanic rocks of the Upper Cretaceous and Tertiary, intrusive rocks from the Upper Cretaceous- Tertiary and sedimentary rocks of the Cenozoic. In this paper a gravimetric study was conducted to determine the configuration and depth of the basement and to develop a structural model of the subsurface. For this purpose a consistent gravimetric survey in 3 profiles was conducted. To complement this study, gravimetric data obtained by INEGI (96 gravimetric stations spaced every 4000 m) that correspond to a regional survey was also used. The two sets of data were corrected and processed with the WinGLink software. The profiles were then modeled using the Talwani method. 4 Profiles corresponding to the gravimetric survey and 5 data profiles from INEGI were modeled. Aeromagnetic data from the total field of Tecoripa chart were also processed. The digital information was integrated and processed by generating a data grid. Processes applied to data consisted of reduction to the pole, regional-residual separation and upward continuations. In general, the obtained structural models show intrusive bodies associated with well-defined high gravimetric and magnetic and low gravimetric and magnetic are associated with basins and sedimentary rocks. The obtained geological models show the basement represented by volcanic rocks of the Tarahumara Formation from the Upper Cretaceous which are in contact with sedimentary rocks from the Barranca Group from Upper Cretaceous and limestones from the Middle Ordovician. Both volcanic and sedimentary rocks are intruded by granodiorite- granite with ages of the Tertiary-Oligocene. Based on the superficial geology as well as in the configuration of the basement and the obtained structural model the existence of faults with NW-SE orientation that originate Horst and Graben type structures can be inferred. The basins have depths of 2,000 to 4,000m with sedimentary fillings from the Báucarit Formation and Quaternary sediments.

Thermodynamics and kinetics of RNA tertiary structure formation in the junctionless hairpin ribozyme.

PubMed

White, Neil A; Hoogstraten, Charles G

2017-09-01

The hairpin ribozyme consists of two RNA internal loops that interact to form the catalytically active structure. This docking transition is a rare example of intermolecular formation of RNA tertiary structure without coupling to helix annealing. We have used temperature-dependent surface plasmon resonance (SPR) to characterize the thermodynamics and kinetics of RNA tertiary structure formation for the junctionless form of the ribozyme, in which loops A and B reside on separate molecules. We find docking to be strongly enthalpy-driven and to be accompanied by substantial activation barriers for association and dissociation, consistent with the structural reorganization of both internal loops upon complex formation. Comparisons with the parallel analysis of a ribozyme variant carrying a 2'-O-methyl modification at the self-cleavage site and with published data in other systems reveal a surprising diversity of thermodynamic signatures, emphasizing the delicate balance of contributions to the free energy of formation of RNA tertiary structure. Copyright © 2017 Elsevier B.V. All rights reserved.

The Globular State of the Single-Stranded RNA: Effect of the Secondary Structure Rearrangements

PubMed Central

Grigoryan, Zareh A.; Karapetian, Armen T.

2015-01-01

The mutual influence of the slow rearrangements of secondary structure and fast collapse of the long single-stranded RNA (ssRNA) in approximation of coarse-grained model is studied with analytic calculations. It is assumed that the characteristic time of the secondary structure rearrangement is much longer than that for the formation of the tertiary structure. A nonequilibrium phase transition of the 2nd order has been observed. PMID:26345143

Analysis of gravity data beneath Endut geothermal prospect using horizontal gradient and Euler deconvolution

NASA Astrophysics Data System (ADS)

Supriyanto, Noor, T.; Suhanto, E.

2017-07-01

The Endut geothermal prospect is located in Banten Province, Indonesia. The geological setting of the area is dominated by quaternary volcanic, tertiary sediments and tertiary rock intrusion. This area has been in the preliminary study phase of geology, geochemistry, and geophysics. As one of the geophysical study, the gravity data measurement has been carried out and analyzed in order to understand geological condition especially subsurface fault structure that control the geothermal system in Endut area. After precondition applied to gravity data, the complete Bouguer anomaly have been analyzed using advanced derivatives method such as Horizontal Gradient (HG) and Euler Deconvolution (ED) to clarify the existance of fault structures. These techniques detected boundaries of body anomalies and faults structure that were compared with the lithologies in the geology map. The analysis result will be useful in making a further realistic conceptual model of the Endut geothermal area.

Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution

NASA Astrophysics Data System (ADS)

Schur, Florian K. M.; Hagen, Wim J. H.; Rumlová, Michaela; Ruml, Tomáš; Müller, Barbara; Kräusslich, Hans-Georg; Briggs, John A. G.

2015-01-01

Human immunodeficiency virus type 1 (HIV-1) assembly proceeds in two stages. First, the 55 kilodalton viral Gag polyprotein assembles into a hexameric protein lattice at the plasma membrane of the infected cell, inducing budding and release of an immature particle. Second, Gag is cleaved by the viral protease, leading to internal rearrangement of the virus into the mature, infectious form. Immature and mature HIV-1 particles are heterogeneous in size and morphology, preventing high-resolution analysis of their protein arrangement in situ by conventional structural biology methods. Here we apply cryo-electron tomography and sub-tomogram averaging methods to resolve the structure of the capsid lattice within intact immature HIV-1 particles at subnanometre resolution, allowing unambiguous positioning of all α-helices. The resulting model reveals tertiary and quaternary structural interactions that mediate HIV-1 assembly. Strikingly, these interactions differ from those predicted by the current model based on in vitro-assembled arrays of Gag-derived proteins from Mason-Pfizer monkey virus. To validate this difference, we solve the structure of the capsid lattice within intact immature Mason-Pfizer monkey virus particles. Comparison with the immature HIV-1 structure reveals that retroviral capsid proteins, while having conserved tertiary structures, adopt different quaternary arrangements during virus assembly. The approach demonstrated here should be applicable to determine structures of other proteins at subnanometre resolution within heterogeneous environments.

Empirical Modeling of Information Communication Technology Usage Behaviour among Business Education Teachers in Tertiary Colleges of a Developing Country

ERIC Educational Resources Information Center

Isiyaku, Dauda Dansarki; Ayub, Ahmad Fauzi Mohd; Abdulkadir, Suhaida

2015-01-01

This study has empirically tested the fitness of a structural model in explaining the influence of two exogenous variables (perceived enjoyment and attitude towards ICTs) on two endogenous variables (behavioural intention and teachers' Information Communication Technology (ICT) usage behavior), based on the proposition of Technology Acceptance…

Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes.

PubMed

Fujimoto, Akihiro; Okada, Yukinori; Boroevich, Keith A; Tsunoda, Tatsuhiko; Taniguchi, Hiroaki; Nakagawa, Hidewaki

2016-05-26

Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had ≥3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes.

Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes

PubMed Central

Fujimoto, Akihiro; Okada, Yukinori; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Taniguchi, Hiroaki; Nakagawa, Hidewaki

2016-01-01

Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had ≥3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes. PMID:27225414

Contact Prediction for Beta and Alpha-Beta Proteins Using Integer Linear Optimization and its Impact on the First Principles 3D Structure Prediction Method ASTRO-FOLD

PubMed Central

Rajgaria, R.; Wei, Y.; Floudas, C. A.

2010-01-01

An integer linear optimization model is presented to predict residue contacts in β, α + β, and α/β proteins. The total energy of a protein is expressed as sum of a Cα – Cα distance dependent contact energy contribution and a hydrophobic contribution. The model selects contacts that assign lowest energy to the protein structure while satisfying a set of constraints that are included to enforce certain physically observed topological information. A new method based on hydrophobicity is proposed to find the β-sheet alignments. These β-sheet alignments are used as constraints for contacts between residues of β-sheets. This model was tested on three independent protein test sets and CASP8 test proteins consisting of β, α + β, α/β proteins and was found to perform very well. The average accuracy of the predictions (separated by at least six residues) was approximately 61%. The average true positive and false positive distances were also calculated for each of the test sets and they are 7.58 Å and 15.88 Å, respectively. Residue contact prediction can be directly used to facilitate the protein tertiary structure prediction. This proposed residue contact prediction model is incorporated into the first principles protein tertiary structure prediction approach, ASTRO-FOLD. The effectiveness of the contact prediction model was further demonstrated by the improvement in the quality of the protein structure ensemble generated using the predicted residue contacts for a test set of 10 proteins. PMID:20225257

Freezing-Induced Perturbation of Tertiary Structure of a Monoclonal Antibody

PubMed Central

LIU, LU; BRAUN, LATOYA JONES; WANG, WEI; RANDOLPH, THEODORE W.; CARPENTER, JOHN F.

2014-01-01

We studied the effects of pH and solution additives on freezing-induced perturbations in the tertiary structure of a monoclonal antibody (mAb) by intrinsic tryptophan fluorescence spectroscopy. In general, freezing caused perturbations in the tertiary structure of the mAb, which were reversible or irreversible depending on the pH or excipients present in the formulation. Protein aggregation occurred in freeze–thawed samples in which perturbations of the tertiary structure were observed, but the levels of protein aggregates formed were not proportional to the degree of structural perturbation. Protein aggregation also occurred in freeze–thawed samples without obvious structural perturbations, most likely because of freeze concentration of protein and salts, and thus reduced protein colloidal stability. Therefore, freezing-induced protein aggregation may or may not first involve the perturbation of its native structure, followed by the assembly processes to form aggregates. Depending on the solution conditions, either step can be rate limiting. Finally, this study demonstrates the potential of fluorescence spectroscopy as a valuable tool for screening therapeutic protein formulations subjected to freeze–thaw stress. PMID:24832730

A Method to Predict the Structure and Stability of RNA/RNA Complexes.

PubMed

Xu, Xiaojun; Chen, Shi-Jie

2016-01-01

RNA/RNA interactions are essential for genomic RNA dimerization and regulation of gene expression. Intermolecular loop-loop base pairing is a widespread and functionally important tertiary structure motif in RNA machinery. However, computational prediction of intermolecular loop-loop base pairing is challenged by the entropy and free energy calculation due to the conformational constraint and the intermolecular interactions. In this chapter, we describe a recently developed statistical mechanics-based method for the prediction of RNA/RNA complex structures and stabilities. The method is based on the virtual bond RNA folding model (Vfold). The main emphasis in the method is placed on the evaluation of the entropy and free energy for the loops, especially tertiary kissing loops. The method also uses recursive partition function calculations and two-step screening algorithm for large, complicated structures of RNA/RNA complexes. As case studies, we use the HIV-1 Mal dimer and the siRNA/HIV-1 mutant (T4) to illustrate the method.

Automated protein structure modeling in CASP9 by I-TASSER pipeline combined with QUARK-based ab initio folding and FG-MD-based structure refinement

PubMed Central

Xu, Dong; Zhang, Jian; Roy, Ambrish; Zhang, Yang

2011-01-01

I-TASSER is an automated pipeline for protein tertiary structure prediction using multiple threading alignments and iterative structure assembly simulations. In CASP9 experiments, two new algorithms, QUARK and FG-MD, were added to the I-TASSER pipeline for improving the structural modeling accuracy. QUARK is a de novo structure prediction algorithm used for structure modeling of proteins that lack detectable template structures. For distantly homologous targets, QUARK models are found useful as a reference structure for selecting good threading alignments and guiding the I-TASSER structure assembly simulations. FG-MD is an atomic-level structural refinement program that uses structural fragments collected from the PDB structures to guide molecular dynamics simulation and improve the local structure of predicted model, including hydrogen-bonding networks, torsion angles and steric clashes. Despite considerable progress in both the template-based and template-free structure modeling, significant improvements on protein target classification, domain parsing, model selection, and ab initio folding of beta-proteins are still needed to further improve the I-TASSER pipeline. PMID:22069036

The roles of tertiary amine structure, background organic matter and chloramine species on NDMA formation.

PubMed

Selbes, Meric; Kim, Daekyun; Ates, Nuray; Karanfil, Tanju

2013-02-01

N-nitrosodimethylamine (NDMA), a probable human carcinogen, is a disinfection by-product that has been detected in chloraminated and chlorinated drinking waters and wastewaters. Formation mechanisms and precursors of NDMA are still not well understood. The main objectives of this study were to systematically investigate (i) the effect of tertiary amine structure, (ii) the effect of background natural organic matter (NOM), and (iii) the roles of mono vs. dichloramine species on the NDMA formation. Dimethylamine (DMA) and 20 different tertiary aliphatic and aromatic amines were carefully examined based on their functional groups attached to the basic DMA structure. The wide range (0.02-83.9%) of observed NDMA yields indicated the importance of the structure of tertiary amines, and both stability and electron distribution of the leaving group of tertiary amines on NDMA formation. DMA associated with branched alkyl groups or benzyl like structures having only one carbon between the ring and DMA structure consistently gave higher NDMA yields. Compounds with electron withdrawing groups (EWG) reacted preferentially with monochloramine, whereas compounds with electron donating group (EDG) showed tendency to react with dichloramine to form NDMA. When the selected amines were present in NOM solutions, NDMA formation increased for compounds with EWG while decreased for compounds with EDG. This impact was attributed to the competitions between NOM and amines for chloramine species. The results provided additional information to the commonly accepted mechanism for NDMA formation including chloramine species reacting with tertiary amines and the role of the leaving group on overall NDMA conversion. Copyright © 2012 Elsevier Ltd. All rights reserved.

Lithospheric mantle structure beneath Northern Scotland: Pre-plume remnant or syn-plume signature?

NASA Astrophysics Data System (ADS)

Knapp, J.

2003-04-01

Upper mantle reflectors (Flannan and W) beneath the northwestern British Isles are some of the best-known and most-studied examples of preserved structure within the continental mantle lithosphere, and are spatially coincident with the surface location of early Iceland plume volcanism in the British Tertiary Province. First observed on BIRPS (British Institutions Reflection Profiling Syndicate) marine deep seismic reflection profiles in the early 1980's, these reflectors have subsequently been imaged and correlated on additional reflection and refraction profiles in the offshore area of northern and western Scotland. The age and tectonic significance of these reflectors remains a subject of wide debate, due in part to the absence of robust characterization of the upper mantle velocity structure in this tectonically complex area. Interpretations advanced over the past two decades for the dipping Flannan reflector range from fossilized subduction complex to large-scale extensional shear zone, and span ages from Proterozoic to early Mesozoic. Crustal geology of the region records early Paleozoic continental collision and late Paleozoic to Mesozoic extension. Significant modification of the British lithosphere in early Tertiary time, including dramatic thinning and extensive basaltic intrusion associated with initiation and development of the Iceland plume, suggests either (1) an early Tertiary age for the Flannan reflector or (2) preservation of ancient features within the mantle lithosphere despite such pervasive modification. Exisitng constraints are consistent with a model for early Tertiary origin of the Flannan reflector as the downdip continuation of the Rockall Trough extensional system of latest Cretaceous to earliest Tertiary age during opening of the northern Atlantic Ocean and initiation of the Iceland plume. Lithopsheric thinning beneath present-day northern Scotland could have served to focus the early expression of plume volcanism (British Tertiary Province), despite the inferred distant locus of the initial plume head. Alternatively, preservation of large-scale pre-plume fabric in the Scottish mantle would imply long-lived tectonic heredity in the continental lithospheric mantle, and place important constraints on the plume-related effects (or lack thereof) in the mantle lithosphere.

Mechanisms for creating accommodation space during early Tertiary sedimentation in Tibet.

NASA Astrophysics Data System (ADS)

Studnicki-Gizbert, C.; Burchfiel, B. C.

2003-12-01

The Tibetan plateau is for the most part underlain by rocks of pre-Cenozoic age, a fact that has hindered the identification of Cenozoic shortening structures that can be unequivocally related to the effects of India-Asia collision. Notably, however, the Qiangtang block contains a number of small, short wavelength basins filled with terrestrial sediments of early Tertiary age. Where these basins have been well studied, sedimentation is recognized as having occurred coevally with compressional deformation. The classic treatment of compressional basins appeals to accommodation space created by the flexure of an elastic plate in response to loads created by adjacent thrust fault bound ranges. It is unlikely that the Tertiary basins of the Qiangtang block formed in this manner. The wavelength of a classically modelled flexural basin is a basically a function of the thickness of the elastic plate and the density difference between sedimentary fill and ductile material underlying the plate. Assuming a model of elastic flexure, the very small wavelengths (5 - 30km) characteristic of Qiangtang basins would then imply extremely thin (~ 1-5 km) effective elastic plate thicknesses. These very low values are difficult to reconcile with any reasonable characterization of crustal rheology. Instead, these relatively small basins likely record the creation of accommodation space created by differential uplift across the strike of folds and faults. Stratal geometries and sedimentation rates reflect the kinematics and geometries of local compressional structures and the mechanical basis for the creation of accommodation space remains uncertain. Finally, the origin of these basins makes it unlikely that early Tertiary sedimentation represents a significant fraction of the upper crust of Tibetan plateau.

The structure of a Mesozoic basin beneath the Lake Tana area, Ethiopia, revealed by magnetotelluric imaging

NASA Astrophysics Data System (ADS)

Hautot, Sophie; Whaler, Kathryn; Gebru, Workneh; Desissa, Mohammednur

2006-03-01

The northwestern Plateau of Ethiopia is almost entirely covered with extensive Tertiary continental flood basalts that mask the underlying formations. Mesozoic and Tertiary sediments are exposed in a few locations surrounding the Lake Tana area suggesting that the Tana depression is an extensional basin buried by the 1-2 km thick Eocene-Oligocene flood basalt sequences in this region. A magnetotelluric survey has been carried out to investigate the deep structure of the Tana area. The objectives were to estimate the thickness of the volcanics and anticipated underlying sedimentary basin. We have collected 27 magnetotelluric soundings south and east of Lake Tana. Two-dimensional inversion of the data along a 160 km long profile gives a model consistent with a NW-SE trending sedimentary basin beneath the lava flows. The thickness of sediments overlying the Precambrian basement averages 1.5-2 km, which is comparable to the Blue Nile stratigraphic section, south of the area. A 1 km thickening of sediments over a 30-40 km wide section suggests that the form of the basin is a half-graben. It is suggested that electrically resistive features in the model are related to volcanic materials intruded within the rift basin sediments through normal faults. The results illustrate the strong control of the Precambrian fracture zones on the feeding of the Tertiary Trap series.

Correlation between the radiological observation of isolated tertiary waves on an esophagram and findings on high-resolution esophageal manometry.

PubMed

Halland, M; Ravi, K; Barlow, J; Arora, A

2016-01-01

Barium esophagrams are a frequently performed test, and radiological observations about potential abnormal esophageal motility, such as tertiary contractions, are commonly reported. We sought to assess the correlation between tertiary waves, and in particular isolated tertiary waves, on esophagrams and findings on non-synchronous high-resolution esophageal manometry. We retrospectively reviewed reports of esophagrams performed at a tertiary referral center and identified patients in whom tertiary waves were observed and a high-resolution esophageal manometry had been performed. We defined two groups; group 1 was defined as patients with isolated tertiary waves, whereas group 2 had tertiary waves and evidence of achalasia or an obstructing structural abnormality on the esophagram. We collected data on demographics, dysphagia score, associated findings on esophagram, and need for intervention. We reviewed the reports of 2100 esophagrams of which tertiary waves were noted as an isolated abnormality in 92, and in association with achalasia or a structural obstruction in 61. High-resolution manometry was performed in 17 patients in group 1, and five had evidence of a significant esophageal motility disorder and 4 required any intervention. Twenty-one patients in group 2 underwent manometry, and 18 had a significant esophageal motility disorder. An isolated finding of tertiary waves on an esophagram is rarely associated with a significant esophageal motility disorder that requires intervention. All patients with isolated tertiary waves who required intervention had a dysphagia to liquids. Tertiary contractions, in the absence of dysphagia to liquids, indicate no significant esophageal motility disorder. © 2014 International Society for Diseases of the Esophagus.

Protein backbone engineering as a strategy to advance foldamers toward the frontier of protein-like tertiary structure.

PubMed

Reinert, Zachary E; Horne, W Seth

2014-11-28

A variety of non-biological structural motifs have been incorporated into the backbone of natural protein sequences. In parallel work, diverse unnatural oligomers of de novo design (termed "foldamers") have been developed that fold in defined ways. In this Perspective article, we survey foundational studies on protein backbone engineering, with a focus on alterations made in the context of complex tertiary folds. We go on to summarize recent work illustrating the potential promise of these methods to provide a general framework for the construction of foldamer mimics of protein tertiary structures.

Structural alignment of protein descriptors - a combinatorial model.

PubMed

Antczak, Maciej; Kasprzak, Marta; Lukasiak, Piotr; Blazewicz, Jacek

2016-09-17

Structural alignment of proteins is one of the most challenging problems in molecular biology. The tertiary structure of a protein strictly correlates with its function and computationally predicted structures are nowadays a main premise for understanding the latter. However, computationally derived 3D models often exhibit deviations from the native structure. A way to confirm a model is a comparison with other structures. The structural alignment of a pair of proteins can be defined with the use of a concept of protein descriptors. The protein descriptors are local substructures of protein molecules, which allow us to divide the original problem into a set of subproblems and, consequently, to propose a more efficient algorithmic solution. In the literature, one can find many applications of the descriptors concept that prove its usefulness for insight into protein 3D structures, but the proposed approaches are presented rather from the biological perspective than from the computational or algorithmic point of view. Efficient algorithms for identification and structural comparison of descriptors can become crucial components of methods for structural quality assessment as well as tertiary structure prediction. In this paper, we propose a new combinatorial model and new polynomial-time algorithms for the structural alignment of descriptors. The model is based on the maximum-size assignment problem, which we define here and prove that it can be solved in polynomial time. We demonstrate suitability of this approach by comparison with an exact backtracking algorithm. Besides a simplification coming from the combinatorial modeling, both on the conceptual and complexity level, we gain with this approach high quality of obtained results, in terms of 3D alignment accuracy and processing efficiency. All the proposed algorithms were developed and integrated in a computationally efficient tool descs-standalone, which allows the user to identify and structurally compare descriptors of biological molecules, such as proteins and RNAs. Both PDB (Protein Data Bank) and mmCIF (macromolecular Crystallographic Information File) formats are supported. The proposed tool is available as an open source project stored on GitHub ( https://github.com/mantczak/descs-standalone ).

FuncPatch: a web server for the fast Bayesian inference of conserved functional patches in protein 3D structures.

PubMed

Huang, Yi-Fei; Golding, G Brian

2015-02-15

A number of statistical phylogenetic methods have been developed to infer conserved functional sites or regions in proteins. Many methods, e.g. Rate4Site, apply the standard phylogenetic models to infer site-specific substitution rates and totally ignore the spatial correlation of substitution rates in protein tertiary structures, which may reduce their power to identify conserved functional patches in protein tertiary structures when the sequences used in the analysis are highly similar. The 3D sliding window method has been proposed to infer conserved functional patches in protein tertiary structures, but the window size, which reflects the strength of the spatial correlation, must be predefined and is not inferred from data. We recently developed GP4Rate to solve these problems under the Bayesian framework. Unfortunately, GP4Rate is computationally slow. Here, we present an intuitive web server, FuncPatch, to perform a fast approximate Bayesian inference of conserved functional patches in protein tertiary structures. Both simulations and four case studies based on empirical data suggest that FuncPatch is a good approximation to GP4Rate. However, FuncPatch is orders of magnitudes faster than GP4Rate. In addition, simulations suggest that FuncPatch is potentially a useful tool complementary to Rate4Site, but the 3D sliding window method is less powerful than FuncPatch and Rate4Site. The functional patches predicted by FuncPatch in the four case studies are supported by experimental evidence, which corroborates the usefulness of FuncPatch. The software FuncPatch is freely available at the web site, http://info.mcmaster.ca/yifei/FuncPatch golding@mcmaster.ca Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Novel recombinant insulin analogue with flexible C-terminus in B chain. NMR structure of biosynthetic engineered A22G-B31K-B32R human insulin monomer in water/acetonitrile solution.

PubMed

Borowicz, Piotr; Bocian, Wojciech; Sitkowski, Jerzy; Bednarek, Elżbieta; Mikiewicz-Syguła, Diana; Błażej-Sosnowska, Sylwia; Bogiel, Monika; Rusek, Dorota; Kurzynoga, Dariusz; Kozerski, Lech

2011-11-01

A tertiary structure of recombinant A22(G)-B31(K)-B32(R)-human insulin monomer (insulin GKR) has been characterized by (1)H, (13)C NMR at natural isotopic abundance using NOESY, TOCSY, (1)H/(13)C-GHSQC, and (1)H/(13)C-GHSQC-TOCSY spectra. Translational diffusion studies indicate the monomer structure in water/acetonitrile (65/35vol.%). CSI analysis confirms existence of secondary structure motifs present in human insulin standard (HIS). Both techniques allow to establish that in this solvent recombinant insulin GKR exists as a monomer. Starting from structures calculated by the program CYANA, two different refinement protocols used molecular dynamics simulated annealing with the program AMBER; in vacuum (AMBER_VC), and including a generalized Born solvent model (AMBER_GB). From these calculations an ensemble of 20 structures of lowest energy was chosen which represents the tertiary structure of studied insulin. Here we present novel insulin with added A22(G) amino acid which interacts with β-turn environment resulting in high flexibility of B chain C-terminus. Copyright © 2011 Elsevier B.V. All rights reserved.

Helix A Stabilization Precedes Amino-terminal Lobe Activation upon Calcium Binding to Calmodulin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Baowei; Lowry, David; Mayer, M. Uljana

2008-08-09

The structural coupling between opposing domains of CaM was investigated using the conformationally sensitive biarsenical probe 4,5-bis(1,3,2-dithioarsolan-2-yl)-resorufin (ReAsH), which upon binding to an engineered tetracysteine binding motif near the end of helix A (Thr-5 to Phe-19) becomes highly fluorescent. Changes in conformation and dynamics are reflective of the native CaM structure, as there is no change in the 1H- 15N HSQC NMR spectrum in comparison to wild-type CaM. We find evidence of a conformational intermediate associated with CaM activation, where calcium occupancy of sites in the amino-terminal and carboxyl-terminal lobes of CaM differentially affect the fluorescence intensity of bound ReAsH.more » Insight into the structure of the conformational intermediate is possible from a consideration of calcium-dependent changes in rates of ReAsH binding and helix A mobility, which respectively distinguish secondary structural changes associated with helix A stabilization from the tertiary structural reorganization of the amino-terminal lobe of CaM necessary for high-affinity binding to target proteins. Helix A stabilization is associated with calcium occupancy of sites in the carboxyl-terminal lobe (Kd = 0.36 ± 0.04 μM), which results in a reduction in the rate of ReAsH binding from 4900 M -1 sec -1 to 370 M -1 sec -1. In comparison, tertiary structural changes involving helix A and other structural elements in the amino-terminal lobe requires calcium-occupancy of amino-terminal sites (Kd = 18 ± 3 μM). Observed secondary and tertiary structural changes involving helix A in response to the sequential calcium occupancy of carboxyl- and amino-terminal lobe calcium binding sites suggest an important involvement of helix A in mediating the structural coupling between the opposing domains of CaM. These results are discussed in terms of a model in which carboxyl-terminal lobe calcium activation induces secondary structural changes within the interdomain linker that release helix A, thereby facilitating the formation of calcium binding sites in the amino-terminal lobe and linked tertiary structural rearrangements to form a high-affinity binding cleft that can associate with target proteins.« less

Organizational Commitment and Nurses' Characteristics as Predictors of Job Involvement.

PubMed

Alammar, Kamila; Alamrani, Mashael; Alqahtani, Sara; Ahmad, Muayyad

2016-01-01

To predict nurses' job involvement on the basis of their organizational commitment and personal characteristics at a large tertiary hospital in Saudi Arabia. Data were collected in 2015 from a convenience sample of 558 nurses working at a large tertiary hospital in Riyadh, Saudi Arabia. A cross-sectional correlational design was used in this study. Data were collected using a structured questionnaire. All commitment scales had significant relationships. Multiple linear regression analysis revealed that the model predicted a sizeable proportion of variance in nurses' job involvement (p < 0.001). High organizational commitment enhances job involvement, which may lead to more organizational stability and effectiveness.

Characterization of protein-folding pathways by reduced-space modeling.

PubMed

Kmiecik, Sebastian; Kolinski, Andrzej

2007-07-24

Ab initio simulations of the folding pathways are currently limited to very small proteins. For larger proteins, some approximations or simplifications in protein models need to be introduced. Protein folding and unfolding are among the basic processes in the cell and are very difficult to characterize in detail by experiment or simulation. Chymotrypsin inhibitor 2 (CI2) and barnase are probably the best characterized experimentally in this respect. For these model systems, initial folding stages were simulated by using CA-CB-side chain (CABS), a reduced-space protein-modeling tool. CABS employs knowledge-based potentials that proved to be very successful in protein structure prediction. With the use of isothermal Monte Carlo (MC) dynamics, initiation sites with a residual structure and weak tertiary interactions were identified. Such structures are essential for the initiation of the folding process through a sequential reduction of the protein conformational space, overcoming the Levinthal paradox in this manner. Furthermore, nucleation sites that initiate a tertiary interactions network were located. The MC simulations correspond perfectly to the results of experimental and theoretical research and bring insights into CI2 folding mechanism: unambiguous sequence of folding events was reported as well as cooperative substructures compatible with those obtained in recent molecular dynamics unfolding studies. The correspondence between the simulation and experiment shows that knowledge-based potentials are not only useful in protein structure predictions but are also capable of reproducing the folding pathways. Thus, the results of this work significantly extend the applicability range of reduced models in the theoretical study of proteins.

The latent structure of the functional dyspepsia symptom complex: a taxometric analysis.

PubMed

Van Oudenhove, L; Jasper, F; Walentynowicz, M; Witthöft, M; Van den Bergh, O; Tack, J

2016-07-01

Rome III introduced a subdivision of functional dyspepsia (FD) into postprandial distress syndrome and epigastric pain syndrome, characterized by early satiation/postprandial fullness, and epigastric pain/burning, respectively. However, evidence on their degree of overlap is mixed. We aimed to investigate the latent structure of FD to test whether distinguishable symptom-based subgroups exist. Consecutive tertiary care Rome II FD patients completed the dyspepsia symptom severity scale. Confirmatory factor analysis (CFA) was used to compare the fit of a single factor model, a correlated three-factor model based on Rome III subgroups and a bifactor model consisting of a general FD factor and orthogonal subgroup factors. Taxometric analyses were subsequently used to investigate the latent structure of FD. Nine hundred and fifty-seven FD patients (71.1% women, age 41 ± 14.8) participated. In CFA, the bifactor model yielded a significantly better fit than the two other models (χ² difference tests both p < 0.001). All symptoms had significant loadings on both the general and the subgroup-specific factors (all p < 0.05). Somatization was associated with the general (r = 0.72, p < 0.01), but not the subgroup-specific factors (all r < 0.13, p > 0.05). Taxometric analyses supported a dimensional structure of FD (all CCFI<0.38). We found a dimensional rather than categorical latent structure of the FD symptom complex in tertiary care. A combination of a general dyspepsia symptom reporting factor, which was associated with somatization, and symptom-specific factors reflecting the Rome III subdivision fitted the data best. This has implications for classification, pathophysiology, and treatment of FD. © 2016 John Wiley & Sons Ltd.

Preliminary model of the pre-Tertiary basement rocks beneath Yucca Flat, Nevada Test Site, Nevada, based on analysis of gravity and magnetic data

USGS Publications Warehouse

Phelps, Geoffrey A.; McKee, Edwin H.; Sweetkind, D.; Langenheim, V.E.

2000-01-01

The Environmental Restoration Program of the U.S. Department of Energy, Nevada Operations Office, was developed to investigate the possible consequences to the environment of 40 years of nuclear testing on the Nevada Test Site. The majority of the tests were detonated underground, introducing contaminants into the ground-water system (Laczniak and others, 1996). An understanding of the ground-water flow paths is necessary to evaluate the extent of ground-water contamination. This report provides information specific to Yucca Flat on the Nevada Test Site. Critical to understanding the ground-water flow beneath Yucca Flat is an understanding of the subsurface geology, particularly the structure and distribution of the pre-Tertiary rocks, which comprise both the major regional aquifer and aquitard sequences (Winograd and Thordarson, 1975; Laczniak and others, 1996). Because the pre-Tertiary rocks are not exposed at the surface of Yucca Flat their distribution must be determined through well logs and less direct geophysical methods such as potential field studies. In previous studies (Phelps and others, 1999; Phelps and Mckee, 1999) developed a model of the basement surface of the Paleozoic rocks beneath Yucca Flat and a series of normal faults that create topographic relief on the basement surface. In this study the basement rocks and structure of Yucca Flat are examined in more detail using the basement gravity anomaly derived from the isostatic gravity inversion model of Phelps and others (1999) and high-resolution magnetic data, as part of an effort to gain a better understanding of the Paleozoic rocks beneath Yucca Flat in support of groundwater modeling.

Deep resistivity structure of Yucca Flat, Nevada Test Site, Nevada

USGS Publications Warehouse

Asch, Theodore H.; Rodriguez, Brian D.; Sampson, Jay A.; Wallin, Erin L.; Williams, Jackie M.

2006-01-01

The Department of Energy (DOE) and the National Nuclear Security Administration (NNSA) at their Nevada Site Office are addressing groundwater contamination resulting from historical underground nuclear testing through the Environmental Management program and, in particular, the Underground Test Area project. One issue of concern is the nature of the somewhat poorly constrained pre Tertiary geology and its effects on ground-water flow in the area adjacent to a nuclear test. Ground water modelers would like to know more about the hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey, supported by the DOE and NNSA-NSO, collected and processed data from 51 magnetotelluric (MT) and audio-magnetotelluric (AMT) stations at the Nevada Test Site in and near Yucca Flat to assist in characterizing the pre-Tertiary geology in that area. The primary purpose was to refine the character, thickness, and lateral extent of pre Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (late Devonian - Mississippian-age siliciclastic rocks assigned to the Eleana Formation and Chainman Shale) in the Yucca Flat area. The MT and AMT data have been released in separate USGS Open File Reports. The Nevada Test Site magnetotelluric data interpretation presented in this report includes the results of detailed two-dimensional (2 D) resistivity modeling for each profile (including alternative interpretations) and gross inferences on the three dimensional (3 D) character of the geology beneath each station. The character, thickness, and lateral extent of the Chainman Shale and Eleana Formation that comprise the Upper Clastic Confining Unit are generally well determined in the upper 5 km. Inferences can be made regarding the presence of the Lower Clastic Confining Unit at depths below 5 km. Large fault structures such as the CP Thrust fault, the Carpetbag fault, and the Yucca fault that cross Yucca Flat are also discernable as are other smaller faults. The subsurface electrical resistivity distribution and inferred geologic structures determined by this investigation should help constrain the hydrostratigraphic framework model that is under development.

Diversification of Tertiary Education in Switzerland.

ERIC Educational Resources Information Center

Crausaz, Roselyne

The structure of Switzerland's educational system is described including the types of secondary schools and/or courses and the system of tertiary education. Fields of study, types of institutions, and characteristics of tertiary education in Switzerland are discussed. The chapter on students covers admission procedures, trends in enrollment,…

Evidence for close side-chain packing in an early protein folding intermediate previously assumed to be a molten globule

PubMed Central

Rosen, Laura E.; Connell, Katelyn B.; Marqusee, Susan

2014-01-01

The molten globule, a conformational ensemble with significant secondary structure but only loosely packed tertiary structure, has been suggested to be a ubiquitous intermediate in protein folding. However, it is difficult to assess the tertiary packing of transiently populated species to evaluate this hypothesis. Escherichia coli RNase H is known to populate an intermediate before the rate-limiting barrier to folding that has long been thought to be a molten globule. We investigated this hypothesis by making mimics of the intermediate that are the ground-state conformation at equilibrium, using two approaches: a truncation to generate a fragment mimic of the intermediate, and selective destabilization of the native state using point mutations. Spectroscopic characterization and the response of the mimics to further mutation are consistent with studies on the transient kinetic intermediate, indicating that they model the early intermediate. Both mimics fold cooperatively and exhibit NMR spectra indicative of a closely packed conformation, in contrast to the hypothesis of molten tertiary packing. This result is important for understanding the nature of the subsequent rate-limiting barrier to folding and has implications for the assumption that many other proteins populate molten globule folding intermediates. PMID:25258414

Evidence for close side-chain packing in an early protein folding intermediate previously assumed to be a molten globule.

PubMed

Rosen, Laura E; Connell, Katelyn B; Marqusee, Susan

2014-10-14

The molten globule, a conformational ensemble with significant secondary structure but only loosely packed tertiary structure, has been suggested to be a ubiquitous intermediate in protein folding. However, it is difficult to assess the tertiary packing of transiently populated species to evaluate this hypothesis. Escherichia coli RNase H is known to populate an intermediate before the rate-limiting barrier to folding that has long been thought to be a molten globule. We investigated this hypothesis by making mimics of the intermediate that are the ground-state conformation at equilibrium, using two approaches: a truncation to generate a fragment mimic of the intermediate, and selective destabilization of the native state using point mutations. Spectroscopic characterization and the response of the mimics to further mutation are consistent with studies on the transient kinetic intermediate, indicating that they model the early intermediate. Both mimics fold cooperatively and exhibit NMR spectra indicative of a closely packed conformation, in contrast to the hypothesis of molten tertiary packing. This result is important for understanding the nature of the subsequent rate-limiting barrier to folding and has implications for the assumption that many other proteins populate molten globule folding intermediates.

Molecular data and ecological niche modelling reveal a highly dynamic evolutionary history of the East Asian Tertiary relict Cercidiphyllum (Cercidiphyllaceae).

PubMed

Qi, Xin-Shuai; Chen, Chen; Comes, Hans Peter; Sakaguchi, Shota; Liu, Yi-Hui; Tanaka, Nobuyuki; Sakio, Hitoshi; Qiu, Ying-Xiong

2012-10-01

East Asia's temperate deciduous forests served as sanctuary for Tertiary relict trees, but their ages and response to past climate change remain largely unknown. To address this issue, we elucidated the evolutionary and population demographic history of Cercdiphyllum, comprising species in China/Japan (Cercdiphyllum japonicum) and central Japan (Cercdiphyllum magnificum). Fifty-three populations were genotyped using chloroplast and ribosomal DNA sequences and microsatellite loci to assess molecular structure and diversity in relation to past (Last Glacial Maximum) and present distributions based on ecological niche modelling. Late Tertiary climate cooling was reflected in a relatively recent speciation event, dated at the Mio-/Pliocene boundary. During glacials, the warm-temperate C. japonicum experienced massive habitat losses in some areas (north-central China/north Japan) but increases in others (southwest/-east China, East China Sea landbridge, south Japan). In China, the Sichuan Basin and/or the middle-Yangtze were source areas of postglacial northward recolonization; in Japan, this may have been facilitated through introgressive hybridization with the cool-temperate C. magnificum. Our findings challenge the notion of relative evolutionary and demographic stability of Tertiary relict trees, and may serve as a guideline for assessing the impact of Neogene climate change on the evolution and distribution of East Asian temperate plants. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

Prelude and Fugue, predicting local protein structure, early folding regions and structural weaknesses.

PubMed

Kwasigroch, Jean Marc; Rooman, Marianne

2006-07-15

Prelude&Fugue are bioinformatics tools aiming at predicting the local 3D structure of a protein from its amino acid sequence in terms of seven backbone torsion angle domains, using database-derived potentials. Prelude(&Fugue) computes all lowest free energy conformations of a protein or protein region, ranked by increasing energy, and possibly satisfying some interresidue distance constraints specified by the user. (Prelude&)Fugue detects sequence regions whose predicted structure is significantly preferred relative to other conformations in the absence of tertiary interactions. These programs can be used for predicting secondary structure, tertiary structure of short peptides, flickering early folding sequences and peptides that adopt a preferred conformation in solution. They can also be used for detecting structural weaknesses, i.e. sequence regions that are not optimal with respect to the tertiary fold. http://babylone.ulb.ac.be/Prelude_and_Fugue.

Molecular identification of aiiA homologous gene from endophytic Enterobacter species and in silico analysis of putative tertiary structure of AHL-lactonase.

PubMed

Rajesh, P S; Rai, V Ravishankar

2014-01-03

The aiiA homologous gene known to encode AHL- lactonase enzyme which hydrolyze the N-acylhomoserine lactone (AHL) quorum sensing signaling molecules produced by Gram negative bacteria. In this study, the degradation of AHL molecules was determined by cell-free lysate of endophytic Enterobacter species. The percentage of quorum quenching was confirmed and quantified by HPLC method (p<0.0001). Amplification and sequence BLAST analysis showed the presence of aiiA homologous gene in endophytic Enterobacter asburiae VT65, Enterobacter aerogenes VT66 and Enterobacter ludwigii VT70 strains. Sequence alignment analysis revealed the presence of two zinc binding sites, "HXHXDH" motif as well as tyrosine residue at the position 194. Based on known template available at Swiss-Model, putative tertiary structure of AHL-lactonase was constructed. The result showed that novel endophytic strains of Enterobacter genera encode the novel aiiA homologous gene and its structural importance for future study. Copyright © 2013 Elsevier Inc. All rights reserved.

Cooperative Tertiary Interaction Network Guides RNA Folding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behrouzi, Reza; Roh, Joon Ho; Kilburn, Duncan

2013-04-08

Noncoding RNAs form unique 3D structures, which perform many regulatory functions. To understand how RNAs fold uniquely despite a small number of tertiary interaction motifs, we mutated the major tertiary interactions in a group I ribozyme by single-base substitutions. The resulting perturbations to the folding energy landscape were measured using SAXS, ribozyme activity, hydroxyl radical footprinting, and native PAGE. Double- and triple-mutant cycles show that most tertiary interactions have a small effect on the stability of the native state. Instead, the formation of core and peripheral structural motifs is cooperatively linked in near-native folding intermediates, and this cooperativity depends onmore » the native helix orientation. The emergence of a cooperative interaction network at an early stage of folding suppresses nonnative structures and guides the search for the native state. We suggest that cooperativity in noncoding RNAs arose from natural selection of architectures conducive to forming a unique, stable fold.« less

Tertiary Education in Britian. National Report.

ERIC Educational Resources Information Center

Eggleston, J.

Some of the major trends in British Tertiary education are reviewed. Types of schools and/or courses in British secondary education are examined in relation to student preparation for tertiary education. The present system of higher Education in Britian is described including types of institutions and academic structures, admission requirements,…

The secondary structure and the thermal unfolding parameters of the S-layer protein from Lactobacillus salivarius.

PubMed

Lighezan, Liliana; Georgieva, Ralitsa; Neagu, Adrian

2016-09-01

Surface layer (S-layer) proteins have been identified in the cell envelope of many organisms, such as bacteria and archaea. They self-assemble, forming monomolecular crystalline arrays. Isolated S-layer proteins are able to recrystallize into regular lattices, which proved useful in biotechnology. Here we investigate the structure and thermal unfolding of the S-layer protein isolated from Lactobacillus salivarius 16 strain of human origin. Using circular dichroism (CD) spectroscopy, and the software CDSSTR from DICHROWEB, CONTINLL from CDPro, as well as CDNN, we assess the fractions of the protein's secondary structural elements at temperatures ranging between 10 and 90 °C, and predict the tertiary class of the protein. To study the thermal unfolding of the protein, we analyze the temperature dependence of the CD signal in the far- and near-UV domains. Fitting the experimental data by two- and three-state models of thermal unfolding, we infer the midpoint temperatures, the temperature dependence of the changes in Gibbs free energy, enthalpy, and entropy of the unfolding transitions in standard conditions, and the temperature dependence of the equilibrium constant. We also estimate the changes in heat capacity at constant pressure in standard conditions. The results indicate that the thermal unfolding of the S-layer protein from L. salivarius is highly cooperative, since changes in the secondary and tertiary structures occur simultaneously. The thermodynamic analysis predicts a "cold" transition, at about -3 °C, of both the secondary and tertiary structures. Our findings may be important for the use of S-layer proteins in biotechnology and in biomedical applications.

Thermal aggregation of glycated bovine serum albumin.

PubMed

Rondeau, Philippe; Navarra, Giovanna; Cacciabaudo, Francesco; Leone, Maurizio; Bourdon, Emmanuel; Militello, Valeria

2010-04-01

Aggregation and glycation processes in proteins have a particular interest in medicine fields and in food technology. Serum albumins are model proteins which are able to self-assembly in aggregates and also sensitive to a non-enzymatic glycation in cases of diabetes. In this work, we firstly reported a study on the glycation and oxidation effects on the structure of bovine serum albumin (BSA). The experimental approach is based on the study of conformational changes of BSA at secondary and tertiary structures by FTIR absorption and fluorescence spectroscopy, respectively. Secondly, we analysed the thermal aggregation process on BSA glycated with different glucose concentrations. Additional information on the aggregation kinetics are obtained by light scattering measurements. The results show that glycation process affects the native structure of BSA. Then, the partial unfolding of the tertiary structure which accompanies the aggregation process is similar both in native and glycated BSA. In particular, the formation of aggregates is progressively inhibited with growing concentration of glucose incubated with BSA. These results bring new insights on how aggregation process is affected by modification of BSA induced by glycation. Copyright 2009 Elsevier B.V. All rights reserved.

Epitope targeting of tertiary protein structure enables target-guided synthesis of a potent in-cell inhibitor of botulinum neurotoxin.

PubMed

Farrow, Blake; Wong, Michelle; Malette, Jacquie; Lai, Bert; Deyle, Kaycie M; Das, Samir; Nag, Arundhati; Agnew, Heather D; Heath, James R

2015-06-08

Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Community Pediatric Prevention Partnership: Linking Schools, Providers, and Tertiary Care Services.

ERIC Educational Resources Information Center

Farrior, Kim Crickmore; Engelke, Martha Keehner; Collins, Catherine Shoup; Cox, Carol Gordon

2000-01-01

Describes a partnership among a hospital, a university, private providers, and a local school system and health department to provide school health services. Noteworthy aspects of the project include the organizational structure and funding, implementation of a case management model, and a focus on documenting outcomes. The program has…

Mapping the Typology of Transition Systems in a Liberal Market Economy: The Case of Canada

ERIC Educational Resources Information Center

Arnold, Christine Helen; Wheelahan, Leesa; Moodie, Gavin; Beaulieu, Jacqueline; Taylor-Cline, Jean-Claude

2018-01-01

This research explores links between tertiary education institutions and between tertiary education and the labour market as determinants of provincial and national transition patterns in Canada. The study consists of a provincial analysis that maps the typology of transition systems across Canada's devolved federated tertiary education structure.…

The Missing Link in Australian Tertiary Education: Short-Cycle Higher Education

ERIC Educational Resources Information Center

Moodie, Gavin

2003-01-01

The blurring of the boundary between Australian vocational education and training and higher education is leading to a reconsideration of the current structure of Australian tertiary education. This paper starts with the main overlap of the Australian tertiary education sectors, diplomas and advanced diplomas. The ambiguous treatment of these…

Crustal-scale geological and thermal models of the Beaufort-Mackenzie Basin, Arctic Canada

NASA Astrophysics Data System (ADS)

Sippel, Judith; Scheck-Wenderoth, Magdalena; Kröger, Karsten; Lewerenz, Björn

2010-05-01

The Beaufort-Mackenzie Basin is a petroliferous province in northwest Arctic Canada and one of the best-known segments of the Arctic Ocean margin due to decades of exploration. Our study is part of the programme MOM (Methane On the Move), which aims to quantify the methane contribution from natural petroleum systems to the atmosphere over geological times. Models reflecting the potential of a sedimentary basin to release methane require well-assessed boundary conditions such as the crustal structure and large-scale temperature variation. We focus on the crustal-scale thermal field of the Beaufort-Mackenzie Basin. This Basin has formed on a post-rift, continental margin which, during the Late Cretaceous and Tertiary, developed into the foreland of the North American Cordilleran foldbelt providing space for the accumulation of up to 16 km of foreland deposits. We present a 3D geological model which integrates the present topography, depth maps of Upper Cretaceous and Tertiary horizons (Kroeger et al., 2008, 2009), tops of formations derived from interpreted 2D reflection seismic lines and 284 boreholes (released by the National Energy Board of Canada), and the sequence stratigraphic framework established by previous studies (e.g. Dixon et al., 1996). To determine the position and geometry of the crust-mantle boundary, an isostatic calculation (Airýs model) is applied to the geological model. We present different crustal-scale models combining isostatic modelling, published deep reflection and refraction seismic lines (e.g. Stephenson et al., 1994; O'Leary et al., 1995), and calculations of the 3D conductive thermal field. References: Dixon, J., 1996. Geological Atlas of the Beaufort-Mackenzie Area, Geological Survey of Canada Miscellaneous Report, 59, Ottawa, 173 pp. Kroeger, K.F., Ondrak, R., di Primio, R. and Horsfield, B., 2008. A three-dimensional insight into the Mackenzie Basin (Canada): Implications for the thermal history and hydrocarbon generation potential of Tertiary deltaic sequences, AAPG Bulletin, 92(2): 225-247. Kroeger, K.F., di Primio, R. and Horsfield, B., (2009). Hydrocarbon flow modeling in complex structures (Mackenzie Basin, Canada), AAPG Bulletin, 93(9): 1-25. O'Leary, D.M., Ellis, R.M., Stephenson, R.A., Lane, L.S. and Zelt, C.A., 1995. Crustal structure of the northern Yukon and Mackenzie Delta, northwestern Canada, Journal of Geophysical Research 100(B7): 9905-9920. Stephenson, R.A., Coflin, K.C., Lane, L.S. and Dietrich, J.R., 1994. Crustal structure and tectonics of the southeastern Beaufort Sea continental margin, Tectonics, 13(2): 389-400.

A Self-Assisting Protein Folding Model for Teaching Structural Molecular Biology.

PubMed

Davenport, Jodi; Pique, Michael; Getzoff, Elizabeth; Huntoon, Jon; Gardner, Adam; Olson, Arthur

2017-04-04

Structural molecular biology is now becoming part of high school science curriculum thus posing a challenge for teachers who need to convey three-dimensional (3D) structures with conventional text and pictures. In many cases even interactive computer graphics does not go far enough to address these challenges. We have developed a flexible model of the polypeptide backbone using 3D printing technology. With this model we have produced a polypeptide assembly kit to create an idealized model of the Triosephosphate isomerase mutase enzyme (TIM), which forms a structure known as TIM barrel. This kit has been used in a laboratory practical where students perform a step-by-step investigation into the nature of protein folding, starting with the handedness of amino acids to the formation of secondary and tertiary structure. Based on the classroom evidence we collected, we conclude that these models are valuable and inexpensive resource for teaching structural molecular biology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tertiary structure prediction and identification of druggable pocket in the cancer biomarker – Osteopontin-c

PubMed Central

2014-01-01

Background Osteopontin (Eta, secreted sialoprotein 1, opn) is secreted from different cell types including cancer cells. Three splice variant forms namely osteopontin-a, osteopontin-b and osteopontin-c have been identified. The main astonishing feature is that osteopontin-c is found to be elevated in almost all types of cancer cells. This was the vital point to consider it for sequence analysis and structure predictions which provide ample chances for prognostic, therapeutic and preventive cancer research. Methods Osteopontin-c gene sequence was determined from Breast Cancer sample and was translated to protein sequence. It was then analyzed using various software and web tools for binding pockets, docking and druggability analysis. Due to the lack of homological templates, tertiary structure was predicted using ab-initio method server – I-TASSER and was evaluated after refinement using web tools. Refined structure was compared with known bone sialoprotein electron microscopic structure and docked with CD44 for binding analysis and binding pockets were identified for drug designing. Results Signal sequence of about sixteen amino acid residues was identified using signal sequence prediction servers. Due to the absence of known structures of similar proteins, three dimensional structure of osteopontin-c was predicted using I-TASSER server. The predicted structure was refined with the help of SUMMA server and was validated using SAVES server. Molecular dynamic analysis was carried out using GROMACS software. The final model was built and was used for docking with CD44. Druggable pockets were identified using pocket energies. Conclusions The tertiary structure of osteopontin-c was predicted successfully using the ab-initio method and the predictions showed that osteopontin-c is of fibrous nature comparable to firbronectin. Docking studies showed the significant similarities of QSAET motif in the interaction of CD44 and osteopontins between the normal and splice variant forms of osteopontins and binding pockets analyses revealed several pockets which paved the way to the identification of a druggable pocket. PMID:24401206

Structure and Location of the Regulatory β Subunits in the (αβγδ)4 Phosphorylase Kinase Complex* ♦

PubMed Central

Nadeau, Owen W.; Lane, Laura A.; Xu, Dong; Sage, Jessica; Priddy, Timothy S.; Artigues, Antonio; Villar, Maria T.; Yang, Qing; Robinson, Carol V.; Zhang, Yang; Carlson, Gerald M.

2012-01-01

Phosphorylase kinase (PhK) is a hexadecameric (αβγδ)4 complex that regulates glycogenolysis in skeletal muscle. Activity of the catalytic γ subunit is regulated by allosteric activators targeting the regulatory α, β, and δ subunits. Three-dimensional EM reconstructions of PhK show it to be two large (αβγδ)2 lobes joined with D2 symmetry through interconnecting bridges. The subunit composition of these bridges was unknown, although indirect evidence suggested the β subunits may be involved in their formation. We have used biochemical, biophysical, and computational approaches to not only address the quaternary structure of the β subunits within the PhK complex, i.e. whether they compose the bridges, but also their secondary and tertiary structures. The secondary structure of β was determined to be predominantly helical by comparing the CD spectrum of an αγδ subcomplex with that of the native (αβγδ)4 complex. An atomic model displaying tertiary structure for the entire β subunit was constructed using chemical cross-linking, MS, threading, and ab initio approaches. Nearly all this model is covered by two templates corresponding to glycosyl hydrolase 15 family members and the A subunit of protein phosphatase 2A. Regarding the quaternary structure of the β subunits, they were directly determined to compose the four interconnecting bridges in the (αβγδ)4 kinase core, because a β4 subcomplex was observed through both chemical cross-linking and top-down MS of PhK. The predicted model of the β subunit was docked within the bridges of a cryoelectron microscopic density envelope of PhK utilizing known surface features of the subunit. PMID:22969083

Conformational analysis of processivity clamps in solution demonstrates that tertiary structure does not correlate with protein dynamics.

PubMed

Fang, Jing; Nevin, Philip; Kairys, Visvaldas; Venclovas, Česlovas; Engen, John R; Beuning, Penny J

2014-04-08

The relationship between protein sequence, structure, and dynamics has been elusive. Here, we report a comprehensive analysis using an in-solution experimental approach to study how the conservation of tertiary structure correlates with protein dynamics. Hydrogen exchange measurements of eight processivity clamp proteins from different species revealed that, despite highly similar three-dimensional structures, clamp proteins display a wide range of dynamic behavior. Differences were apparent both for structurally similar domains within proteins and for corresponding domains of different proteins. Several of the clamps contained regions that underwent local unfolding with different half-lives. We also observed a conserved pattern of alternating dynamics of the α helices lining the inner pore of the clamps as well as a correlation between dynamics and the number of salt bridges in these α helices. Our observations reveal that tertiary structure and dynamics are not directly correlated and that primary structure plays an important role in dynamics. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tertiary network in mammalian mitochondrial tRNAAsp revealed by solution probing and phylogeny

PubMed Central

Messmer, Marie; Pütz, Joern; Suzuki, Takeo; Suzuki, Tsutomu; Sauter, Claude; Sissler, Marie; Catherine, Florentz

2009-01-01

Primary and secondary structures of mammalian mitochondrial (mt) tRNAs are divergent from canonical tRNA structures due to highly skewed nucleotide content and large size variability of D- and T-loops. The nonconservation of nucleotides involved in the expected network of tertiary interactions calls into question the rules governing a functional L-shaped three-dimensional (3D) structure. Here, we report the solution structure of human mt-tRNAAsp in its native post-transcriptionally modified form and as an in vitro transcript. Probing performed with nuclease S1, ribonuclease V1, dimethylsulfate, diethylpyrocarbonate and lead, revealed several secondary structures for the in vitro transcribed mt-tRNAAsp including predominantly the cloverleaf. On the contrary, the native tRNAAsp folds into a single cloverleaf structure, highlighting the contribution of the four newly identified post-transcriptional modifications to correct folding. Reactivities of nucleotides and phosphodiester bonds in the native tRNA favor existence of a full set of six classical tertiary interactions between the D-domain and the variable region, forming the core of the 3D structure. Reactivities of D- and T-loop nucleotides support an absence of interactions between these domains. According to multiple sequence alignments and search for conservation of Leontis–Westhof interactions, the tertiary network core building rules apply to all tRNAAsp from mammalian mitochondria. PMID:19767615

General mechanism of two-state protein folding kinetics.

PubMed

Rollins, Geoffrey C; Dill, Ken A

2014-08-13

We describe here a general model of the kinetic mechanism of protein folding. In the Foldon Funnel Model, proteins fold in units of secondary structures, which form sequentially along the folding pathway, stabilized by tertiary interactions. The model predicts that the free energy landscape has a volcano shape, rather than a simple funnel, that folding is two-state (single-exponential) when secondary structures are intrinsically unstable, and that each structure along the folding path is a transition state for the previous structure. It shows how sequential pathways are consistent with multiple stochastic routes on funnel landscapes, and it gives good agreement with the 9 order of magnitude dependence of folding rates on protein size for a set of 93 proteins, at the same time it is consistent with the near independence of folding equilibrium constant on size. This model gives estimates of folding rates of proteomes, leading to a median folding time in Escherichia coli of about 5 s.

Preparation of functional polyamine scaffolds via Mitsunobu post-polymerization modification reactions.

PubMed

Kakuchi, Ryohei; Theato, Patrick

2014-03-01

A Mitsunobu reaction of trifluoroacetamide (TFA amide) and alcohols is used in a postpolymerization modification process. The reaction is conducted on polystyrene (PSt) bearing 20 mol% TFA amide groups with 4-methyl benzyl alcohol in the presence of a N,N,N′,N ′-tetramethylazodicarboxamide and tributylphosphine as mediators. The Mitsunobu reaction on polymer proceeds efficiently, as confirmed by the obvious precipitation generation during the reaction and the conversion of TFA amide moiety reached 88.6% confirmed by 19 F NMR measurement, yielding PSt bearing tertiary TFA amide moieties. The obtained polymers featuring tertiary TFA amide moieties are deprotected in the presence of tetrabutylammonium hydroxide as a base to afford corresponding polymers featuring functionalized polyamine scaffolds with 92.5% conversion. In addition, the precise structural assignment is proven by synthesis and analysis of the model monomeric compounds and the respective model polymers.

Why Do Tertiary Education Graduates Regret Their Study Program? A Comparison between Spain and the Netherlands

ERIC Educational Resources Information Center

Kucel, Aleksander; Vilalta-Bufi, Montserrat

2013-01-01

In this paper we investigate the determinants of regret of study program for tertiary education graduates in Spain and the Netherlands. These two countries differ in their educational system in terms of the tracking structure in their secondary education and the strength of their education-labor market linkages in tertiary education. Therefore, by…

Social media use profile, social skills, and nurse-patient interaction among Registered Nurses in tertiary hospitals: A structural equation model analysis.

PubMed

Mariano, Micah Celine O; Maniego, John Christian M; Manila, Hariette Lou Marie D; Mapanoo, Ram Cedrick C; Maquiran, Kerwin Miguel A; Macindo, John Rey B; Tejero, Lourdes Marie S; Torres, Gian Carlo S

2018-04-01

Social media has become increasingly important over the past decades and has been integrated in various environments, including the healthcare setting. Yet, the influence of social media use on the social skills and nurse-patient interaction of nurses is an area in nursing that requires further studies. This study determined the interrelationships among social media use profile, social skills, and nurse-patient interaction of Registered Nurses in tertiary hospitals. Employing structural equation modeling, a descriptive-correlational study was conducted among 212 consecutively-selected nurses from two tertiary hospitals. Consenting respondents completed a two-part survey composed of the respondent profile sheet and the Social Skills Inventory. The respondent profile sheet assessed demographic profile and social media use profile in terms of the mode, frequency, and duration of utilization. Three trained team members observed each nurse-patient dyad and completed the Nurse-Patient Bonding Instrument. A good fit model illustrated the negative effects of frequent social media use to patient openness (β = -0.18, p < 0.05) and engagement (β = -0.11, p ≤ 0.05). Longer use of social media on a daily basis, however, positively affected both dimensions of social skills. Accessing social media platforms using non-handheld devices showed the most influential positive effects to social skills and nurse-patient interaction. Additionally, although verbal social skills positively affected most dimensions of nurse-patient interaction, non-verbal social skills negatively influenced patient engagement (β = -0.19, p = 0.019) and nurse openness (β = -0.38, p ≤ 0.05). The structural model illustrates the effects of using social media on the social skills and nurse-patient interaction of nurses and emphasizes the need for implementing institutional policies on the judicious use and application of social media in the workplace. Further, social skills development programs geared toward having a balanced social skill must be implemented. Copyright © 2018 Elsevier Ltd. All rights reserved.

RNA Tertiary Interactions in a Riboswitch Stabilize the Structure of a Kink Turn

PubMed Central

Schroeder, Kersten T.; Daldrop, Peter; Lilley, David M.J.

2011-01-01

Summary The kink turn is a widespread RNA motif that introduces an acute kink into the axis of duplex RNA, typically comprising a bulge followed by a G⋅A and A⋅G pairs. The kinked conformation is stabilized by metal ions, or the binding of proteins including L7Ae. We now demonstrate a third mechanism for the stabilization of k-turn structure, involving tertiary interactions within a larger RNA structure. The SAM-I riboswitch contains an essential standard k-turn sequence that kinks a helix so that its terminal loop can make a long-range interaction. We find that some sequence variations in the k-turn within the riboswitch do not prevent SAM binding, despite preventing the folding of the k-turn in isolation. Furthermore, two crystal structures show that the sequence-variant k-turns are conventionally folded within the riboswitch. This study shows that the folded structure of the k-turn can be stabilized by tertiary interactions within a larger RNA structure. PMID:21893284

Lessons from an evolving rRNA: 16S and 23S rRNA structures from a comparative perspective

NASA Technical Reports Server (NTRS)

Gutell, R. R.; Larsen, N.; Woese, C. R.

1994-01-01

The 16S and 23S rRNA higher-order structures inferred from comparative analysis are now quite refined. The models presented here differ from their immediate predecessors only in minor detail. Thus, it is safe to assert that all of the standard secondary-structure elements in (prokaryotic) rRNAs have been identified, with approximately 90% of the individual base pairs in each molecule having independent comparative support, and that at least some of the tertiary interactions have been revealed. It is interesting to compare the rRNAs in this respect with tRNA, whose higher-order structure is known in detail from its crystal structure (36) (Table 2). It can be seen that rRNAs have as great a fraction of their sequence in established secondary-structure elements as does tRNA. However, the fact that the former show a much lower fraction of identified tertiary interactions and a greater fraction of unpaired nucleotides than the latter implies that many of the rRNA tertiary interactions remain to be located. (Alternatively, the ribosome might involve protein-rRNA rather than intramolecular rRNA interactions to stabilize three-dimensional structure.) Experimental studies on rRNA are consistent to a first approximation with the structures proposed here, confirming the basic assumption of comparative analysis, i.e., that bases whose compositions strictly covary are physically interacting. In the exhaustive study of Moazed et al. (45) on protection of the bases in the small-subunit rRNA against chemical modification, the vast majority of bases inferred to pair by covariation are found to be protected from chemical modification, both in isolated small-subunit rRNA and in the 30S subunit. The majority of the tertiary interactions are reflected in the chemical protection data as well (45). On the other hand, many of the bases not shown as paired in Fig. 1 are accessible to chemical attack (45). However, in this case a sizeable fraction of them are also protected against chemical modification (in the isolated rRNA), which suggests that considerable higher-order structure remains to be found (although all of it may not involve base-base interactions and so may not be detectable by comparative analysis). The agreement between the higher-order structure of the small-subunit rRNA and protection against chemical modification is not perfect, however; some bases shown to covary canonically are accessible to chemical modification (45).(ABSTRACT TRUNCATED AT 400 WORDS).

Polyphase tertiary fold-and-thrust tectonics in the Belluno Dolomites: new mapping, kinematic analysis, and 3D modelling

NASA Astrophysics Data System (ADS)

Chistolini, Filippo; Bistacchi, Andrea; Massironi, Matteo; Consonni, Davide; Cortinovis, Silvia

2014-05-01

The Belluno Dolomites are comprised in the eastern sector of the Southern Alps, which corresponds to the fold-and-thrust belt at the retro-wedge of the Alpine collisional orogen. They are characterized by a complex and polyphase fold-and-thrust tectonics, highlighted by multiple thrust sheets and thrust-related folding. We have studied this tectonics in the Vajont area where a sequence of Jurassic, Cretaceous and Tertiary units have been involved in multiple deformations. The onset of contractional tectonics in this part of the Alps is constrained to be Tertiary (likely Post-Eocene) by structural relationships with the Erto Flysch, whilst in the Mesozoic tectonics was extensional. We have recognized two contractional deformation phases (D1 and D2 in the following), of which only the second was mentioned in previous studies of the area and attributed to the Miocene Neoalpine event. D1 and D2 are characterized by roughly top-to-WSW (possibly Dinaric) and top-to-S (Alpine) transport directions respectively, implying a 90° rotation of the regional-scale shortening axis, and resulting in complex thrust and fold interference and reactivation patterns. Geological mapping and detailed outcrop-scale kinematic analysis allowed us to characterize the kinematics and chronology of deformations. Particularly, relative chronology was unravelled thanks to (1) diagnostic fold interference patterns and (2) crosscutting relationships between thrust faults and thrust-related folds. A km-scale D1 syncline, filled with the Eocene Erto Flysch and "decapitated" by a D2 thrust fault, provides the best map-scale example of crosscutting relationships allowing to reconstruct the faulting history. Due to the strong competence contrast between Jurassic carbonates and Tertiary flysch, in this syncline spectacular duplexes were also developed during D2. In order to quantitatively characterize the complex interference pattern resulting from two orthogonal thrusting and folding events, we performed a dip-domain analysis that allowed to categorize the different fold limbs and reduce the uncertainty in the reconstruction of the fault network topology in map view. This enabled us to reconstruct a high-quality, low-uncertainty 3D structural and geological model, which unambiguously proves that deformations with a top-to-WSW Dinaric transport direction propagate farther to the west than previously supposed in this part of the Southern Alps. Our new structural reconstruction of the Vajont valley have also clarified the structural control on the 1963 catastrophic landslide (which caused over 2000 losses). Besides being a challenging natural laboratory for testing analysis and modelling methodologies to be used when reconstructing in 3D this kind of complex interference structures, the Vajont area also provides useful clues on the still-enigmatic structures in the frontal part of the Friuli-Venetian Southern Alps, buried in the Venetian Plain foredeep. These include active seismogenic thrust-faults and, at the same time, represent a growing interest for the oil industry.

Unconstrained Structure Formation in Coarse-Grained Protein Simulations

NASA Astrophysics Data System (ADS)

Bereau, Tristan

The ability of proteins to fold into well-defined structures forms the basis of a wide variety of biochemical functions in and out of the cell membrane. Many of these processes, however, operate at time- and length-scales that are currently unattainable by all-atom computer simulations. To cope with this difficulty, increasingly more accurate and sophisticated coarse-grained models are currently being developed. In the present thesis, we introduce a solvent-free coarse-grained model for proteins. Proteins are modeled by four beads per amino acid, providing enough backbone resolution to allow for accurate sampling of local conformations. It relies on simple interactions that emphasize structure, such as hydrogen bonds and hydrophobicity. Realistic alpha/beta content is achieved by including an effective nearest-neighbor dipolar interaction. Parameters are tuned to reproduce both local conformations and tertiary structures. By studying both helical and extended conformations we make sure the force field is not biased towards any particular secondary structure. Without any further adjustments or bias a realistic oligopeptide aggregation scenario is observed. The model is subsequently applied to various biophysical problems: (i) kinetics of folding of two model peptides, (ii) large-scale amyloid-beta oligomerization, and (iii) protein folding cooperativity. The last topic---defined by the nature of the finite-size thermodynamic transition exhibited upon folding---was investigated from a microcanonical perspective: the accurate evaluation of the density of states can unambiguously characterize the nature of the transition, unlike its corresponding canonical analysis. Extending the results of lattice simulations and theoretical models, we find that it is the interplay between secondary structure and the loss of non-native tertiary contacts which determines the nature of the transition. Finally, we combine the peptide model with a high-resolution, solvent-free, lipid model. The lipid force field was systematically tuned to reproduce the structural and mechanical properties of phosphatidylcholine bilayers. The two models were cross-parametrized against atomistic potential of mean force curves for the insertion of single amino acid side chains into a bilayer. Coarse-grained transmembrane protein simulations were then compared with experiments and atomistic simulations to validate the force field. The transferability of the two models across amino acid sequences and lipid species permits the investigation of a wide variety of scenarios, while the absence of explicit solvent allows for studies of large-scale phenomena.

New Mexico structural zone - An analogue of the Colorado mineral belt

USGS Publications Warehouse

Sims, P.K.; Stein, H.J.; Finn, C.A.

2002-01-01

Updated aeromagnetic maps of New Mexico together with current knowledge of the basement geology in the northern part of the state (Sangre de Cristo and Sandia-Manzano Mountains)-where basement rocks were exposed in Precambrian-cored uplifts-indicate that the northeast-trending Proterozoic shear zones that controlled localization of ore deposits in the Colorado mineral belt extend laterally into New Mexico. The shear zones in New Mexico coincide spatially with known epigenetic precious- and base-metal ore deposits; thus, the mineralized belts in the two states share a common inherited basement tectonic setting. Reactivation of the basement structures in Late Cretaceous-Eocene and Mid-Tertiary times provided zones of weakness for emplacement of magmas and conduits for ore-forming solutions. Ore deposits in the Colorado mineral belt are of both Late Cretaceous-Eocene and Mid-Tertiary age; those in New Mexico are predominantly Mid-Tertiary in age, but include Late Cretaceous porphyry-copper deposits in southwestern New Mexico. The mineralized belt in New Mexico, named the New Mexico structural zone, is 250-km wide. The northwest boundary is the Jemez subzone (or the approximately equivalent Globe belt), and the southeastern boundary was approximately marked by the Santa Rita belt. Three groups (subzones) of mineral deposits characterize the structural zone: (1) Mid-Tertiary porphyry molybdenite and alkaline-precious-metal deposits, in the northeast segment of the Jemez zone; (2) Mid-Tertiary epithermal precious-metal deposits in the Tijeras (intermediate) zone; and (3) Late Cretaceous porphyry-copper deposits in the Santa Rita zone. The structural zone was inferred to extend from New Mexico into adjacent Arizona. The structural zone provides favorable sites for exploration, particularly those parts of the Jemez subzone covered by Neogene volcanic and sedimentary rocks. ?? 2002 Published by Elsevier Science B.V.

A sampling-based method for ranking protein structural models by integrating multiple scores and features.

PubMed

Shi, Xiaohu; Zhang, Jingfen; He, Zhiquan; Shang, Yi; Xu, Dong

2011-09-01

One of the major challenges in protein tertiary structure prediction is structure quality assessment. In many cases, protein structure prediction tools generate good structural models, but fail to select the best models from a huge number of candidates as the final output. In this study, we developed a sampling-based machine-learning method to rank protein structural models by integrating multiple scores and features. First, features such as predicted secondary structure, solvent accessibility and residue-residue contact information are integrated by two Radial Basis Function (RBF) models trained from different datasets. Then, the two RBF scores and five selected scoring functions developed by others, i.e., Opus-CA, Opus-PSP, DFIRE, RAPDF, and Cheng Score are synthesized by a sampling method. At last, another integrated RBF model ranks the structural models according to the features of sampling distribution. We tested the proposed method by using two different datasets, including the CASP server prediction models of all CASP8 targets and a set of models generated by our in-house software MUFOLD. The test result shows that our method outperforms any individual scoring function on both best model selection, and overall correlation between the predicted ranking and the actual ranking of structural quality.

Identification of phosphates involved in catalysis by the ribozyme RNase P RNA.

PubMed Central

Harris, M E; Pace, N R

1995-01-01

The RNA subunit of ribonuclease P (RNase P RNA) is a catalytic RNA that cleaves precursor tRNAs to generate mature tRNA 5' ends. Little is known concerning the identity and arrangement of functional groups that constitute the active site of this ribozyme. We have used an RNase P RNA-substrate conjugate that undergoes rapid, accurate, and efficient self-cleavage in vitro to probe, by phosphorothioate modification-interference, functional groups required for catalysis. We identify four phosphate oxygens where substitution by sulfur significantly reduces the catalytic rate (50-200-fold). Interference at one site was partially rescued in the presence of manganese, suggesting a direct involvement in binding divalent metal ion cofactors required for catalysis. All sites are located in conserved sequence and secondary structure, and positioned adjacent to the substrate phosphate in a tertiary structure model of the ribozyme-substrate complex. The spatial arrangement of phosphorothioate-sensitive sites in RNase P RNA was found to resemble the distribution of analogous positions in the secondary and potential tertiary structures of other large catalytic RNAs. PMID:7585250

Structure-activity relationships in the fusion of small unilamellar phosphatidylcholine vesicles induced by a model peptide.

PubMed

da Costa, M H; Chaimovich, H

1997-09-01

Limited proteolysis of fatty acid-free bovine serum albumin by pepsin yields several well characterized peptides, one of which (P9, M(r) 9,000), induces fusion of small unilamellar vesicles (SUV) of phosphatidylcholine at pH 3.6. Circular dichroism (CD) of P9 solutions confirmed that the peptide undergoes a reversible transition between pH 7 and pH 3.6. The spectral changes observed with CD suggest that in the low pH conformation there is a decrease in the alpha-helical contents and an exposure of hydrophobic residues. CD and differential ultraviolet spectroscopy demonstrated that P9 binds to micelles of hexadecylphosphorylcholine and the binding produces changes in the tertiary structure of the peptide. Reduction and carboxymethylation of the two disulfide bridges of P9 produced loss of the ability to induce fusion of SUV, although the reduced peptide binds to vesicles, induces loss of entrapped marker and produces vesicle disruption. In the active form P9 exposes hydrophobic groups, one amphiphilic alpha-helix and requires the integrity of the disulfide bridge-stabilized tertiary structure.

RNA chaperone StpA loosens interactions of the tertiary structure in the td group I intron in vivo

PubMed Central

Waldsich, Christina; Grossberger, Rupert; Schroeder, Renée

2002-01-01

Efficient splicing of the td group I intron in vivo is dependent on the ribosome. In the absence of translation, the pre-mRNA is trapped in nonnative-splicing-incompetent conformations. Alternatively, folding of the pre-mRNA can be promoted by the RNA chaperone StpA or by the group I intron-specific splicing factor Cyt-18. To understand the mechanism of action of RNA chaperones, we probed the impact of StpA on the structure of the td intron in vivo. Our data suggest that StpA loosens tertiary interactions. The most prominent structural change was the opening of the base triples, which are involved in the correct orientation of the two major intron core domains. In line with the destabilizing activity of StpA, splicing of mutant introns with a reduced structural stability is sensitive to StpA. In contrast, Cyt-18 strengthens tertiary contacts, thereby rescuing splicing of structurally compromised td mutants in vivo. Our data provide direct evidence for protein-induced conformational changes within catalytic RNA in vivo. Whereas StpA resolves tertiary contacts enabling the RNA to refold, Cyt-18 contributes to the overall compactness of the td intron in vivo. PMID:12208852

Probing the structural dynamics of the CRISPR-Cas9 RNA-guided DNA-cleavage system by coarse-grained modeling.

PubMed

Zheng, Wenjun

2017-02-01

In the adaptive immune systems of many bacteria and archaea, the Cas9 endonuclease forms a complex with specific guide/scaffold RNA to identify and cleave complementary target sequences in foreign DNA. This DNA targeting machinery has been exploited in numerous applications of genome editing and transcription control. However, the molecular mechanism of the Cas9 system is still obscure. Recently, high-resolution structures have been solved for Cas9 in different structural forms (e.g., unbound forms, RNA-bound binary complexes, and RNA-DNA-bound tertiary complexes, corresponding to an inactive state, a pre-target-bound state, and a cleavage-competent or product state), which offered key structural insights to the Cas9 mechanism. To further probe the structural dynamics of Cas9 interacting with RNA and DNA at the amino-acid level of details, we have performed systematic coarse-grained modeling using an elastic network model and related analyses. Our normal mode analysis predicted a few key modes of collective motions that capture the observed conformational changes featuring large domain motions triggered by binding of RNA and DNA. Our flexibility analysis identified specific regions with high or low flexibility that coincide with key functional sites (such as DNA/RNA-binding sites, nuclease cleavage sites, and key hinges). We also identified a small set of hotspot residues that control the energetics of functional motions, which overlap with known functional sites and offer promising targets for future mutagenesis efforts to improve the specificity of Cas9. Finally, we modeled the conformational transitions of Cas9 from the unbound form to the binary complex and then the tertiary complex, and predicted a distinct sequence of domain motions. In sum, our findings have offered rich structural and dynamic details relevant to the Cas9 machinery, and will guide future investigation and engineering of the Cas9 systems. Proteins 2017; 85:342-353. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

An implicit divalent counterion force field for RNA molecular dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henke, Paul S.; Mak, Chi H., E-mail: cmak@usc.edu; Center of Applied Mathematical Sciences, University of Southern California, Los Angeles, California 90089

How to properly account for polyvalent counterions in a molecular dynamics simulation of polyelectrolytes such as nucleic acids remains an open question. Not only do counterions such as Mg{sup 2+} screen electrostatic interactions, they also produce attractive intrachain interactions that stabilize secondary and tertiary structures. Here, we show how a simple force field derived from a recently reported implicit counterion model can be integrated into a molecular dynamics simulation for RNAs to realistically reproduce key structural details of both single-stranded and base-paired RNA constructs. This divalent counterion model is computationally efficient. It works with existing atomistic force fields, or coarse-grainedmore » models may be tuned to work with it. We provide optimized parameters for a coarse-grained RNA model that takes advantage of this new counterion force field. Using the new model, we illustrate how the structural flexibility of RNA two-way junctions is modified under different salt conditions.« less

Thermochronological evidence for polyphase post-rift reactivation in SE Brazil

NASA Astrophysics Data System (ADS)

Cogné, N.; Gallagher, K.; Cobbold, P. R.; Riccomini, C.

2012-04-01

The continental margin of SE Brazil shows good evidence for tectonic activity well after the break-up of Western Gondwana (see Cobbold et al., 2001 for a review). Additionally, SE Brazil ranks as an HEPM (high elevation passive margin), summits reaching 2800 m. To constrain the onshore evolution of the margin, especially during the Tertiary, we did a new thermochronological and structural study. After an initial regional study, during which we found additional evidence for a major phase of exhumation during the Late Cretaceous to Early Tertiary (Cogné et al., 2011), we focussed on a region that was clearly subject to Tertiary tectonics. This region includes the Tertiary Taubaté basin and the adjacent Serra do Mar and Serra da Mantiqueira. We used two thermochronolgical methods on the same samples, apatite fission tracks (AFT) and U-Th/He on apatite (AHe). AFT ages range from 129.3±4.3 Ma to 60.7±1.9 Ma with mean track lengths (MTL) from 14.31±0.24 μm to 11.41±0.23 μm, whereas AHe ages range from 519.6±16.6 to 10.1±0.1 Ma. A subset of AHe ages, selected on the basis of data consistency and geological arguments, has a smaller range (122.4±2.5 to 45.1±1.5 Ma). We have combined inverse and forward modelling to assess the range of acceptable thermal histories. Results of inverse modelling confirm our earlier study by showing a Late Cretaceous phase of cooling. Around the onshore Taubaté Basin, for a limited number of samples, another period of cooling occurred during the Early Tertiary, around the time when the basin formed. The inferred thermal histories for most of the samples also imply a later reheating, followed by a Neogene cooling. According to forward modelling, the evidence for reheating seems to be robust around the margins of the Taubaté Basin, but elsewhere the data cannot really discriminate between this and a less complex thermal history. However forward modelling and geologically independent information support the conclusion that the whole area cooled and uplifted during the Neogene. The synchronicity of the cooling phases with tectonic pulses in the Andes and in NE Brazil, as well as the tectonic setting of the Tertiary basins (Cogné et al., submitted) lead us to attribute these phases to a plate-wide compressive stress, which reactivated inherited structures during the Late Cretaceous and Tertiary. The relief of the margin is therefore due, more to polyphase post-rift reactivation and uplift, than to rifting itself. - Cobbold, P.R., Meisling, K.E., Mount, V.S., 2001. Reactivation of an obliquely rifted margin, Campos and Santos Basins, Southeastern Brazil. AAPG Bulletin 85, 1925-1944. - Cogné, N., Gallagher, K., Cobbold, P.R., 2011. Post-rift reactivation of the onshore margin of southeast Brazil: Evidence from apatite (U-Th)/He and fission-track data. Earth and Planetary Science Letters 309, 118-130. - Cogné, N., Cobbold, P.R., Riccomini, C., Gallagher, K. Tectonic setting of the Taubaté basin (southeastern Brazil): insights from regional seismic profiles and outcrop data. Submitted to Journal of South American Earth Sciences.

Detection of groundwater conduits in limestones with gravity surveys: data from the area of the Chicxulub Impact crater, Yucatan Peninsula, Mexico.

PubMed

Kinsland, G L; Hurtado, M; Pope, K O

2000-04-15

Small negative gravity anomalies are found in gravity data from along the northwestern shoreline of the Yucatan Peninsula. These anomalies are shown to be due to elongate, shallow anomalous porosity zones in the Tertiary carbonates. These zones are caused primarily by groundwater solution and are presently active conduits for groundwater flow. The association of these small gravity anomalies with known topographic and structural features of the area, which partially overlies the Chicxulub Impact crater, indicates their development was influenced by structures, faults and/or fractures, within the Tertiary and pre-Tertiary carbonates.

Detection of groundwater conduits in limestones with gravity surveys: data from the area of the Chicxulub Impact crater, Yucatan Peninsula, Mexico

NASA Technical Reports Server (NTRS)

Kinsland, G. L.; Hurtado, M.; Pope, K. O.; Ocampo, A. C. (Principal Investigator)

2000-01-01

Small negative gravity anomalies are found in gravity data from along the northwestern shoreline of the Yucatan Peninsula. These anomalies are shown to be due to elongate, shallow anomalous porosity zones in the Tertiary carbonates. These zones are caused primarily by groundwater solution and are presently active conduits for groundwater flow. The association of these small gravity anomalies with known topographic and structural features of the area, which partially overlies the Chicxulub Impact crater, indicates their development was influenced by structures, faults and/or fractures, within the Tertiary and pre-Tertiary carbonates.

CONFOLD2: improved contact-driven ab initio protein structure modeling.

PubMed

Adhikari, Badri; Cheng, Jianlin

2018-01-25

Contact-guided protein structure prediction methods are becoming more and more successful because of the latest advances in residue-residue contact prediction. To support contact-driven structure prediction, effective tools that can quickly build tertiary structural models of good quality from predicted contacts need to be developed. We develop an improved contact-driven protein modelling method, CONFOLD2, and study how it may be effectively used for ab initio protein structure prediction with predicted contacts as input. It builds models using various subsets of input contacts to explore the fold space under the guidance of a soft square energy function, and then clusters the models to obtain the top five models. CONFOLD2 obtains an average reconstruction accuracy of 0.57 TM-score for the 150 proteins in the PSICOV contact prediction dataset. When benchmarked on the CASP11 contacts predicted using CONSIP2 and CASP12 contacts predicted using Raptor-X, CONFOLD2 achieves a mean TM-score of 0.41 on both datasets. CONFOLD2 allows to quickly generate top five structural models for a protein sequence when its secondary structures and contacts predictions at hand. The source code of CONFOLD2 is publicly available at https://github.com/multicom-toolbox/CONFOLD2/ .

Probing RNA tertiary structure: interhelical crosslinking of the hammerhead ribozyme.

PubMed Central

Sigurdsson, S T; Tuschl, T; Eckstein, F

1995-01-01

Distinct structural models for the hammerhead ribozyme derived from single-crystal X-ray diffraction and fluorescence resonance energy transfer (FRET) measurements have been compared. Both models predict the same overall geometry, a wishbone shape with helices II and III nearly colinear and helix I positioned close to helix II. However, the relative orientations of helices I and II are different. To establish whether one of the models represents a kinetically active structure, a new crosslinking procedure was developed in which helices I and II of hammerhead ribozymes were disulfide-crosslinked via the 2' positions of specific sugar residues. Crosslinking residues on helices I and II that are close according to the X-ray structure did not appreciably reduce the catalytic efficiency. In contrast, crosslinking residues closely situated according to the FRET model dramatically reduced the cleavage rate by at least three orders of magnitude. These correlations between catalytic efficiencies and spatial proximities are consistent with the X-ray structure. PMID:7489517

Evaluation of sequence alignments and oligonucleotide probes with respect to three-dimensional structure of ribosomal RNA using ARB software package

PubMed Central

Kumar, Yadhu; Westram, Ralf; Kipfer, Peter; Meier, Harald; Ludwig, Wolfgang

2006-01-01

Background Availability of high-resolution RNA crystal structures for the 30S and 50S ribosomal subunits and the subsequent validation of comparative secondary structure models have prompted the biologists to use three-dimensional structure of ribosomal RNA (rRNA) for evaluating sequence alignments of rRNA genes. Furthermore, the secondary and tertiary structural features of rRNA are highly useful and successfully employed in designing rRNA targeted oligonucleotide probes intended for in situ hybridization experiments. RNA3D, a program to combine sequence alignment information with three-dimensional structure of rRNA was developed. Integration into ARB software package, which is used extensively by the scientific community for phylogenetic analysis and molecular probe designing, has substantially extended the functionality of ARB software suite with 3D environment. Results Three-dimensional structure of rRNA is visualized in OpenGL 3D environment with the abilities to change the display and overlay information onto the molecule, dynamically. Phylogenetic information derived from the multiple sequence alignments can be overlaid onto the molecule structure in a real time. Superimposition of both statistical and non-statistical sequence associated information onto the rRNA 3D structure can be done using customizable color scheme, which is also applied to a textual sequence alignment for reference. Oligonucleotide probes designed by ARB probe design tools can be mapped onto the 3D structure along with the probe accessibility models for evaluation with respect to secondary and tertiary structural conformations of rRNA. Conclusion Visualization of three-dimensional structure of rRNA in an intuitive display provides the biologists with the greater possibilities to carry out structure based phylogenetic analysis. Coupled with secondary structure models of rRNA, RNA3D program aids in validating the sequence alignments of rRNA genes and evaluating probe target sites. Superimposition of the information derived from the multiple sequence alignment onto the molecule dynamically allows the researchers to observe any sequence inherited characteristics (phylogenetic information) in real-time environment. The extended ARB software package is made freely available for the scientific community via . PMID:16672074

Efficient Ligation of the Schistosoma Hammerhead Ribozyme †

PubMed Central

Canny, Marella D.; Jucker, Fiona M.; Pardi, Arthur

2011-01-01

The hammerhead ribozyme from Schistosoma mansoni is the best characterized of the natural hammerhead ribozymes. Biophysical, biochemical, and structural studies have shown that the formation of the loop-loop tertiary interaction between stems I and II alters the global folding, cleavage kinetics, and conformation of the catalytic core of this hammerhead, leading to a ribozyme that is readily cleaved under physiological conditions. This study investigates the ligation kinetics and the internal equilibrium between cleavage and ligation for the Schistosoma hammerhead. Single turnover kinetic studies on a construct where the ribozyme cleaves and ligates substrate(s) in trans showed up to 23% ligation when starting from fully cleaved products. This was achieved by a ~2,000-fold increase in the rate of ligation compared to a minimal hammerhead without the loop-loop tertiary interaction, yielding an internal equilibrium that ranges from 2–3 at physiological Mg2+ ion concentrations (0.1 –1 mM). Thus, the natural Schistosoma hammerhead ribozyme is almost as efficient at ligation as it is at cleavage. The results here are consistent with a model where formation of the loop-loop tertiary interaction leads to a higher population of catalytically active molecules, and where formation of this tertiary interaction has a much larger effect on the ligation than the cleavage activity of the Schistosoma hammerhead ribozyme. PMID:17319693

Structure-Function Study of Tertiary Amines as Switchable Polarity Solvents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aaron D. Wilson; Frederick F. Stewart

2014-02-01

A series of tertiary amines have been screened for their function as switchable polarity solvents (SPS). The relative ratios of tertiary amine and carbonate species as well as maximum possible concentration were determined through quantitative 1H and 13C NMR spectroscopy. The viscosities of the polar SPS solutions were measured and ranged from near water in dilute systems through to gel formation at high concentrations. The van't Hoff indices for SPS solutions were measured through freezing point depression studies as a proxy for osmotic pressures. A new form of SPS with an amine : carbonate ratio significantly greater than unity hasmore » been identified. Tertiary amines that function as SPS at ambient pressures appear to be limited to molecules with fewer than 12 carbons. The N,N-dimethyl-n-alkylamine structure has been identified as important to the function of an SPS.« less

Three-dimensional tertiary structure of yeast phenylalanine transfer RNA

NASA Technical Reports Server (NTRS)

Kim, S. H.; Sussman, J. L.; Suddath, F. L.; Quigley, G. J.; Mcpherson, A.; Wang, A. H. J.; Seeman, N. C.; Rich, A.

1974-01-01

Results of an analysis and interpretation of a 3-A electron density map of yeast phenylalanine transfer RNA. Some earlier detailed assignments of nucleotide residues to electron density peaks are found to be in error, even though the overall tracing of the backbone conformation of yeast phenylalanine transfer RNA was generally correct. A new, more comprehensive interpretation is made which makes it possible to define the tertiary interactions in the molecule. The new interpretation makes it possible to visualize a number of tertiary interactions which not only explain the structural role of most of the bases which are constant in transfer RNAs, but also makes it possible to understand in a direct and simple fashion the chemical modification data on transfer RNA. In addition, this pattern of tertiary interactions provides a basis for understanding the general three-dimensional folding of all transfer RNA molecules.

Electronic polarization stabilizes tertiary structure prediction of HP-36.

PubMed

Duan, Li L; Zhu, Tong; Zhang, Qing G; Tang, Bo; Zhang, John Z H

2014-04-01

Molecular dynamic (MD) simulations with both implicit and explicit solvent models have been carried out to study the folding dynamics of HP-36 protein. Starting from the extended conformation, the secondary structure of all three helices in HP-36 was formed in about 50 ns and remained stable in the remaining simulation. However, the formation of the tertiary structure was difficult. Although some intermediates were close to the native structure, the overall conformation was not stable. Further analysis revealed that the large structure fluctuation of loop and hydrophobic core regions was devoted mostly to the instability of the structure during MD simulation. The backbone root-mean-square deviation (RMSD) of the loop and hydrophobic core regions showed strong correlation with the backbone RMSD of the whole protein. The free energy landscape indicated that the distribution of main chain torsions in loop and turn regions was far away from the native state. Starting from an intermediate structure extracted from the initial AMBER simulation, HP-36 was found to generally fold to the native state under the dynamically adjusted polarized protein-specific charge (DPPC) simulation, while the peptide did not fold into the native structure when AMBER force filed was used. The two best folded structures were extracted and taken into further simulations in water employing AMBER03 charge and DPPC for 25 ns. Result showed that introducing polarization effect into interacting potential could stabilize the near-native protein structure.

Structure and Orientation of T4 Lysozyme Bound to the Small Heat Shock Protein α-Crystallin

PubMed Central

Claxton, Derek P.; Zou, Ping; Mchaourab, Hassane S.

2008-01-01

Summary We have determined the structural changes that accompany the formation of a stable complex between a destabilized mutant of T4 lysozyme (T4L) and the small heat-shock protein α-crystallin. Using pairs of fluorescence or spin label probes to fingerprint the T4L tertiary fold, we demonstrate that binding disrupts tertiary packing in the two domains as well as across the active site cleft. Furthermore, increased distances between i and i+4 residues of helices support a model in which the bound structure is not native-like but significantly unfolded. In the confines of the oligomer, T4L has a preferential orientation with residues in the more hydrophobic C-terminal domain sequestered in a buried environment while residues in the N-terminal domain are exposed to the aqueous solvent. Furthermore, EPR spectral lineshapes of sites in the N-terminal domain are narrower than in the folded, unbound T4L reflecting an unstructured backbone and an asymmetric pattern of contacts between T4L and α-crystallin. The net orientation is not affected by the location of the destabilizing mutation consistent with the notion that binding is not triggered by recognition of localized unfolding. Together, the structural and thermodynamic data indicate that the stably bound conformation of T4L is unfolded and support a model in which the two-modes of substrate binding originate from two discrete binding sites on the chaperone. PMID:18062989

Blocking Protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera

PubMed Central

2012-01-01

Background Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vector-born diseases after malaria and sleeping sickness. Toxicity of available drugs and drug resistance development by protozoa in recent years has made Leishmaniasis cure difficult and challenging. This urges the need to discover new antileishmanial-drug targets and antileishmanial-drug development. Results Tertiary structure of leishmanial protein kinase C was predicted and found stable with a RMSD of 5.8Å during MD simulations. Natural compound withaferin A inhibited the predicted protein at its active site with -28.47 kcal/mol binding free energy. Withanone was also found to inhibit LPKC with good binding affinity of -22.57 kcal/mol. Both withaferin A and withanone were found stable within the binding pocket of predicted protein when MD simulations of ligand-bound protein complexes were carried out to examine the consistency of interactions between the two. Conclusions Leishmanial protein kinase C (LPKC) has been identified as a potential target to develop drugs against Leishmaniasis. We modelled and refined the tertiary structure of LPKC using computational methods such as homology modelling and molecular dynamics simulations. This structure of LPKC was used to reveal mode of inhibition of two previous experimentally reported natural compounds from Withania somnifera - withaferin A and withanone. PMID:23281834

Kotai Antibody Builder: automated high-resolution structural modeling of antibodies.

PubMed

Yamashita, Kazuo; Ikeda, Kazuyoshi; Amada, Karlou; Liang, Shide; Tsuchiya, Yuko; Nakamura, Haruki; Shirai, Hiroki; Standley, Daron M

2014-11-15

Kotai Antibody Builder is a Web service for tertiary structural modeling of antibody variable regions. It consists of three main steps: hybrid template selection by sequence alignment and canonical rules, 3D rendering of alignments and CDR-H3 loop modeling. For the last step, in addition to rule-based heuristics used to build the initial model, a refinement option is available that uses fragment assembly followed by knowledge-based scoring. Using targets from the Second Antibody Modeling Assessment, we demonstrate that Kotai Antibody Builder generates models with an overall accuracy equal to that of the best-performing semi-automated predictors using expert knowledge. Kotai Antibody Builder is available at http://kotaiab.org standley@ifrec.osaka-u.ac.jp. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Patients' assessment of quality of care in public tertiary hospitals with and without accreditation: comparative cross-sectional study.

PubMed

Aboshaiqah, Ahmad E; Alonazi, Wadi B; Patalagsa, Joel Gonzales

2016-11-01

To compare patients' assessment of quality of care provided by public tertiary hospitals grouped according to accreditation status. Healthcare institutions worldwide are increasingly adopting accreditation as continuing initiative aimed at improving structures, processes and outcomes associated with quality of care. Patients being recipients of health care need to participate in assessing the quality of care they experienced while confined for therapeutic management. Comparative, cross-sectional. Data were collected from patients confined in public tertiary hospitals (n = 517 in four with accreditation and n = 542 in four without accreditation) in Riyadh, Saudi Arabia between February 2011-June 2011. Patients rated key performance indicators grouped under the dimensions of structure, process and outcome. Mann-Whitney U-test, Spearman Correlation Coefficient and coefficient of determination were used in analysing data. Patients in accredited public tertiary hospitals perceived structure, outcome and overall quality of care statistically higher than patients in non-accredited hospitals. No statistical differences were found in process (access and communication) indicators. Accreditation status is marginally associated with structure; outcome; and overall quality of care. The proportion of variance in the ranks of accreditation status explained the proportion of variance in the ranks of structure; outcome; and overall quality of care. The results apparently showed better structure, outcome and overall quality of care in accredited hospitals. Accreditation's association in the overall quality of care apparently remained unclear. Further studies are needed to appreciate the contribution of accreditation. © 2016 John Wiley & Sons Ltd.

Halogen dependent symmetry change in two series of wheel cluster organic frameworks built from La18 tertiary building units.

PubMed

Fang, Wei-Hui; Zhang, Lei; Zhang, Jian; Yang, Guo-Yu

2016-01-25

Two series of wheel cluster organic frameworks (WCOFs) built from La18 tertiary building units are hydrothermally made, which show halogen-dependent structural symmetry, and demonstrate different chiral performances.

Spatial and Temporal Strain Distribution Along the Central Red Sea Rift - A Study of the Hamd-Jizil Basin in Saudi Arabia

NASA Astrophysics Data System (ADS)

Szymanski, E.; Stockli, D.; Johnson, P.; Kattan, F. H.; Al Shamari, A.

2006-12-01

Numerous models exploring the rupturing modes and mechanisms of continental lithosphere are based on geological evidence from the Red Sea/Gulf of Suez rift system. Individually, the Red Sea basin is the prototype for many models of orthogonal continental rifting. Despite being a classic example of continental extension, many temporal and spatial strain distribution aspects, as well as the dynamic evolution of the rift architecture of the Red Sea, remain poorly constrained. Critical data come mostly from the Gulf of Suez and the Egyptian and Yemeni margins of the Red Sea; the rift flanks in Sudan and Saudi Arabia have remained largely unstudied, leaving a large information gap along the central portions of the rift system. Improving continental lithosphere rupture models requires an absolute understanding of the timing and magnitude of strain partitioning along the full rift flank. This study focuses on the development of extensional structures, syn- extensional sedimentary deposits, and rift-related Tertiary basaltic volcanism along the central flank of the rift system in Saudi Arabia. Geo- and thermochronometric techniques are used to elucidate the evolution of inboard and outboard strain markers manifested by structurally-controlled extensional basins that parallel the trend of the main Red Sea rift. Constraints on the dynamics of rift flank deformation are achieved through the collection of thermochronometric transects that traverse both the entire Arabian shield and individual normal faults that bound inland basins. Preliminary results show inland basins as asymmetric half-grabens filled by tilted Cenozoic sedimentary strata and separated by exhumed basement fault blocks. The most prominent extensional basin is the NW-trending Hamd-Jizil basin, located north of Madinah, measuring ~200 km along strike and up to 20 km in width. The Hamd-Jizil basin is structurally characterized by two half-grabens exposing a series of syn-rift siliciclastic sedimentary sections below Tertiary basalts. In certain areas, thick basalt sequences provide basin infill and appear faulted by a younger series of normal faults. Work continues on the production of further geo- and thermochronologic data for the Tertiary basalt sequences as well as the entire rift flank region.

The role of atomic level steric effects and attractive forces in protein folding.

PubMed

Lammert, Heiko; Wolynes, Peter G; Onuchic, José N

2012-02-01

Protein folding into tertiary structures is controlled by an interplay of attractive contact interactions and steric effects. We investigate the balance between these contributions using structure-based models using an all-atom representation of the structure combined with a coarse-grained contact potential. Tertiary contact interactions between atoms are collected into a single broad attractive well between the C(β) atoms between each residue pair in a native contact. Through the width of these contact potentials we control their tolerance for deviations from the ideal structure and the spatial range of attractive interactions. In the compact native state dominant packing constraints limit the effects of a coarse-grained contact potential. During folding, however, the broad attractive potentials allow an early collapse that starts before the native local structure is completely adopted. As a consequence the folding transition is broadened and the free energy barrier is decreased. Eventually two-state folding behavior is lost completely for systems with very broad attractive potentials. The stabilization of native-like residue interactions in non-perfect geometries early in the folding process frequently leads to structural traps. Global mirror images are a notable example. These traps are penalized by the details of the repulsive interactions only after further collapse. Successful folding to the native state requires simultaneous guidance from both attractive and repulsive interactions. Copyright © 2011 Wiley Periodicals, Inc.

Adolescent smoking and tertiary education: opposing pathways linking socio-economic background to alcohol consumption.

PubMed

Green, Michael J; Leyland, Alastair H; Sweeting, Helen; Benzeval, Michaela

2016-08-01

If socio-economic disadvantage is associated with more adolescent smoking, but less participation in tertiary education, and smoking and tertiary education are both associated with heavier drinking, these may represent opposing pathways to heavy drinking. This paper examines contextual variation in the magnitude and direction of these associations. Comparing cohort studies. United Kingdom. Participants were from the 1958 National Child Development Study (NCDS58; n = 15 672), the British birth cohort study (BCS70; n = 12 735) and the West of Scotland Twenty-07 1970s cohort (T07; n = 1515). Participants self-reported daily smoking and weekly drinking in adolescence (age 16 years) and heavy drinking (> 14/21 units in past week) in early adulthood (ages 22-26 years). Parental occupational class (manual versus non-manual) indicated socio-economic background. Education beyond age 18 was coded as tertiary. Models were adjusted for parental smoking and drinking, family structure and adolescent psychiatric distress. Respondents from a manual class were more likely to smoke and less likely to enter tertiary education (e.g. in NCDS58, probit coefficients were 0.201 and -0.765, respectively; P < 0.001 for both) than respondents from a non-manual class. Adolescent smokers were more likely to drink weekly in adolescence (0.346; P < 0.001) and more likely to drink heavily in early adulthood (0.178; P < 0.001) than adolescent non-smokers. Respondents who participated in tertiary education were more likely to drink heavily in early adulthood (0.110 for males, 0.182 for females; P < 0.001 for both) than respondents with no tertiary education. With some variation in magnitude, these associations were consistent across all three cohorts. In Britain, young adults are more likely to drink heavily both if they smoke and participate in tertiary education (college and university) despite socio-economic background being associated in opposite directions with these risk factors. © 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Learning to teach mathematical modelling in secondary and tertiary education

NASA Astrophysics Data System (ADS)

Ferri, Rita Borromeo

2017-07-01

Since 2003 mathematical modelling in Germany is not only a topic for scientific disciplines in university mathematics courses, but also in school starting with primary school. This paper shows what mathematical modelling means in school and how it can be taught as a basis for complex modeling problems in tertiary education.

General Mechanism of Two-State Protein Folding Kinetics

PubMed Central

Rollins, Geoffrey C.; Dill, Ken A.

2016-01-01

We describe here a general model of the kinetic mechanism of protein folding. In the Foldon Funnel Model, proteins fold in units of secondary structures, which form sequentially along the folding pathway, stabilized by tertiary interactions. The model predicts that the free energy landscape has a volcano shape, rather than a simple funnel, that folding is two-state (single-exponential) when secondary structures are intrinsically unstable, and that each structure along the folding path is a transition state for the previous structure. It shows how sequential pathways are consistent with multiple stochastic routes on funnel landscapes, and it gives good agreement with the 9 order of magnitude dependence of folding rates on protein size for a set of 93 proteins, at the same time it is consistent with the near independence of folding equilibrium constant on size. This model gives estimates of folding rates of proteomes, leading to a median folding time in Escherichia coli of about 5 s. PMID:25056406

A Pseudo-Atomic Model of the COPII Cage Obtained from CryoEM and Mass Spectrometry Analyses

PubMed Central

Noble, Alex J.; Zhang, Qian; O’Donnell, Jason; Hariri, Hanaa; Bhattacharya, Nilakshee; Marshall, Alan G.

2012-01-01

COPII vesicles transport proteins from the ER to the Golgi apparatus. Previous cryoEM structures of the COPII cage lacked the resolution necessary to determine the residues of Sec13 and Sec31 that mediate assembly and flexibility of the COPII cage. Here we present a 12Å-resolution structure of the COPII cage, where the tertiary structure of Sec13 and Sec31 is clearly identifiable. We employ this structure and a homology model of the Sec13-Sec31 complex to create a reliable pseudo-atomic model of the COPII cage. We combined this model with hydrogen/deuterium exchange mass spectrometry analysis to characterize four distinct contact regions at the vertices of the COPII cage. Furthermore, we found that the 2-fold symmetry of the Sec31 dimeric region of Sec13-31 is broken on cage formation, and that the resulting hinge is essential to form the proper edge geometry in COPII cages. PMID:23262493

Template-based protein structure modeling using the RaptorX web server.

PubMed

Källberg, Morten; Wang, Haipeng; Wang, Sheng; Peng, Jian; Wang, Zhiyong; Lu, Hui; Xu, Jinbo

2012-07-19

A key challenge of modern biology is to uncover the functional role of the protein entities that compose cellular proteomes. To this end, the availability of reliable three-dimensional atomic models of proteins is often crucial. This protocol presents a community-wide web-based method using RaptorX (http://raptorx.uchicago.edu/) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling. RaptorX distinguishes itself from other servers by the quality of the alignment between a target sequence and one or multiple distantly related template proteins (especially those with sparse sequence profiles) and by a novel nonlinear scoring function and a probabilistic-consistency algorithm. Consequently, RaptorX delivers high-quality structural models for many targets with only remote templates. At present, it takes RaptorX ~35 min to finish processing a sequence of 200 amino acids. Since its official release in August 2011, RaptorX has processed ~6,000 sequences submitted by ~1,600 users from around the world.

Template-based protein structure modeling using the RaptorX web server

PubMed Central

Källberg, Morten; Wang, Haipeng; Wang, Sheng; Peng, Jian; Wang, Zhiyong; Lu, Hui; Xu, Jinbo

2016-01-01

A key challenge of modern biology is to uncover the functional role of the protein entities that compose cellular proteomes. To this end, the availability of reliable three-dimensional atomic models of proteins is often crucial. This protocol presents a community-wide web-based method using RaptorX (http://raptorx.uchicago.edu/) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling. RaptorX distinguishes itself from other servers by the quality of the alignment between a target sequence and one or multiple distantly related template proteins (especially those with sparse sequence profiles) and by a novel nonlinear scoring function and a probabilistic-consistency algorithm. Consequently, RaptorX delivers high-quality structural models for many targets with only remote templates. At present, it takes RaptorX ~35 min to finish processing a sequence of 200 amino acids. Since its official release in August 2011, RaptorX has processed ~6,000 sequences submitted by ~1,600 users from around the world. PMID:22814390

Färoe-Iceland Ridge Experiment: 1. Crustal structure of northeastern Iceland

USGS Publications Warehouse

Staples, Robert K.; White, Robert S.; Brandsdottir, Bryndis; Menke, William; Maguire, Peter K.H.; McBride, John H.

1997-01-01

Results from the Färoe-Iceland Ridge Experiment (FIRE) constrain the crustal thickness as 19 km under the Northern Volcanic Zone of Iceland and 35 km under older Tertiary areas of northeastern Iceland. The Moho is defined by strong P wave and S wave reflections. Synthetic seismogram modeling of the Moho reflection indicates mantle velocities of at least 8.0 km/s beneath the Tertiary areas of northeastern Iceland and at least 7.9 km/s beneath the neovolcanic zone. Crustal diving rays resolve the structure of the upper and lower crust. Surface P wave velocities are 1.1–4.0 km/s in Quaternary rocks and are rather higher, 4.4–4.7 km/s, in the Tertiary basalts that outcrop elsewhere. The highest crustal P wave velocities observed directly from diving rays are 7.1 km/s, from rays that turn at 24 km depth. Velocities of 7.35 km/s at the base of the crust are inferred from extrapolation of the lower crustal velocity gradient (0.024 s−1). A Poisson's ratio of approximately 0.27, equivalent to an S wave to P wave travel time ratio of 1.78, is measured throughout the crust east of the neovolcanic zone. The Poisson's ratio and the steep Moho topography (in places up to 30° from the horizontal) indicate that the entire crust outside the neovolcanic zone is cool (<800°C). Gravity data are well matched by a velocity/density conversion of our seismic crustal model and indicate a region of low mantle density beneath the neovolcanic zone, believed to be due to elevated mantle temperatures. The crustal thickness in the neovolcanic zone is consistent with geochemical estimates of the melt generation, placing constraints on the flow within the Iceland mantle plume.

Magnetotelluric Data, Central Yucca Flat, Nevada Test Site, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T.H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT sounding data for Central Yucca Flat, Profile 1, as shown in figure 1. No interpretation of the data is included here.« less

Magnetotelluric Data, North Central Yucca Flat, Nevada Test Site, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T.H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT sounding data for north central Yucca Flat, Profile 7, as shown in Figure 1. No interpretation of the data is included here.« less

Magnetotelluric Data, Northern Frenchman Flat, Nevada Test Site Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T. H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT sounding data for Frenchman Flat Profile 3, as shown in Figure 1. No interpretation of the data is included here.« less

Magnetotelluric Data, Across Quartzite Ridge, Nevada Test Site, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T.H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT soundings across Quartzite Ridge, Profiles 5, 6a, and 6b, as shown in Figure 1. No interpretation of the data is included here.« less

Magnetotelluric Data, Southern Yucca Flat, Nevada Test Site, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T.H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT sounding data for Southern Yucca Flat, Profile 4, as shown in Figure 1. No interpretation of the data is included here.« less

Magnetotelluric Data, Northern Yucca Flat, Nevada Test Site, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

J.M. Williams; B.D. Rodriguez, and T.H. Asch

2005-11-23

Nuclear weapons are integral to the defense of the United States. The U.S. Department of Energy, as the steward of these devices, must continue to gauge the efficacy of the individual weapons. This could be accomplished by occasional testing at the Nevada Test Site (NTS) in Nevada, northwest of Las Vegas. Yucca Flat Basin is one of the testing areas at the NTS. One issue of concern is the nature of the somewhat poorly constrained pre-Tertiary geology and its effects on ground-water flow in the area subsequent to a nuclear test. Ground-water modelers would like to know more about themore » hydrostratigraphy and geologic structure to support a hydrostratigraphic framework model that is under development for the Yucca Flat Corrective Action Unit (CAU). During 2003, the U.S. Geological Survey (USGS) collected and processed Magnetotelluric (MT) and Audio-magnetotelluric (AMT) data at the Nevada Test Site in and near Yucca Flat to help characterize this pre-Tertiary geology. That work will help to define the character, thickness, and lateral extent of pre-Tertiary confining units. In particular, a major goal has been to define the upper clastic confining unit (UCCU) in the Yucca Flat area. Interpretation will include a three-dimensional (3-D) character analysis and two-dimensional (2-D) resistivity model. The purpose of this report is to release the MT sounding data for Profile 2, (fig. 1), located in the northern Yucca Flat area. No interpretation of the data is included here.« less

Fluorescence Competition Assay Measurements of Free Energy Changes for RNA Pseudoknots†

PubMed Central

2009-01-01

RNA pseudoknots have important functions, and thermodynamic stability is a key to predicting pseudoknots in RNA sequences and to understanding their functions. Traditional methods, such as UV melting and differential scanning calorimetry, for measuring RNA thermodynamics are restricted to temperature ranges around the melting temperature for a pseudoknot. Here, we report RNA pseudoknot free energy changes at 37 °C measured by fluorescence competition assays. Sequence-dependent studies for the loop 1−stem 2 region reveal (1) the individual nearest-neighbor hydrogen bonding (INN-HB) model provides a reasonable estimate for the free energy change when a Watson−Crick base pair in stem 2 is changed, (2) the loop entropy can be estimated by a statistical polymer model, although some penalty for certain loop sequences is necessary, and (3) tertiary interactions can significantly stabilize pseudoknots and extending the length of stem 2 may alter tertiary interactions such that the INN-HB model does not predict the net effect of adding a base pair. The results can inform writing of algorithms for predicting and/or designing RNA secondary structures. PMID:19921809

An Investigation of G-Quadruplex Structural Polymorphism in the Human Telomere Using a Combined Approach of Hydrodynamic Bead Modeling and Molecular Dynamics Simulation

PubMed Central

2015-01-01

Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures. PMID:24779348

Protein Folding and Self-Organized Criticality

NASA Astrophysics Data System (ADS)

Bajracharya, Arun; Murray, Joelle

Proteins are known to fold into tertiary structures that determine their functionality in living organisms. However, the complex dynamics of protein folding and the way they consistently fold into the same structures is not fully understood. Self-organized criticality (SOC) has provided a framework for understanding complex systems in various systems (earthquakes, forest fires, financial markets, and epidemics) through scale invariance and the associated power law behavior. In this research, we use a simple hydrophobic-polar lattice-bound computational model to investigate self-organized criticality as a possible mechanism for generating complexity in protein folding.

The role of ion mobility spectrometry-mass spectrometry in the analysis of protein reference standards.

PubMed

Pritchard, Caroline; O'Connor, Gavin; Ashcroft, Alison E

2013-08-06

To achieve comparability of measurement results of protein amount of substance content between clinical laboratories, suitable reference materials are required. The impact on measurement comparability of potential differences in the tertiary and quaternary structure of protein reference standards is as yet not well understood. With the use of human growth hormone as a model protein, the potential of ion mobility spectrometry-mass spectrometry as a tool to assess differences in the structure of protein reference materials and their interactions with antibodies has been investigated here.

Quantitative theory of hydrophobic effect as a driving force of protein structure

PubMed Central

Perunov, Nikolay; England, Jeremy L

2014-01-01

Various studies suggest that the hydrophobic effect plays a major role in driving the folding of proteins. In the past, however, it has been challenging to translate this understanding into a predictive, quantitative theory of how the full pattern of sequence hydrophobicity in a protein shapes functionally important features of its tertiary structure. Here, we extend and apply such a phenomenological theory of the sequence-structure relationship in globular protein domains, which had previously been applied to the study of allosteric motion. In an effort to optimize parameters for the model, we first analyze the patterns of backbone burial found in single-domain crystal structures, and discover that classic hydrophobicity scales derived from bulk physicochemical properties of amino acids are already nearly optimal for prediction of burial using the model. Subsequently, we apply the model to studying structural fluctuations in proteins and establish a means of identifying ligand-binding and protein–protein interaction sites using this approach. PMID:24408023

Geophysical Investigation of Avon Valley, West-Central Montana, using Gravity and Seismic Reflection Profiling

NASA Astrophysics Data System (ADS)

Knatterud, L.; Mosolf, J.; Speece, M. A.; Zhou, X.

2014-12-01

The Avon Valley and adjacent mountains in west-central Montana lie within the Lewis and Clark Line, a major system of WNW-striking faults and folds that transect the more northerly structural grain of the northern Rockies and represent alternating episodes of transtensional and transpressional deformation. The northwest-trending valley has been previously interpreted as an extensional half graben filled with Tertiary sedimentary and volcanic deposits; however, little-to-no geophysical constraints on basin architecture or the thickness of Tertiary fill have been reported. A major northwest-striking fault with significant normal displacement clearly bounds the valley to the northeast, juxtaposing Tertiary sedimentary deposits against Proterozoic-Mesozoic units deformed by shortening structures and crosscut by Cretaceous granitic intrusions. Tertiary volcanic deposits unconformably overlying faulted and folded Phanerozoic-Proterozoic sequences in the eastern Garnet Range bound the valley to the southwest, but in the past no faults had been mapped along this margin. New mapping by the Montana Bureau of Mines and Geology (MBMG) has identified a system of high-angle, northwest- and northeast-striking, oblique-slip faults along the southwest border of the Avon calling into question if the valley is a half, full, or asymmetrical graben. Geophysical data has recently been acquired by Montana Tech to help define the structural architecture of the Avon Valley and the thickness of its Tertiary fill. Gravity data and a short seismic reflection profile have been collected and a preliminary interpretation of these data indicates a half graben with a series of normal faults bounding the western side of the valley. Ongoing gravity data collection throughout 2014 should refine this interpretation by better defining the bedrock-Tertiary interface at depth.

Architecture of a Diels-Alderase ribozyme with a preformed catalytic pocket.

PubMed

Keiper, Sonja; Bebenroth, Dirk; Seelig, Burckhard; Westhof, Eric; Jäschke, Andres

2004-09-01

Artificial ribozymes catalyze a variety of chemical reactions. Their structures and reaction mechanisms are largely unknown. We have analyzed a ribozyme catalyzing Diels-Alder cycloaddition reactions by comprehensive mutation analysis and a variety of probing techniques. New tertiary interactions involving base pairs between nucleotides of the 5' terminus and a large internal loop forming a pseudoknot fold were identified. The probing data indicate a preformed tertiary structure that shows no major changes on substrate or product binding. Based on these observations, a molecular architecture featuring a Y-shaped arrangement is proposed. The tertiary structure is formed in a rather unusual way; that is, the opposite sides of the asymmetric internal loop are clamped by the four 5'-terminal nucleotides, forming two adjacent two base-pair helices. It is proposed that the catalytic pocket is formed by a wedge within one of these helices.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiong, J.-P.; Stehle, T.; Zhang, R.

The structural basis for the divalent cation-dependent binding of heterodimeric alpha beta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alpha Vbeta 3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alpha V and beta 3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. Themore » tertiary rearrangements take place in beta A, the ligand-binding domain of beta 3; in the complex, beta A acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alpha V relative to beta 3.« less

Regional frontier exploration in Sinu basin, northwestern Colombia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindberg, F.A.; Ellis, J.M.; Dekker, L.L.

1989-03-01

In 1983, Gulf and Ecopetrol undertook a regional hydrocarbon evaluation of northwestern Colombia, during the course of which much of the Sinu basin was mapped by field geologists aided by low-altitude aerial photographs. Additional seismic and airborne radar data were acquired to assist in developing a regional structural model. The dominant structures of the Sinu basin were produced by westward-vergent thrust faults, which are offset on the order of 10 to 20 km by northwest-southeast-trending compartmental faults. Numerous mud volcanos are surface expressions of overpressured shales, which migrate upward along both thrust and strike-slip faults. Thrust faults are expressed, onmore » the surface, by steep-sided, asymmetrical anticlines, which are separated by broad synclines filled with clastics shed during Tertiary thrusting. The extremely thick section of Tertiary sediments is dominated by shale but contains some potential reservoir sandstones. These resistive sandstones could be accurately mapped on the radar imagery and projected into the subsurface allowing traps to be better defined. Combining field geology with geologic interpretation of aerial photographs and radar images was very effective in developing a regional structural framework of the Sinu basin.« less

Rapid search for tertiary fragments reveals protein sequence–structure relationships

PubMed Central

Zhou, Jianfu; Grigoryan, Gevorg

2015-01-01

Finding backbone substructures from the Protein Data Bank that match an arbitrary query structural motif, composed of multiple disjoint segments, is a problem of growing relevance in structure prediction and protein design. Although numerous protein structure search approaches have been proposed, methods that address this specific task without additional restrictions and on practical time scales are generally lacking. Here, we propose a solution, dubbed MASTER, that is both rapid, enabling searches over the Protein Data Bank in a matter of seconds, and provably correct, finding all matches below a user-specified root-mean-square deviation cutoff. We show that despite the potentially exponential time complexity of the problem, running times in practice are modest even for queries with many segments. The ability to explore naturally plausible structural and sequence variations around a given motif has the potential to synthesize its design principles in an automated manner; so we go on to illustrate the utility of MASTER to protein structural biology. We demonstrate its capacity to rapidly establish structure–sequence relationships, uncover the native designability landscapes of tertiary structural motifs, identify structural signatures of binding, and automatically rewire protein topologies. Given the broad utility of protein tertiary fragment searches, we hope that providing MASTER in an open-source format will enable novel advances in understanding, predicting, and designing protein structure. PMID:25420575

Effects of urea induced protein conformational changes on ion exchange chromatographic behavior.

PubMed

Hou, Ying; Hansen, Thomas B; Staby, Arne; Cramer, Steven M

2010-11-19

Urea is widely employed to facilitate protein separations in ion exchange chromatography at various scales. In this work, five model proteins were used to examine the chromatographic effects of protein conformational changes induced by urea in ion exchange chromatography. Linear gradient experiments were carried out at various urea concentrations and the protein secondary and tertiary structures were evaluated by far UV CD and fluorescence measurements, respectively. The results indicated that chromatographic retention times were well correlated with structural changes and that they were more sensitive to tertiary structural change. Steric Mass Action (SMA) isotherm parameters were also examined and the results indicated that urea induced protein conformational changes could affect both the characteristic charge and equilibrium constants in these systems. Dynamic light scattering analysis of changes in protein size due to urea-induced unfolding indicated that the size of the protein was not correlated with SMA parameter changes. These results indicate that while urea-induced structural changes can have a marked effect on protein chromatographic behavior in IEX, this behavior can be quite complicated and protein specific. These differences in protein behavior may provide insight into how these partially unfolded proteins are interacting with the resin material. Copyright © 2010 Elsevier B.V. All rights reserved.

Specific and total N-nitrosamines formation potentials of nitrogenous micropollutants during chloramination.

PubMed

Piazzoli, Andrea; Breider, Florian; Aquillon, Caroline Gachet; Antonelli, Manuela; von Gunten, Urs

2018-05-15

N-nitrosamines are a group of potent human carcinogens that can be formed during oxidative treatment of drinking water and wastewater. Many tertiary and quaternary amines present in consumer products (e.g., pharmaceuticals, personal care and household products) are known to be N-nitrosodimethylamine (NDMA) precursors during chloramination, but the formation of other N-nitrosamines has been rarely studied. This study investigates the specific and total N-nitrosamine (TONO) formation potential (FP) of various precursors from nitrogen-containing micropollutants (chlorhexidine, metformin, benzalkonium chloride and cetyltrimethylammonium chloride) and tertiary and quaternary model amines (trimethyl amine, N,N-dimethylbutyl amine, N,N-dimethylbenzyl amine and tetramethyl ammonium). All the studied nitrogenous micropollutants displayed quantifiable TONO FP, with molar yields in the range 0.04-11.92%. However, the observed TONO pools constituted mostly of uncharacterized species, not included in US-EPA 8270 N-nitrosamines standard mix. Only the quaternary ammonium compound benzalkonium chloride showed quantifiable NDMA FP (0.56% molar yield), however, explaining only a minor fraction of the observed TONO FP. The studied model amines showed molar NDMA yields from 0.10% (trimethyl amine) to 5.05% (N,N-dimethylbenzyl amine), very similar to the molar TONO yields. The comparison of the FPs of micropollutants and model compounds showed that the presence of electron donating functional groups (such as a benzyl group) in tertiary and quaternary amine precursors leads to a higher formation of NDMA and uncharacterized N-nitrosamines, respectively. LC-qTOF screening of a list of proposed N-nitrosamine structures has enabled to identify a novel N-nitrosamine (N-nitroso-N-methyldodecylamine) from the chloramination of benzalkonium chloride. This finding supports the hypothesis that different functional groups in quaternary amines can act as leaving groups during chloramination and form differing N-nitrosamine structures at significant yield. Molar TONO yields determined for micropollutants were finally validated under experimental conditions closer to real water matrices, confirming their representativeness also for lower concentration ranges. Copyright © 2018 Elsevier Ltd. All rights reserved.

Distinct Tertiary Lymphoid Structure Associations and Their Prognostic Relevance in HER2 Positive and Negative Breast Cancers.

PubMed

Liu, Xia; Tsang, Julia Y S; Hlaing, Thazin; Hu, Jintao; Ni, Yun-Bi; Chan, Siu Ki; Cheung, Sai Yin; Tse, Gary M

2017-11-01

The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as tertiary lymphoid structures (TLS), play a key role in determining patient survival. In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined. Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c-kit expression. Tertiary lymphoid structures were significantly related to better disease-free survival (DFS) in HER2 positive (HER2+) breast cancers (log-rank = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2-) TLS positive (particularly estrogen receptor positive [ER+] HER2-) cases. In the ER+ HER2- cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement. Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies. Despite recent interest on the clinical value of tumor infiltrating lymphocyte (TIL), little was known on the clinical significance on their spatial organization as tertiary lymphoid structures (TLS). Although TLS showed similar relationships with clinicopathologic features and biomarkers as TIL, the prognostic value of TLS, particularly in HER2 positive cancers, was independent of TIL. Moreover, tumor infiltration could be present in TLS which appears to be related to tumor invasion in HER2 negative cancers. Overall, the results demonstrated the additional value for TLS in HER2 cancer subtypes. Further investigations and its standardized evaluation will enhance its use as standard practice. © AlphaMed Press 2017.

A Biome map for Modelling Global Mid-Pliocene Climate Change

NASA Astrophysics Data System (ADS)

Salzmann, U.; Haywood, A. M.

2006-12-01

The importance of vegetation-climate feedbacks was highlighted by several paleo-climate modelling exercises but their role as a boundary condition in Tertiary modelling has not been fully recognised or explored. Several paleo-vegetation datasets and maps have been produced for specific time slabs or regions for the Tertiary, but the vegetation classifications that have been used differ, thus making meaningful comparisons difficult. In order to facilitate further investigations into Tertiary climate and environmental change we are presently implementing the comprehensive GIS database TEVIS (Tertiary Environment and Vegetation Information System). TEVIS integrates marine and terrestrial vegetation data, taken from fossil pollen, leaf or wood, into an internally consistent classification scheme to produce for different time slabs global Tertiary Biome and Mega- Biome maps (Harrison & Prentice, 2003). In the frame of our ongoing 5-year programme we present a first global vegetation map for the mid-Pliocene time slab, a period of sustained global warmth. Data were synthesised from the PRISM data set (Thompson and Fleming 1996) after translating them to the Biome classification scheme and from new literature. The outcomes of the Biome map are compared with modelling results using an advanced numerical general circulation model (HadAM3) and the BIOME 4 vegetation model. Our combined proxy data and modelling approach will provide new palaeoclimate datasets to test models that are used to predict future climate change, and provide a more rigorous picture of climate and environmental changes during the Neogene.

Conformational and functional similarities between glutaredoxin and thioredoxins.

PubMed Central

Eklund, H; Cambillau, C; Sjöberg, B M; Holmgren, A; Jörnvall, H; Höög, J O; Brändén, C I

1984-01-01

The tertiary structures of thioredoxin from Escherichia coli and bacteriophage T4 have been compared and aligned giving a common fold of 68 C alpha atoms with a root mean square difference of 2.6 A. The amino acid sequence of glutaredoxin has been aligned to those of the thioredoxins assuming that glutaredoxin has the same common fold. A model of the glutaredoxin molecule was built on a vector display using this alignment and the T4 thioredoxin tertiary structure. By comparison of the model with those of the thioredoxins, we have identified a molecular surface area on one side of the redox-active S-S bridge which we suggest is the binding area of these molecules for redox interactions with other proteins. This area comprises residues 33-34, 75-76 and 91-93 in E. coli thioredoxin; 15-16, 65-66 and 76-78 in T4 thioredoxin and 12-13, 59-60 and 69-71 in glutaredoxin. In all three molecules, this part of the surface is flat and hydrophobic. Charged groups are completely absent. In contrast, there is a cluster of charged groups on the other side of the S-S bridge which we suggest participates in the mechanisms of the redox reactions. In particular, a lysine residue close to an aromatic ring is conserved in all molecules. PMID:6378624

Metal stabilization of collagen and de novo designed mimetic peptides

PubMed Central

Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

2017-01-01

We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix. PMID:26225466

Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides.

PubMed

Parmar, Avanish S; Xu, Fei; Pike, Douglas H; Belure, Sandeep V; Hasan, Nida F; Drzewiecki, Kathryn E; Shreiber, David I; Nanda, Vikas

2015-08-18

We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

Prediction of protein tertiary structure from sequences using a very large back-propagation neural network

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, X.; Wilcox, G.L.

1993-12-31

We have implemented large scale back-propagation neural networks on a 544 node Connection Machine, CM-5, using the C language in MIMD mode. The program running on 512 processors performs backpropagation learning at 0.53 Gflops, which provides 76 million connection updates per second. We have applied the network to the prediction of protein tertiary structure from sequence information alone. A neural network with one hidden layer and 40 million connections is trained to learn the relationship between sequence and tertiary structure. The trained network yields predicted structures of some proteins on which it has not been trained given only their sequences.more » Presentation of the Fourier transform of the sequences accentuates periodicity in the sequence and yields good generalization with greatly increased training efficiency. Training simulations with a large, heterologous set of protein structures (111 proteins from CM-5 time) to solutions with under 2% RMS residual error within the training set (random responses give an RMS error of about 20%). Presentation of 15 sequences of related proteins in a testing set of 24 proteins yields predicted structures with less than 8% RMS residual error, indicating good apparent generalization.« less

Ensemble-based evaluation for protein structure models.

PubMed

Jamroz, Michal; Kolinski, Andrzej; Kihara, Daisuke

2016-06-15

Comparing protein tertiary structures is a fundamental procedure in structural biology and protein bioinformatics. Structure comparison is important particularly for evaluating computational protein structure models. Most of the model structure evaluation methods perform rigid body superimposition of a structure model to its crystal structure and measure the difference of the corresponding residue or atom positions between them. However, these methods neglect intrinsic flexibility of proteins by treating the native structure as a rigid molecule. Because different parts of proteins have different levels of flexibility, for example, exposed loop regions are usually more flexible than the core region of a protein structure, disagreement of a model to the native needs to be evaluated differently depending on the flexibility of residues in a protein. We propose a score named FlexScore for comparing protein structures that consider flexibility of each residue in the native state of proteins. Flexibility information may be extracted from experiments such as NMR or molecular dynamics simulation. FlexScore considers an ensemble of conformations of a protein described as a multivariate Gaussian distribution of atomic displacements and compares a query computational model with the ensemble. We compare FlexScore with other commonly used structure similarity scores over various examples. FlexScore agrees with experts' intuitive assessment of computational models and provides information of practical usefulness of models. https://bitbucket.org/mjamroz/flexscore dkihara@purdue.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Ensemble-based evaluation for protein structure models

PubMed Central

Jamroz, Michal; Kolinski, Andrzej; Kihara, Daisuke

2016-01-01

Motivation: Comparing protein tertiary structures is a fundamental procedure in structural biology and protein bioinformatics. Structure comparison is important particularly for evaluating computational protein structure models. Most of the model structure evaluation methods perform rigid body superimposition of a structure model to its crystal structure and measure the difference of the corresponding residue or atom positions between them. However, these methods neglect intrinsic flexibility of proteins by treating the native structure as a rigid molecule. Because different parts of proteins have different levels of flexibility, for example, exposed loop regions are usually more flexible than the core region of a protein structure, disagreement of a model to the native needs to be evaluated differently depending on the flexibility of residues in a protein. Results: We propose a score named FlexScore for comparing protein structures that consider flexibility of each residue in the native state of proteins. Flexibility information may be extracted from experiments such as NMR or molecular dynamics simulation. FlexScore considers an ensemble of conformations of a protein described as a multivariate Gaussian distribution of atomic displacements and compares a query computational model with the ensemble. We compare FlexScore with other commonly used structure similarity scores over various examples. FlexScore agrees with experts’ intuitive assessment of computational models and provides information of practical usefulness of models. Availability and implementation: https://bitbucket.org/mjamroz/flexscore Contact: dkihara@purdue.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307633

Secondary and tertiary isoquinoline alkaloids from Xylopia parviflora.

PubMed

Nishiyama, Yumi; Moriyasu, Masataka; Ichimaru, Momoyo; Iwasa, Kinuko; Kato, Atsushi; Mathenge, Simon G; Chalo Mutiso, Patrick B; Juma, Francis D

2006-12-01

From the secondary and tertiary alkaloidal fractions of the root and the bark of Xylopia parviflora (Annonaceae), the isoquinoline alkaloids, 10,11-dihydroxy-1,2-dimethoxynoraporphine and parvinine were isolated, along with 39 known alkaloids. Their structures were determined on the basis of analysis of spectroscopic data.

Large-scale model quality assessment for improving protein tertiary structure prediction.

PubMed

Cao, Renzhi; Bhattacharya, Debswapna; Adhikari, Badri; Li, Jilong; Cheng, Jianlin

2015-06-15

Sampling structural models and ranking them are the two major challenges of protein structure prediction. Traditional protein structure prediction methods generally use one or a few quality assessment (QA) methods to select the best-predicted models, which cannot consistently select relatively better models and rank a large number of models well. Here, we develop a novel large-scale model QA method in conjunction with model clustering to rank and select protein structural models. It unprecedentedly applied 14 model QA methods to generate consensus model rankings, followed by model refinement based on model combination (i.e. averaging). Our experiment demonstrates that the large-scale model QA approach is more consistent and robust in selecting models of better quality than any individual QA method. Our method was blindly tested during the 11th Critical Assessment of Techniques for Protein Structure Prediction (CASP11) as MULTICOM group. It was officially ranked third out of all 143 human and server predictors according to the total scores of the first models predicted for 78 CASP11 protein domains and second according to the total scores of the best of the five models predicted for these domains. MULTICOM's outstanding performance in the extremely competitive 2014 CASP11 experiment proves that our large-scale QA approach together with model clustering is a promising solution to one of the two major problems in protein structure modeling. The web server is available at: http://sysbio.rnet.missouri.edu/multicom_cluster/human/. © The Author 2015. Published by Oxford University Press.

Protein single-model quality assessment by feature-based probability density functions.

PubMed

Cao, Renzhi; Cheng, Jianlin

2016-04-04

Protein quality assessment (QA) has played an important role in protein structure prediction. We developed a novel single-model quality assessment method-Qprob. Qprob calculates the absolute error for each protein feature value against the true quality scores (i.e. GDT-TS scores) of protein structural models, and uses them to estimate its probability density distribution for quality assessment. Qprob has been blindly tested on the 11th Critical Assessment of Techniques for Protein Structure Prediction (CASP11) as MULTICOM-NOVEL server. The official CASP result shows that Qprob ranks as one of the top single-model QA methods. In addition, Qprob makes contributions to our protein tertiary structure predictor MULTICOM, which is officially ranked 3rd out of 143 predictors. The good performance shows that Qprob is good at assessing the quality of models of hard targets. These results demonstrate that this new probability density distribution based method is effective for protein single-model quality assessment and is useful for protein structure prediction. The webserver of Qprob is available at: http://calla.rnet.missouri.edu/qprob/. The software is now freely available in the web server of Qprob.

Factors Influencing Changes in Eating Patterns Among Hong Kong Young Adults Transitioning to Tertiary Education.

PubMed

Kwok, Sin Tung; Capra, Sandra; Leveritt, Michael

2016-05-01

Transitioning to tertiary education is a significant life course event that has the potential to influence lifelong eating patterns. This study used a theoretic model developed from a life course perspective to examine factors influencing the change of food choices among 31 young adults in Hong Kong after they moved on to tertiary education. Qualitative analysis of transcripts based on the constant comparative method revealed that present life course experiences, especially increased autonomy, and social-environmental factors strongly influenced young adults' present food choices. A model was developed from life course theory and social-ecological theory to reflect the factors that led to change of food choices among participants. The model provides unique insights on food choices of the future adult population. It could also be used as a reference for the development of nutrition education interventions targeting tertiary students as they experience increased autonomy. In conclusion, food choices of young adults on transitioning to tertiary education are strongly influenced by increased autonomy and change of social and environmental factors. © 2016 APJPH.

Proposed structure of putative glucose channel in GLUT1 facilitative glucose transporter.

PubMed Central

Zeng, H; Parthasarathy, R; Rampal, A L; Jung, C Y

1996-01-01

A family of structurally related intrinsic membrane proteins (facilitative glucose transporters) catalyzes the movement of glucose across the plasma membrane of animal cells. Evidence indicates that these proteins show a common structural motif where approximately 50% of the mass is embedded in lipid bilayer (transmembrane domain) in 12 alpha-helices (transmembrane helices; TMHs) and accommodates a water-filled channel for substrate passage (glucose channel) whose tertiary structure is currently unknown. Using recent advances in protein structure prediction algorithms we proposed here two three-dimensional structural models for the transmembrane glucose channel of GLUT1 glucose transporter. Our models emphasize the physical dimension and water accessibility of the channel, loop lengths between TMHs, the macrodipole orientation in four-helix bundle motif, and helix packing energy. Our models predict that five TMHs, either TMHs 3, 4, 7, 8, 11 (Model 1) or TMHs 2, 5, 11, 8, 7 (Model 2), line the channel, and the remaining TMHs surround these channel-lining TMHs. We discuss how our models are compatible with the experimental data obtained with this protein, and how they can be used in designing new biochemical and molecular biological experiments in elucidation of the structural basis of this important protein function. Images FIGURE 1 FIGURE 2 FIGURE 4 FIGURE 5 PMID:8770183

Macromolecular ab initio phasing enforcing secondary and tertiary structure.

PubMed

Millán, Claudia; Sammito, Massimo; Usón, Isabel

2015-01-01

Ab initio phasing of macromolecular structures, from the native intensities alone with no experimental phase information or previous particular structural knowledge, has been the object of a long quest, limited by two main barriers: structure size and resolution of the data. Current approaches to extend the scope of ab initio phasing include use of the Patterson function, density modification and data extrapolation. The authors' approach relies on the combination of locating model fragments such as polyalanine α-helices with the program PHASER and density modification with the program SHELXE. Given the difficulties in discriminating correct small substructures, many putative groups of fragments have to be tested in parallel; thus calculations are performed in a grid or supercomputer. The method has been named after the Italian painter Arcimboldo, who used to compose portraits out of fruit and vegetables. With ARCIMBOLDO, most collections of fragments remain a 'still-life', but some are correct enough for density modification and main-chain tracing to reveal the protein's true portrait. Beyond α-helices, other fragments can be exploited in an analogous way: libraries of helices with modelled side chains, β-strands, predictable fragments such as DNA-binding folds or fragments selected from distant homologues up to libraries of small local folds that are used to enforce nonspecific tertiary structure; thus restoring the ab initio nature of the method. Using these methods, a number of unknown macromolecules with a few thousand atoms and resolutions around 2 Å have been solved. In the 2014 release, use of the program has been simplified. The software mediates the use of massive computing to automate the grid access required in difficult cases but may also run on a single multicore workstation (http://chango.ibmb.csic.es/ARCIMBOLDO_LITE) to solve straightforward cases.

The Performance in Context Model: A 21st Century Tertiary Dance Teaching Pedagogy

ERIC Educational Resources Information Center

Stevens, Kym; Huddy, Avril

2016-01-01

Despite tertiary institutions acknowledging that reflective practice is an essential component of undergraduate dance teacher training, there is often a disparity between the tertiary students' reflective skills and the more sophisticated reflective ability needed to navigate the twenty-first-century workforce. This paper charts the evolution of a…

Blended Learning and Team Teaching: Adapting Pedagogy in Response to the Changing Digital Tertiary Environment

ERIC Educational Resources Information Center

Crawford, Renée; Jenkins, Louise

2017-01-01

Increased accessibility of advanced technology, the targeted use of online learning platforms, student flexible learning expectations and the pressures of faculty budget constraints and priorities have called into question the effectiveness of traditional tertiary teaching and learning models. The tertiary education context must evolve at a pace…

Chilean Universities in the Transition to a Market-Driven Policy Regime

ERIC Educational Resources Information Center

Katz, Jorge; Spence, Randy

2009-01-01

This paper briefly reviews the historical development of the university system in Chile, and describes the current structure of funding, supply and demand for tertiary education, research and university services. Both public and private universities in Chile have expanded and restructured, access to tertiary education has improved, and…

Structural basis of DNA folding and recognition in an AMP-DNA aptamer complex: distinct architectures but common recognition motifs for DNA and RNA aptamers complexed to AMP.

PubMed

Lin, C H; Patel, D J

1997-11-01

Structural studies by nuclear magnetic resonance (NMR) of RNA and DNA aptamer complexes identified through in vitro selection and amplification have provided a wealth of information on RNA and DNA tertiary structure and molecular recognition in solution. The RNA and DNA aptamers that target ATP (and AMP) with micromolar affinity exhibit distinct binding site sequences and secondary structures. We report below on the tertiary structure of the AMP-DNA aptamer complex in solution and compare it with the previously reported tertiary structure of the AMP-RNA aptamer complex in solution. The solution structure of the AMP-DNA aptamer complex shows, surprisingly, that two AMP molecules are intercalated at adjacent sites within a rectangular widened minor groove. Complex formation involves adaptive binding where the asymmetric internal bubble of the free DNA aptamer zippers up through formation of a continuous six-base mismatch segment which includes a pair of adjacent three-base platforms. The AMP molecules pair through their Watson-Crick edges with the minor groove edges of guanine residues. These recognition G.A mismatches are flanked by sheared G.A and reversed Hoogsteen G.G mismatch pairs. The AMP-DNA aptamer and AMP-RNA aptamer complexes have distinct tertiary structures and binding stoichiometries. Nevertheless, both complexes have similar structural features and recognition alignments in their binding pockets. Specifically, AMP targets both DNA and RNA aptamers by intercalating between purine bases and through identical G.A mismatch formation. The recognition G.A mismatch stacks with a reversed Hoogsteen G.G mismatch in one direction and with an adenine base in the other direction in both complexes. It is striking that DNA and RNA aptamers selected independently from libraries of 10(14) molecules in each case utilize identical mismatch alignments for molecular recognition with micromolar affinity within binding-site pockets containing common structural elements.

Conformational changes of a chemically modified HRP: formation of a molten globule like structure at pH 5

PubMed Central

Bamdad, Kourosh; Ranjbar, Bijan; Naderi-Manesh, Hossein; Sadeghi, Mehdi

2014-01-01

Horseradish peroxidase is an all alpha-helical enzyme, which widely used in biochemistry applications mainly because of its ability to enhance the weak signals of target molecules. This monomeric heme-containing plant peroxidase is also used as a reagent for the organic synthesis, biotransformation, chemiluminescent assays, immunoassays, bioremediation, and treatment of wastewaters as well. Accordingly, enhancing stability and catalytic activity of this protein for biotechnological uses has been one of the important issues in the field of biological investigations in recent years. In this study, pH-induced structural alterations of native (HRP), and modified (MHRP) forms of Horseradish peroxidase have been investigated. Based on the results, dramatic loss of the tertiary structure and also the enzymatic activity for both forms of enzymes recorded at pH values lower than 6 and higher than 8. Ellipticiy measurements, however, indicated very slight variations in the secondary structure for MHRP at pH 5. Spectroscopic analysis also indicated that melting of the tertiary structure of MHRP at pH 5 starts at around 45 °C, which is associated to the pKa of His 42 that has a serious role in keeping of the heme prostethic group in its native position through natural hydrogen bond network in the enzyme structure. According to our data, a molten globule like structure of a chemically modified form of Horseradish peroxidase at pH 5 with initial steps of conformational transition in tertiary structure with almost no changes in the secondary structure has been detected. Despite of some conformational changes in the tertiary structure of MHRP at pH 5, this modified form still keeps its catalytic activity to some extent besides enhanced thermal stability. These findings also indicated that a molten globular state does not necessarily preclude efficient catalytic activity. PMID:26417287

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURES TO METHYL TERTIARY-BUTYL ETHER

EPA Science Inventory

Humans can be exposed by inhalation, ingestion, or dermal absorption to methyl tertiary-butyl ether (MTBE), an oxygenated fuel additive, from contaminated water sources. The purpose of this research was to develop a physiologically based pharmacokinetic model describing in human...

REFINED PBPK MODEL OF AGGREGATE EXPOSURE TO METHYL TERTIARY-BUTYL ETHER

EPA Science Inventory

Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically-based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary met...

Refinement of protein termini in template-based modeling using conformational space annealing.

PubMed

Park, Hahnbeom; Ko, Junsu; Joo, Keehyoung; Lee, Julian; Seok, Chaok; Lee, Jooyoung

2011-09-01

The rapid increase in the number of experimentally determined protein structures in recent years enables us to obtain more reliable protein tertiary structure models than ever by template-based modeling. However, refinement of template-based models beyond the limit available from the best templates is still needed for understanding protein function in atomic detail. In this work, we develop a new method for protein terminus modeling that can be applied to refinement of models with unreliable terminus structures. The energy function for terminus modeling consists of both physics-based and knowledge-based potential terms with carefully optimized relative weights. Effective sampling of both the framework and terminus is performed using the conformational space annealing technique. This method has been tested on a set of termini derived from a nonredundant structure database and two sets of termini from the CASP8 targets. The performance of the terminus modeling method is significantly improved over our previous method that does not employ terminus refinement. It is also comparable or superior to the best server methods tested in CASP8. The success of the current approach suggests that similar strategy may be applied to other types of refinement problems such as loop modeling or secondary structure rearrangement. Copyright © 2011 Wiley-Liss, Inc.

Positive selection sites in tertiary structure of Leguminosae chalcone isomerase 1.

PubMed

Wang, R K; Zhan, S F; Zhao, T J; Zhou, X L; Wang, C E

2015-03-20

Isoflavonoids and the related synthesis enzyme, chalcone isomerase 1 (CHI1), are unique in the Leguminosae, with diverse biological functions. Among the Leguminosae, the soybean is an important oil, protein crop, and model plant. In this study, we aimed to detect the generation pattern of Leguminosae CHI1. Genome-wide sequence analysis of CHI in 3 Leguminosae and 3 other closely related model plants was performed; the expression levels of soybean chalcone isomerases were also analyzed. By comparing positively selected sites and their protein structures, we retrieved the evolution patterns for Leguminosae CHI1. A total of 28 CHI and 7 FAP3 (CHI4) genes were identified and separated into 4 clades: CHI1, CHI2, CHI3, and FAP3. Soybean genes belonging to the same chalcone isomerase subfamily had similar expression patterns. CHI1, the unique chalcone isomerase subfamily in Leguminosae, showed signs of significant positive selection as well as special expression characteristics, indicating an accelerated evolution throughout its divergence. Eight sites were identified as undergoing positive selection with high confidence. When mapped onto the tertiary structure of CHI1, these 8 sites were observed surrounding the enzyme substrate only; some of them connected to the catalytic core of CHI. Thus, we inferred that the generation of Leguminosae CHI1 is dependent on the positively selected amino acids surrounding its catalytic substrate. In other words, the evolution of CHI1 was driven by specific selection or processing conditions within the substrate.

Effects of a high-pressure treatment on the wheat alpha-amylase inhibitor and its relationship to elimination of allergenicity

NASA Astrophysics Data System (ADS)

Yamamoto, S.; Takanohashi, K.; Hara, T.; Odani, S.; Suzuki, A.; Nishiumi, T.

2010-03-01

In this study, the effects of high-pressure treatment on structure and allergeincity of alpha amylase inhibitor (a-AI) were investigated. The pressure-induced structural changes of α-AI were estimated by fluorescence spectra and by fourth derivative UV-spectroscopy for probed tyrosine residues and by circular dichroism (CD) spectroscopy. The changes in the tertiary structure detected by fluorescence spectra and by fourth derivative UV-spectroscopy under high pressure were indicated at over 300 MPa. Measurements of CD spectroscopy suggested that the effects of a high-pressure treatment on changes in the secondary structure of α-AI were little. From our results, pressure-induced changes of the α-AI structure were not apparent. On the other hands, the IgE-specific binding activities of pressurized α-AI to sera from allergic patients against wheat, which is estimated by observations of dot-blotting, were decreased by high-pressure treatment. It is known that the pressure-induced elimination of allergenicity is related to the tertiary structural changes of allergen molecules. This study are suspected that the epitopes of α-AI do not contain tyrosine residues, and thus the decrease of IgE-specific binding activities is probably caused by the tertiary structural changes of these parts of α-AI.

Impact of the structural integrity of the three-way junction of adenovirus VAI RNA on PKR inhibition

PubMed Central

Dzananovic, Edis; Astha; Chojnowski, Grzegorz; Deo, Soumya; Booy, Evan P.; Padilla-Meier, Pauline; McEleney, Kevin; Bujnicki, Janusz M.; McKenna, Sean A.

2017-01-01

Highly structured RNA derived from viral genomes is a key cellular indicator of viral infection. In response, cells produce the interferon inducible RNA-dependent protein kinase (PKR) that, when bound to viral dsRNA, phosphorylates eukaryotic initiation factor 2α and attenuates viral protein translation. Adenovirus can evade this line of defence through transcription of a non-coding RNA, VAI, an inhibitor of PKR. VAI consists of three base-paired regions that meet at a three-way junction; an apical stem responsible for the interaction with PKR, a central stem required for inhibition, and a terminal stem. Recent studies have highlighted the potential importance of the tertiary structure of the three-way junction to PKR inhibition by enabling interaction between regions of the central and terminal stems. To further investigate the role of the three-way junction, we characterized the binding affinity and inhibitory potential of central stem mutants designed to introduce subtle alterations. These results were then correlated with small-angle X-ray scattering solution studies and computational tertiary structural models. Our results demonstrate that while mutations to the central stem have no observable effect on binding affinity to PKR, mutations that appear to disrupt the structure of the three-way junction prevent inhibition of PKR. Therefore, we propose that instead of simply sequestering PKR, a specific structural conformation of the PKR-VAI complex may be required for inhibition. PMID:29053745

Post-breakup tectonics in southeast Brazil from thermochronological data and combined inverse-forward thermal history modeling

NASA Astrophysics Data System (ADS)

Cogné, Nathan; Gallagher, Kerry; Cobbold, Peter R.; Riccomini, Claudio; Gautheron, Cecile

2012-11-01

The continental margin of southeast Brazil is elevated. Onshore Tertiary basins and Late Cretaceous/Paleogene intrusions are good evidence for post breakup tectono-magmatic activity. To constrain the impact of post-rift reactivation on the geological history of the area, we carried out a new thermochronological study. Apatite fission track ages range from 60.7 ± 1.9 Ma to 129.3 ± 4.3 Ma, mean track lengths from 11.41 ± 0.23 μm to 14.31 ± 0.24 μm and a subset of the (U-Th)/He ages range from 45.1 ± 1.5 to 122.4 ± 2.5 Ma. Results of inverse thermal history modeling generally support the conclusions from an earlier study for a Late Cretaceous phase of cooling. Around the onshore Taubaté Basin, for a limited number of samples, the first detectable period of cooling occurred during the Early Tertiary. The inferred thermal histories for many samples also imply subsequent reheating followed by Neogene cooling. Given the uncertainty of the inversion results, we did deterministic forward modeling to assess the range of possibilities of this Tertiary part of the thermal history. The evidence for reheating seems to be robust around the Taubaté Basin, but elsewhere the data cannot discriminate between this and a less complex thermal history. However, forward modeling results and geological information support the conclusion that the whole area underwent cooling during the Neogene. The synchronicity of the cooling phases with Andean tectonics and those in NE Brazil leads us to assume a plate-wide compressional stress that reactivated inherited structures. The present-day topographic relief of the margin reflects a contribution from post-breakup reactivation and uplift.

From Ramachandran Maps to Tertiary Structures of Proteins.

PubMed

DasGupta, Debarati; Kaushik, Rahul; Jayaram, B

2015-08-27

Sequence to structure of proteins is an unsolved problem. A possible coarse grained resolution to this entails specification of all the torsional (Φ, Ψ) angles along the backbone of the polypeptide chain. The Ramachandran map quite elegantly depicts the allowed conformational (Φ, Ψ) space of proteins which is still very large for the purposes of accurate structure generation. We have divided the allowed (Φ, Ψ) space in Ramachandran maps into 27 distinct conformations sufficient to regenerate a structure to within 5 Å from the native, at least for small proteins, thus reducing the structure prediction problem to a specification of an alphanumeric string, i.e., the amino acid sequence together with one of the 27 conformations preferred by each amino acid residue. This still theoretically results in 27(n) conformations for a protein comprising "n" amino acids. We then investigated the spatial correlations at the two-residue (dipeptide) and three-residue (tripeptide) levels in what may be described as higher order Ramachandran maps, with the premise that the allowed conformational space starts to shrink as we introduce neighborhood effects. We found, for instance, for a tripeptide which potentially can exist in any of the 27(3) "allowed" conformations, three-fourths of these conformations are redundant to the 95% confidence level, suggesting sequence context dependent preferred conformations. We then created a look-up table of preferred conformations at the tripeptide level and correlated them with energetically favorable conformations. We found in particular that Boltzmann probabilities calculated from van der Waals energies for each conformation of tripeptides correlate well with the observed populations in the structural database (the average correlation coefficient is ∼0.8). An alpha-numeric string and hence the tertiary structure can be generated for any sequence from the look-up table within minutes on a single processor and to a higher level of accuracy if secondary structure can be specified. We tested the methodology on 100 small proteins, and in 90% of the cases, a structure within 5 Å is recovered. We thus believe that the method presented here provides the missing link between Ramachandran maps and tertiary structures of proteins. A Web server to convert a tertiary structure to an alphanumeric string and to predict the tertiary structure from the sequence of a protein using the above methodology is created and made freely accessible at http://www.scfbio-iitd.res.in/software/proteomics/rm2ts.jsp.

Use of terbium as a probe of tRNA tertiary structure and folding.

PubMed Central

Hargittai, M R; Musier-Forsyth, K

2000-01-01

Lanthanide metals such as terbium have previously been shown to be useful for mapping metal-binding sites in RNA. Terbium binds to the same sites on RNA as magnesium, however, with a much higher affinity. Thus, low concentrations of terbium ions can easily displace magnesium and promote phosphodiester backbone scission. At higher concentrations, terbium cleaves RNA in a sequence-independent manner, with a preference for single-stranded, non-Watson-Crick base-paired regions. Here, we show that terbium is a sensitive probe of human tRNALys,3 tertiary structure and folding. When 1 microM tRNA is used, the optimal terbium ion concentration for detecting Mg2+-induced tertiary structural changes is 50-60 microM. Using these concentrations of RNA and terbium, a magnesium-dependent folding transition with a midpoint (KMg) of 2.6 mM is observed for unmodified human tRNALys,3. At lower Tb3+ concentrations, cleavage is restricted to nucleotides that constitute specific metal-binding pockets. This small chemical probe should also be useful for detecting protein induced structural changes in RNA. PMID:11105765

Who Has to Pay for Their Education? Evidence from European Tertiary Education

ERIC Educational Resources Information Center

Lim, Gieyoung; Kim, Chong-Uk

2013-01-01

In this article, we investigate a positive tertiary education externality in 18 European countries. Using a simple Cobb-Douglas-type production function with constant returns to scale, we find that there are positive spillover effects from tertiary education in European countries. According to our model prediction, on average, 72,000 new employed…

Historical review: another 50th anniversary--new periodicities in coiled coils.

PubMed

Gruber, Markus; Lupas, Andrei N

2003-12-01

In 1953, Francis Crick and Linus Pauling both proposed models of supercoiled alpha helices ('coiled coils') for the structure of keratin. These were the first attempts at modelling the tertiary structure of a protein. Crick emphasized the packing mode of the side-chains ('knobs-into-holes'), which required a periodicity of seven residues over two helical turns (7/2) and a supercoil in the opposite sense of the constituent helices. By contrast, Pauling envisaged a broader set of periodicities (4/1, 7/2, 18/5, 15/4, 11/3) and supercoils of both senses. Crick's model became canonical and the 'heptad repeat' essentially synonymous with coiled coils, but 50 years later new crystal structures and protein sequences show that the less common periodicities envisaged by Pauling also occur in coiled coils, adding a variant packing mode ('knobs-to-knobs') to the standard model. Pauling's laboratory notebooks suggest that he searched unsuccessfully for this packing mode in 1953.

Understanding the General Packing Rearrangements Required for Successful Template Based Modeling of Protein Structure from a CASP Experiment

PubMed Central

Day, Ryan; Joo, Hyun; Chavan, Archana; Lennox, Kristin P.; Chen, Ann; Dahl, David B.; Vannucci, Marina; Tsai, Jerry W.

2012-01-01

As an alternative to the common template based protein structure prediction methods based on main-chain position, a novel side-chain centric approach has been developed. Together with a Bayesian loop modeling procedure and a combination scoring function, the Stone Soup algorithm was applied to the CASP9 set of template based modeling targets. Although the method did not generate as large of perturbations to the template structures as necessary, the analysis of the results gives unique insights into the differences in packing between the target structures and their templates. Considerable variation in packing is found between target and template structures even when the structures are close, and this variation is found due to 2 and 3 body packing interactions. Outside the inherent restrictions in packing representation of the PDB, the first steps in correctly defining those regions of variable packing have been mapped primarily to local interactions, as the packing at the secondary and tertiary structure are largely conserved. Of the scoring functions used, a loop scoring function based on water structure exhibited some promise for discrimination. These results present a clear structural path for further development of a side-chain centered approach to template based modeling. PMID:23266765

Understanding the general packing rearrangements required for successful template based modeling of protein structure from a CASP experiment.

PubMed

Day, Ryan; Joo, Hyun; Chavan, Archana C; Lennox, Kristin P; Chen, Y Ann; Dahl, David B; Vannucci, Marina; Tsai, Jerry W

2013-02-01

As an alternative to the common template based protein structure prediction methods based on main-chain position, a novel side-chain centric approach has been developed. Together with a Bayesian loop modeling procedure and a combination scoring function, the Stone Soup algorithm was applied to the CASP9 set of template based modeling targets. Although the method did not generate as large of perturbations to the template structures as necessary, the analysis of the results gives unique insights into the differences in packing between the target structures and their templates. Considerable variation in packing is found between target and template structures even when the structures are close, and this variation is found due to 2 and 3 body packing interactions. Outside the inherent restrictions in packing representation of the PDB, the first steps in correctly defining those regions of variable packing have been mapped primarily to local interactions, as the packing at the secondary and tertiary structure are largely conserved. Of the scoring functions used, a loop scoring function based on water structure exhibited some promise for discrimination. These results present a clear structural path for further development of a side-chain centered approach to template based modeling. Copyright © 2012 Elsevier Ltd. All rights reserved.

High-Throughput, Data-Rich Cellular RNA Device Engineering

PubMed Central

Townshend, Brent; Kennedy, Andrew B.; Xiang, Joy S.; Smolke, Christina D.

2015-01-01

Methods for rapidly assessing sequence-structure-function landscapes and developing conditional gene-regulatory devices are critical to our ability to manipulate and interface with biology. We describe a framework for engineering RNA devices from preexisting aptamers that exhibit ligand-responsive ribozyme tertiary interactions. Our methodology utilizes cell sorting, high-throughput sequencing, and statistical data analyses to enable parallel measurements of the activities of hundreds of thousands of sequences from RNA device libraries in the absence and presence of ligands. Our tertiary interaction RNA devices exhibit improved performance in terms of gene silencing, activation ratio, and ligand sensitivity as compared to optimized RNA devices that rely on secondary structure changes. We apply our method to building biosensors for diverse ligands and determine consensus sequences that enable ligand-responsive tertiary interactions. These methods advance our ability to develop broadly applicable genetic tools and to elucidate understanding of the underlying sequence-structure-function relationships that empower rational design of complex biomolecules. PMID:26258292

The Development of Adult and Community Education Policy in New Zealand: Insights from Popper

ERIC Educational Resources Information Center

Slater, Gloria

2009-01-01

This paper examines the process by which all post-compulsory education in New Zealand has become integrated under one administrative structure, the Tertiary Education Commission (TEC), with the intention of developing a single coordinated system of tertiary education. In particular, adult and community education (ACE), the least formal and…

PASS Student Leader and Mentor Roles: A Tertiary Leadership Pathway

ERIC Educational Resources Information Center

Skalicky, Jane; Caney, Annaliese

2010-01-01

In relation to developing leadership skills during tertiary studies, this paper considers the leadership pathway afforded by a Peer Assisted Study Sessions (PASS) program which includes the traditional PASS Leader role and a more senior PASS Mentor role. Data was collected using a structured survey with open-ended questions designed to capture the…

Online or on Campus: A Student Tertiary Education Cost Model Comparing the Two, with a Quality Proviso

ERIC Educational Resources Information Center

Ioakimidis, Marilou

2007-01-01

This paper presents the development and validation of a two-level hierarchical cost model for tertiary education, which enables prospective students to compare the total cost of attending a traditional Baccalaureate degree education with that of the same programme taken through distance e-learning. The model was validated by a sample of Greek…

In silico modeling techniques for predicting the tertiary structure of human H4 receptor.

PubMed

Zaid, Hilal; Raiyn, Jamal; Osman, Midhat; Falah, Mizied; Srouji, Samer; Rayan, Anwar

2016-01-01

First cloned in 2000, the human Histamine H4 Receptor (hH4R) is the last member of the histamine receptors family discovered so far, it belongs to the GPCR super-family and is involved in a wide variety of immunological and inflammatory responses. Potential hH4R antagonists are proposed to have therapeutic potential for the treatment of allergies, inflammation, asthma and colitis. So far, no hH4R ligands have been successfully introduced to the pharmaceutical market, which creates a strong demand for new selective ligands to be developed. in silico techniques and structural based modeling are likely to facilitate the achievement of this goal. In this review paper we attempt to cover the fundamental concepts of hH4R structure modeling and its implementations in drug discovery and development, especially those that have been experimentally tested and to highlight some ideas that are currently being discussed on the dynamic nature of hH4R and GPCRs, in regards to computerized techniques for 3-D structure modeling.

The use of team-based, guided inquiry learning to overcome educational disadvantages in learning human physiology: a structural equation model.

PubMed

Rathner, Joseph A; Byrne, Graeme

2014-09-01

The study of human bioscience is viewed as a crucial curriculum in allied health. Nevertheless, bioscience (and particularly physiology) is notoriously difficult for undergraduates, particularly academically disadvantaged students. So endemic are the high failure rates (particularly in nursing) that it has come to be known as "the human bioscience problem." In the present report, we describe the outcomes for individual success in studying first-year human physiology in a subject that emphasises team-based active learning as the major pedagogy for mastering subject learning outcomes. Structural equation modeling was used to develop a model of the impact team learning had on individual performance. Modeling was consistent with the idea that students with similar academic abilities (as determined by tertiary entrance rank) were advantaged (scored higher on individual assessment items) by working in strong teams (teams that scored higher in team-based assessments). Analysis of covariance revealed that students who studied the subject with active learning as the major mode of learning activities outperformed students who studied the subject using the traditional didactic teaching format (lectures and tutorials, P = 0.000). After adjustment for tertiary entrance rank (via analysis of covariance) on two individual tests (the final exam and a late-semester in-class test), individual student grades improved by 8% (95% confidence interval: 6-10%) and 12% (95% confidence interval: 10-14%) when students engaged in team-based active learning. These data quantitatively support the notion that weaker students working in strong teams can overcome their educational disadvantages. Copyright © 2014 The American Physiological Society.

The use of team-based, guided inquiry learning to overcome educational disadvantages in learning human physiology: a structural equation model

PubMed Central

Byrne, Graeme

2014-01-01

The study of human bioscience is viewed as a crucial curriculum in allied health. Nevertheless, bioscience (and particularly physiology) is notoriously difficult for undergraduates, particularly academically disadvantaged students. So endemic are the high failure rates (particularly in nursing) that it has come to be known as “the human bioscience problem.” In the present report, we describe the outcomes for individual success in studying first-year human physiology in a subject that emphasises team-based active learning as the major pedagogy for mastering subject learning outcomes. Structural equation modeling was used to develop a model of the impact team learning had on individual performance. Modeling was consistent with the idea that students with similar academic abilities (as determined by tertiary entrance rank) were advantaged (scored higher on individual assessment items) by working in strong teams (teams that scored higher in team-based assessments). Analysis of covariance revealed that students who studied the subject with active learning as the major mode of learning activities outperformed students who studied the subject using the traditional didactic teaching format (lectures and tutorials, P = 0.000). After adjustment for tertiary entrance rank (via analysis of covariance) on two individual tests (the final exam and a late-semester in-class test), individual student grades improved by 8% (95% confidence interval: 6–10%) and 12% (95% confidence interval: 10–14%) when students engaged in team-based active learning. These data quantitatively support the notion that weaker students working in strong teams can overcome their educational disadvantages. PMID:25179611

DFT and TD-DFT calculations of metallotetraphenylporphyrin and metallotetraphenylporphyrin fullerene complexes as potential dye sensitizers for solar cells

NASA Astrophysics Data System (ADS)

El Mahdy, A. M.; Halim, Shimaa Abdel; Taha, H. O.

2018-05-01

Density functional theory (DFT) and time-dependent DFT calculations have been employed to model metallotetraphenylporphyrin dyes and metallotetraphenylporphyrin -fullerene complexes in order to investigate the geometries, electronic structures, the density of states, non-linear optical properties (NLO), IR-vis spectra, molecular electrostatic potential contours, and electrophilicity. To calculate the excited states of the tetraphenyl porphyrin analogs, time-dependent density functional theory (TD-DFT) are used. Their UV-vis spectra were also obtained and a comparison with available experimental and theoretical results is included. The results reveal that the metal and the tertiary butyl groups of the dyes are electron donors, and the tetraphenylporphyrin rings are electron acceptors. The HOMOs of the dyes fall within the (TiO2)60 and Ti38O76 band gaps and support the issue of typical interfacial electron transfer reaction. The resulting potential drop of Mn-TPP-C60 increased by ca. 3.50% under the effect of the tertiary butyl groups. The increase in the potential drop indicates that the tertiary butyl complexes could be a better choice for the strong operation of the molecular rectifiers. The introduction of metal atom and tertiary butyl groups to the tetraphenyl porphyrin moiety leads to a stronger response to the external electric field and induces higher photo-to-current conversion efficiency. This also shifts the absorption in the dyes and makes them potential candidates for harvesting light in the entire visible and near IR region for photovoltaic applications.

Framework of Assessment for the Evaluation of Thinking Skills of Tertiary Level Students

ERIC Educational Resources Information Center

Heng, Chan Swee; Ziguang, Yan

2015-01-01

In the 21st century, students are required to master thinking skills in order to deal with many situations that arise in the tertiary environment which later would translate into the workplace. Nowadays, thinking skills play a vital role in tertiary education. To provide an approach for teachers, this paper identifies a 4-step model that can be…

Identification of kinetically hot residues in proteins.

PubMed Central

Demirel, M. C.; Atilgan, A. R.; Jernigan, R. L.; Erman, B.; Bahar, I.

1998-01-01

A number of recent studies called attention to the presence of kinetically important residues underlying the formation and stabilization of folding nuclei in proteins, and to the possible existence of a correlation between conserved residues and those participating in the folding nuclei. Here, we use the Gaussian network model (GNM), which recently proved useful in describing the dynamic characteristics of proteins for identifying the kinetically hot residues in folded structures. These are the residues involved in the highest frequency fluctuations near the native state coordinates. Their high frequency is a manifestation of the steepness of the energy landscape near their native state positions. The theory is applied to a series of proteins whose kinetically important residues have been extensively explored: chymotrypsin inhibitor 2, cytochrome c, and related C2 proteins. Most of the residues previously pointed out to underlie the folding process of these proteins, and to be critically important for the stabilization of the tertiary fold, are correctly identified, indicating a correlation between the kinetic hot spots and the early forming structural elements in proteins. Additionally, a strong correlation between kinetically hot residues and loci of conserved residues is observed. Finally, residues that may be important for the stability of the tertiary structure of CheY are proposed. PMID:9865946

Design of structurally distinct proteins using strategies inspired by evolution

DOE PAGES

Jacobs, T. M.; Williams, B.; Williams, T.; ...

2016-05-06

Natural recombination combines pieces of preexisting proteins to create new tertiary structures and functions. In this paper, we describe a computational protocol, called SEWING, which is inspired by this process and builds new proteins from connected or disconnected pieces of existing structures. Helical proteins designed with SEWING contain structural features absent from other de novo designed proteins and, in some cases, remain folded at more than 100°C. High-resolution structures of the designed proteins CA01 and DA05R1 were solved by x-ray crystallography (2.2 angstrom resolution) and nuclear magnetic resonance, respectively, and there was excellent agreement with the design models. Finally, thismore » method provides a new strategy to rapidly create large numbers of diverse and designable protein scaffolds.« less

Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action

PubMed Central

2014-01-01

A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled. PMID:25815138

Structure and evolution of the northern Oman margin: gravity and seismic constraints over the Zagros-Makran-Oman collision zone

NASA Astrophysics Data System (ADS)

Ravaut, P.; Bayer, R.; Hassani, R.; Rousset, D.; Yahya'ey, A. Al

1997-09-01

The obduction process in Oman during Late Cretaceous time, and continental-to-oceanic subduction along the Zagros-Makran region during the Tertiary are consequences of the Arabian-Eurasian collision, resulting in construction of complex structures composed of the Oman ophiolite belt, the Zagros continental mountain belt and the Makran subduction zone with its associated accretionary wedge. In this paper, we jointly interpret Bouguer anomaly and available petroleum seismic profiles in terms of crustal structures. We show that the gravity anomaly in northern Oman is characterized by a high-amplitude negative-positive couple. The negative anomaly is coincident with Late Cretaceous (Fiqa) and Tertiary (Pabdeh) foreland basins and with the Zagros-Oman mountain belts, whereas the positive anomaly is correlated to the ophiolite massifs. The Bouguer anomaly map indicates the presence of a post-Late Cretaceous sedimentary basin, the Sohar basin, centred north of the Batinah plain. We interpret the negative/positive couple in terms of loading of the elastic Arabian lithosphere. We estimate the different Cretaceous-to-Recent loads, including topography, ophiolite nappes, sedimentary fill and the accretionary prism of the Makran trench. A new method, using Mindlin's elastic plate theory, is proposed to model the 2D deflection of the heterogeneous elastic Arabian plate, taking into account boundary conditions at the ends of the subducted plate. We show that remnant ophiolites are isolated from Tethyan oceanic lithosphere in the Gulf of Oman by a continental basement ridge, a NW prolongation of the Saih-Hatat window. Loading the northward-limited ophiolite blocks explains the deflection of the Fiqa foredeep basin. West of the Musandam Peninsula, the Tertiary Pabdeh foredeep is probably related to the emplacement of a 8-km-thick tectonic prism located on the Musandam Peninsula and in the Strait of Hormuz. Final 2D density models along profiles through the Oman mountain belt and the Gulf of Oman are discussed in the framework of Late Cretaceous obduction of the Tethys and synchronous subduction and exhumation of the Oman margin.

The structure of the Zechstein 3 stringer in the northern Netherlands, and its implications for salt kinematics and rheology

NASA Astrophysics Data System (ADS)

Strozyk, Frank; Urai, Janos; Li, Shiyuan; Schmatz, Joyce; Biehl, Bianca; Reuning, Lars; Raith, Alexander; Abe, Steffen; van Gent, Heijn; de Keijzer, Martin; Kukla, Peter

2016-04-01

The thick, late Permian Zechstein evaporites in the northern Netherlands are exceptionally well imaged in extensive 3D seismic and well datasets. The prominent seismic reflections of the thick, anhydrite-rich Zechstein 3 stringer, which is encased in thick layers of rock salt, provide a basin-scale view of the 3D internal structure of the Zechstein salt. The interpretation of the Z3 stringer was used as a strain marker for the different intra-salt deformation styles and salt flows. Furthermore, models of competing rheologies (pressure solution vs. dislocation creep, Newtonian vs. Power law) were tested in numerical simulations of the gravitational sinking of Z3 stringer fragments through the salt over geologic time in the Tertiary. The results show that several structural stringer styles can be linked to regional variation in salt kinematics. These mainly comprise local early syn-depositional gravitational movement, passive salt diapirism by differential loading in the Triassic, and reactive diapirism during contractions starting in the Cretaceous. The thickness and deformation degree of the individual salt layers thereby played a major role in the development of regionally distinctive styles of intra-salt structures, which can be linked to breaking and fold patterns in the stringer. When differential stresses in the salt relaxed across large parts of the northern Netherlands in the Tertiary, stringer fragments physically isolated in the salt did not significantly sink through the salt. The salt surrounding the fragments can not have deformed by Newtonian solution-precipitation creep, because the fragments would have sunk to base salt. Considering also results from geomechanical modelling and analysis of Zechstein salt samples, we conclude that this behaviour can only be explained by strong changes in salt rheology to non-Newtonian.

Curriculum Development in Outdoor Education: Tasmanian Teachers' Perspectives on the New Pre-Tertiary Outdoor Leadership Course

ERIC Educational Resources Information Center

Dyment, Janet; Morse, Marcus; Shaw, Simon; Smith, Heidi

2014-01-01

The paper examines how outdoor education teachers in Tasmania, Australia have implemented and perceive a new pre-tertiary Outdoor Leadership curriculum document. It draws on an analysis of in-depth semi-structured interviews with 11 outdoor education teachers. The results revealed that teachers were generally welcoming of the new higher-order…

Asian Students' Perceptions of Group Work and Group Assignments in a New Zealand Tertiary Institution

ERIC Educational Resources Information Center

Li, Mingsheng; Campbell, Jacqui

2008-01-01

This study, conducted in 2005 in a New Zealand tertiary institution, examines Asian students' perceptions of the much-promulgated cooperative learning concepts in the form of group work and group assignments. Twenty-two Asian students participated in one-hour individual face-to-face semi-structured interviews. The study found that Asian students…

Structure of the Tucson Basin, Arizona from gravity and aeromagnetic data

USGS Publications Warehouse

Rystrom, Victoria Louise

2003-01-01

Interpretation of gravity and high-resolution aeromagnetic data reveal the three-dimensional geometry of the Tuscson Basin, Arizona and the lithology of its basement. Limited drill hole and seismic data indicate that the maximum depth to the crystalline basement is approximately 3600 meters and that the sedimentary sequences in the upper ~2000 m of the basin were deposited during the most recent extensional episode that commenced about 13 Ma. The negative density contrasts between these upper Neogene and Quaternary sedimentary sequences and the adjacent country rock produce a Bouguer residual gravity low, whose steep gradients clearly define the lateral extent of the upper ~2000m of the basin. The aeromagnetic maps show large positive anomalies associated with deeply buried, late Cretaceous-early Tertiary and mid-Tertiary igneous rocks at and below the surface of the basin. These magnetic anomalies provide insight into the older (>13 Ma) and deeper structures of the basin. Simultaneous 2.5-dimensional modeling of both gravity and magnetic anomalies constrained by geologic and seismic data delineates the thickness of the basin and the dips of the buried faults that bound the basin. This geologic-based forward modeling approach to using geophysical data is shown to result in more information about the geologic and tectonic history of the basin as well as more accurate depth to basement determinations than using generalized geophysical inversion techniques.

A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

PubMed

Jiang, Bowen; Yu, Hua; Zhang, Yongrong; Feng, Hanping; Hoag, Stephen W

2017-12-01

There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn's Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads. In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT® FS 30 D to develop a colonic delivery system. The secondary and tertiary structure change and aggregation of BSA during spray layering process was examined. The BSA layered beads were then challenged in an accelerated stability study using International Council for Harmonization (ICH) conditions. The in vitro release of BSA from enteric coated beads was examined using United States Pharmacopeia (USP) dissolution apparatus 1. No significant changes in the secondary and tertiary structure or aggregation profile of BSA were observed after the spray layering process. Degradation of BSA to different extents was detected after storing at 25°C and 40°C for 38 days. Enteric coated BSA beads were intact in acidic media while released BSA in pH 7.4 phosphate buffer. We showed the feasibility of delivering proteins to colon in vitro using multiparticulate system.

Role of extensional structures on the location of folds and thrusts during tectonic inversion (northern Iberian Chain, Spain)

NASA Astrophysics Data System (ADS)

Cortés, Angel L.; Liesa, Carlos L.; Soria, Ana R.; Meléndez, Alfonso

1999-03-01

The Aguilón Subbasin (NE Spain) was originated daring the Late Jurassic-Early Cretaceous rifting due to the action of large normal faults, probably inherited from Late Variscan fracturing. WNW-ESE normal faults limit two major troughs filled by continental deposits (Valanginian to Early Barremian). NE-SW faults control the location of subsidiary depocenters within these troughs. These basins were weakly inverted during the Tertiary with folds and thrusts striking E-W to WNW-ESE involving the Mesozoic-Tertiary cover with a maximum estimated shortening of about 12 %. Tertiary compression did not produce the total inversion of the Mesozoic basin but extensional structures are responsible for the location of major Tertiary folds. Shortening of the cover during the Tertiary involved both reactivation of some normal faults and development of folds and thrusts nucleated on basement extensional steps. The inversion style depends mainly on the occurrence and geometry of normal faults limiting the basin. Steep normal faults were not reactivated but acted as buttresses to the cover translation. Around these faults, affecting both basement and cover, folds and thrusts were nucleated due to the stress rise in front of major faults. Within the cover, the buttressing against normal faults consists of folding and faulting implying little shortening without development of ceavage or other evidence of internal deformation.

Spatio-temporal observations of tertiary ozone maximum

NASA Astrophysics Data System (ADS)

Sofieva, V. F.; Kyrölä, E.; Verronen, P. T.; Seppälä, A.; Tamminen, J.; Marsh, D. R.; Smith, A. K.; Bertaux, J.-L.; Hauchecorne, A.; Dalaudier, F.; Fussen, D.; Vanhellemont, F.; Fanton D'Andon, O.; Barrot, G.; Guirlet, M.; Fehr, T.; Saavedra, L.

2009-03-01

We present spatio-temporal distributions of tertiary ozone maximum (TOM), based on GOMOS (Global Ozone Monitoring by Occultation of Stars) ozone measurements in 2002-2006. The tertiary ozone maximum is typically observed in the high-latitude winter mesosphere at altitude ~72 km. Although the explanation for this phenomenon has been found recently - low concentrations of odd-hydrogen cause the subsequent decrease in odd-oxygen losses - models have had significant deviations from existing observations until recently. Good coverage of polar night regions by GOMOS data has allowed for the first time obtaining spatial and temporal observational distributions of night-time ozone mixing ratio in the mesosphere. The distributions obtained from GOMOS data have specific features, which are variable from year to year. In particular, due to a long lifetime of ozone in polar night conditions, the downward transport of polar air by the meridional circulation is clearly observed in the tertiary ozone maximum time series. Although the maximum tertiary ozone mixing ratio is achieved close to the polar night terminator (as predicted by the theory), TOM can be observed also at very high latitudes, not only in the beginning and at the end, but also in the middle of winter. We have compared the observational spatio-temporal distributions of tertiary ozone maximum with that obtained using WACCM (Whole Atmosphere Community Climate Model) and found that the specific features are reproduced satisfactorily by the model. Since ozone in the mesosphere is very sensitive to HOx concentrations, energetic particle precipitation can significantly modify the shape of the ozone profiles. In particular, GOMOS observations have shown that the tertiary ozone maximum was temporarily destroyed during the January 2005 and December 2006 solar proton events as a result of the HOx enhancement from the increased ionization.

Spatio-temporal observations of the tertiary ozone maximum

NASA Astrophysics Data System (ADS)

Sofieva, V. F.; Kyrölä, E.; Verronen, P. T.; Seppälä, A.; Tamminen, J.; Marsh, D. R.; Smith, A. K.; Bertaux, J.-L.; Hauchecorne, A.; Dalaudier, F.; Fussen, D.; Vanhellemont, F.; Fanton D'Andon, O.; Barrot, G.; Guirlet, M.; Fehr, T.; Saavedra, L.

2009-07-01

We present spatio-temporal distributions of the tertiary ozone maximum (TOM), based on GOMOS (Global Ozone Monitoring by Occultation of Stars) ozone measurements in 2002-2006. The tertiary ozone maximum is typically observed in the high-latitude winter mesosphere at an altitude of ~72 km. Although the explanation for this phenomenon has been found recently - low concentrations of odd-hydrogen cause the subsequent decrease in odd-oxygen losses - models have had significant deviations from existing observations until recently. Good coverage of polar night regions by GOMOS data has allowed for the first time to obtain spatial and temporal observational distributions of night-time ozone mixing ratio in the mesosphere. The distributions obtained from GOMOS data have specific features, which are variable from year to year. In particular, due to a long lifetime of ozone in polar night conditions, the downward transport of polar air by the meridional circulation is clearly observed in the tertiary ozone maximum time series. Although the maximum tertiary ozone mixing ratio is achieved close to the polar night terminator (as predicted by the theory), TOM can be observed also at very high latitudes, not only in the beginning and at the end, but also in the middle of winter. We have compared the observational spatio-temporal distributions of the tertiary ozone maximum with that obtained using WACCM (Whole Atmosphere Community Climate Model) and found that the specific features are reproduced satisfactorily by the model. Since ozone in the mesosphere is very sensitive to HOx concentrations, energetic particle precipitation can significantly modify the shape of the ozone profiles. In particular, GOMOS observations have shown that the tertiary ozone maximum was temporarily destroyed during the January 2005 and December 2006 solar proton events as a result of the HOx enhancement from the increased ionization.

Incorporating modeling and simulations in undergraduate biophysical chemistry course to promote understanding of structure-dynamics-function relationships in proteins.

PubMed

Hati, Sanchita; Bhattacharyya, Sudeep

2016-01-01

A project-based biophysical chemistry laboratory course, which is offered to the biochemistry and molecular biology majors in their senior year, is described. In this course, the classroom study of the structure-function of biomolecules is integrated with the discovery-guided laboratory study of these molecules using computer modeling and simulations. In particular, modern computational tools are employed to elucidate the relationship between structure, dynamics, and function in proteins. Computer-based laboratory protocols that we introduced in three modules allow students to visualize the secondary, super-secondary, and tertiary structures of proteins, analyze non-covalent interactions in protein-ligand complexes, develop three-dimensional structural models (homology model) for new protein sequences and evaluate their structural qualities, and study proteins' intrinsic dynamics to understand their functions. In the fourth module, students are assigned to an authentic research problem, where they apply their laboratory skills (acquired in modules 1-3) to answer conceptual biophysical questions. Through this process, students gain in-depth understanding of protein dynamics-the missing link between structure and function. Additionally, the requirement of term papers sharpens students' writing and communication skills. Finally, these projects result in new findings that are communicated in peer-reviewed journals. © 2016 The International Union of Biochemistry and Molecular Biology.

The Spread of Higher Education around the Globe: A Cross- Country Analysis of Gross Tertiary Education Enrollment, 1999-2005

ERIC Educational Resources Information Center

Yu, Patricia; Delaney, Jennifer A.

2016-01-01

Many nation-states have realized the importance of tertiary education and the world has seen a corollary increase in tertiary education enrollments. Using Berry and Berry's event history model as a framework, this study tests both the internal features of each country and the influence that nation-states have on each other with regard to setting…

MEASUREMENT OF EXHALED BREATH AND VENOUS BLOOD TO DEVELOP A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURE TO METHYL TERTIARY-BUTYL ETHER AND THE PRODUCTION OF THE BIOMARKER TERTIARY-BUTYL ALCOHOL

EPA Science Inventory

Methyl tertiary-butyl ether (MTBE) is a common fuel additive used to increase the availability of oxygen in gasoline to reduce winter-time carbon monoxide emissions from automobiles. Also, MTBE boosts gasoline "octane" rating and, as such, allows reduction of benzene...

The Cretaceous/Tertiary Extinction Controversy Reconsidered.

ERIC Educational Resources Information Center

McCartney, Kevin; Nienstedt, Jeffrey

1986-01-01

Reviews varying positions taken in the Cretaceous/Tertiary (K/Y) extinction controversy. Analyzes and contests the meteoritic impact theory known as the Alvarez Model. Presents an alternative working hypothesis explaining the K/T transition. (ML)

Structural controls on Carlin-type gold mineralization in the gold bar district, Eureka County, Nevada

USGS Publications Warehouse

Yigit, O.; Nelson, E.P.; Hitzman, M.W.; Hofstra, A.H.

2003-01-01

The Gold Bar district in the southern Roberts Mountains, 48 km northwest of Eureka, Nevada, contains one main deposit (Gold Bar), five satellite deposits, and other resources. Approximately 0.5 Moz of gold have been recovered from a resource of 1,639,000 oz of gold in Carlin-type gold deposits in lower plate, miogeoclinal carbonate rocks below the Roberts Mountains thrust. Host rocks are unit 2 of the Upper Member of the Devonian Denay Formation and the Bartine Member of the McColley Canyon Formation. Spatial and temporal relations between structures and gold mineralization indicate that both pre-Tertiary and Tertiary structures were important controls on gold mineralization. Gold mineralization occurs primarily along high-angle Tertiary normal faults, some of which are reactivated reverse faults of Paleozoic or Mesozoic age. Most deposits are localized at the intersection of northwest- and northeast-striking faults. Alteration includes decalcification, and to a lesser extent, silicification along high-angle faults. Jasperoid (pervasive silicification), which formed along most faults and in some strata-bound zones, accounts for a small portion of the ore in every deposit. In the Gold Canyon deposit, a high-grade jasperoid pipe formed along a Tertiary normal fault which was localized along a zone of overturned fault-propagation folds and thrust faults of Paleozoic or Mesozoic age.

Geology and tectonic development of the continental margin north of Alaska

USGS Publications Warehouse

Grantz, A.; Eittreim, S.; Dinter, D.A.

1979-01-01

The continental margin north of Alaska, as interpreted from seismic reflection profiles, is of the Atlantic type and consists of three sectors of contrasting structure and stratigraphy. The Chukchi sector, on the west, is characterized by the deep late Mesozoic and Tertiary North Chukchi basin and the Chukchi Continental Borderland. The Barrow sector of central northern Alaska is characterized by the Barrow arch and a moderately thick continental terrace build of Albian to Tertiary clastic sediment. The terrace sedimentary prism is underlain by lower Paleozoic metasedimentary rocks. The Barter Island sector of northeastern Alaska and Yukon Territory is inferred to contain a very thick prism of Jurassic, Cretaceous and Tertiary marine and nonmarine clastic sediment. Its structure is dominated by a local deep Tertiary depocenter and two regional structural arches. We postulate that the distinguishing characteristics of the three sectors are inherited from the configuration of the rift that separated arctic Alaska from the Canadian Arctic Archipelago relative to old pre-rift highlands, which were clastic sediment sources. Where the rift lay relatively close to northern Alaska, in the Chukchi and Barter Island sectors, and locally separated Alaska from the old source terranes, thick late Mesozoic and Tertiary sedimentary prisms extend farther south beneath the continental shelf than in the intervening Barrow sector. The boundary between the Chukchi and Barrow sectors is relatively well defined by geophysical data, but the boundary between the Barrow and Barter Island sectors can only be inferred from the distribution and thickness of Jurassic and Cretaceous sedimentary rocks. These boundaries may be extensions of oceanic fracture zones related to the rifting that is postulated to have opened the Canada Basin, probably beginning during the Early Jurassic. ?? 1979.

Coevolutionary modeling of protein sequences: Predicting structure, function, and mutational landscapes

NASA Astrophysics Data System (ADS)

Weigt, Martin

Over the last years, biological research has been revolutionized by experimental high-throughput techniques, in particular by next-generation sequencing technology. Unprecedented amounts of data are accumulating, and there is a growing request for computational methods unveiling the information hidden in raw data, thereby increasing our understanding of complex biological systems. Statistical-physics models based on the maximum-entropy principle have, in the last few years, played an important role in this context. To give a specific example, proteins and many non-coding RNA show a remarkable degree of structural and functional conservation in the course of evolution, despite a large variability in amino acid sequences. We have developed a statistical-mechanics inspired inference approach - called Direct-Coupling Analysis - to link this sequence variability (easy to observe in sequence alignments, which are available in public sequence databases) to bio-molecular structure and function. In my presentation I will show, how this methodology can be used (i) to infer contacts between residues and thus to guide tertiary and quaternary protein structure prediction and RNA structure prediction, (ii) to discriminate interacting from non-interacting protein families, and thus to infer conserved protein-protein interaction networks, and (iii) to reconstruct mutational landscapes and thus to predict the phenotypic effect of mutations. References [1] M. Figliuzzi, H. Jacquier, A. Schug, O. Tenaillon and M. Weigt ''Coevolutionary landscape inference and the context-dependence of mutations in beta-lactamase TEM-1'', Mol. Biol. Evol. (2015), doi: 10.1093/molbev/msv211 [2] E. De Leonardis, B. Lutz, S. Ratz, S. Cocco, R. Monasson, A. Schug, M. Weigt ''Direct-Coupling Analysis of nucleotide coevolution facilitates RNA secondary and tertiary structure prediction'', Nucleic Acids Research (2015), doi: 10.1093/nar/gkv932 [3] F. Morcos, A. Pagnani, B. Lunt, A. Bertolino, D. Marks, C. Sander, R. Zecchina, J.N. Onuchic, T. Hwa, M. Weigt, ''Direct-coupling analysis of residue co-evolution captures native contacts across many protein families'', Proc. Natl. Acad. Sci. 108, E1293-E1301 (2011).

Modeling disordered protein interactions from biophysical principles

PubMed Central

Christoffer, Charles; Terashi, Genki

2017-01-01

Disordered protein-protein interactions (PPIs), those involving a folded protein and an intrinsically disordered protein (IDP), are prevalent in the cell, including important signaling and regulatory pathways. IDPs do not adopt a single dominant structure in isolation but often become ordered upon binding. To aid understanding of the molecular mechanisms of disordered PPIs, it is crucial to obtain the tertiary structure of the PPIs. However, experimental methods have difficulty in solving disordered PPIs and existing protein-protein and protein-peptide docking methods are not able to model them. Here we present a novel computational method, IDP-LZerD, which models the conformation of a disordered PPI by considering the biophysical binding mechanism of an IDP to a structured protein, whereby a local segment of the IDP initiates the interaction and subsequently the remaining IDP regions explore and coalesce around the initial binding site. On a dataset of 22 disordered PPIs with IDPs up to 69 amino acids, successful predictions were made for 21 bound and 18 unbound receptors. The successful modeling provides additional support for biophysical principles. Moreover, the new technique significantly expands the capability of protein structure modeling and provides crucial insights into the molecular mechanisms of disordered PPIs. PMID:28394890

Evaporite geometries and diagenetic traps, lower San Andres, Northwest shelf, New Mexico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keller, D.R.

An east-west-trending belt of lower San Andres oil fields extends 80 mi across southeastern New Mexico from the Pecos River near Roswell to the Texas-New Mexico border. These fields are along a porosity pinch-out zone where porous carbonates grade laterally into bedded anhydrite and halite. The lower San Andres traps are associated with pre-Tertiary structural or stratigraphic traps. Oil and water production relationships from these fields are not consistent with present-day structure. These fields have been commonly interpreted to be hydrodynamic traps created by the eastern flow of fresh surface water that enters the lower San Andres outcrops west ofmore » Pecos River. There is no evidence, however, that surface water has moved through the lower San Andres in this area. This conclusion is supported by the fact that formation-water resistivities are uniform throughout the producing trend, no significant dissolution of carbonates or evaporites has occurred, and there has been no increase in biogradation of oils adjacent to the lower San Andres outcrops. These fields actually are diagenetic traps created by porosity occlusion in the water column beneath the oil accumulations. Hydrocarbons originally were trapped in pre-Tertiary structural and structural-stratigraphic traps. Bedded evaporites were effective barriers to vertical and lateral hydrocarbon migration. Eastward tilting of the Northwest shelf during the Tertiary opened these traps, but the oil remained in these structurally unfavorable positions because of the diagenetic sealing. The gas-solution drive in these reservoirs is a result of this sealing. The sequence of events leading to diagenetic entrapment include (1) Triassic and Jurassic migration of hydrocarbons into broad, low-relief post-San Andres structural and structural-stratigraphic traps; (2) rapid occlusion of porosity in the water column beneath oil reservoirs, and (3) Tertiary tilt-out traps.« less

Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino

2010-08-12

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

Discovery of tertiary sulfonamides as potent liver X receptor antagonists.

PubMed

Zuercher, William J; Buckholz, Richard G; Campobasso, Nino; Collins, Jon L; Galardi, Cristin M; Gampe, Robert T; Hyatt, Stephen M; Merrihew, Susan L; Moore, John T; Oplinger, Jeffrey A; Reid, Paul R; Spearing, Paul K; Stanley, Thomas B; Stewart, Eugene L; Willson, Timothy M

2010-04-22

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

Tertiary alphabet for the observable protein structural universe.

PubMed

Mackenzie, Craig O; Zhou, Jianfu; Grigoryan, Gevorg

2016-11-22

Here, we systematically decompose the known protein structural universe into its basic elements, which we dub tertiary structural motifs (TERMs). A TERM is a compact backbone fragment that captures the secondary, tertiary, and quaternary environments around a given residue, comprising one or more disjoint segments (three on average). We seek the set of universal TERMs that capture all structure in the Protein Data Bank (PDB), finding remarkable degeneracy. Only ∼600 TERMs are sufficient to describe 50% of the PDB at sub-Angstrom resolution. However, more rare geometries also exist, and the overall structural coverage grows logarithmically with the number of TERMs. We go on to show that universal TERMs provide an effective mapping between sequence and structure. We demonstrate that TERM-based statistics alone are sufficient to recapitulate close-to-native sequences given either NMR or X-ray backbones. Furthermore, sequence variability predicted from TERM data agrees closely with evolutionary variation. Finally, locations of TERMs in protein chains can be predicted from sequence alone based on sequence signatures emergent from TERM instances in the PDB. For multisegment motifs, this method identifies spatially adjacent fragments that are not contiguous in sequence-a major bottleneck in structure prediction. Although all TERMs recur in diverse proteins, some appear specialized for certain functions, such as interface formation, metal coordination, or even water binding. Structural biology has benefited greatly from previously observed degeneracies in structure. The decomposition of the known structural universe into a finite set of compact TERMs offers exciting opportunities toward better understanding, design, and prediction of protein structure.

Tertiary alphabet for the observable protein structural universe

PubMed Central

Mackenzie, Craig O.; Zhou, Jianfu; Grigoryan, Gevorg

2016-01-01

Here, we systematically decompose the known protein structural universe into its basic elements, which we dub tertiary structural motifs (TERMs). A TERM is a compact backbone fragment that captures the secondary, tertiary, and quaternary environments around a given residue, comprising one or more disjoint segments (three on average). We seek the set of universal TERMs that capture all structure in the Protein Data Bank (PDB), finding remarkable degeneracy. Only ∼600 TERMs are sufficient to describe 50% of the PDB at sub-Angstrom resolution. However, more rare geometries also exist, and the overall structural coverage grows logarithmically with the number of TERMs. We go on to show that universal TERMs provide an effective mapping between sequence and structure. We demonstrate that TERM-based statistics alone are sufficient to recapitulate close-to-native sequences given either NMR or X-ray backbones. Furthermore, sequence variability predicted from TERM data agrees closely with evolutionary variation. Finally, locations of TERMs in protein chains can be predicted from sequence alone based on sequence signatures emergent from TERM instances in the PDB. For multisegment motifs, this method identifies spatially adjacent fragments that are not contiguous in sequence—a major bottleneck in structure prediction. Although all TERMs recur in diverse proteins, some appear specialized for certain functions, such as interface formation, metal coordination, or even water binding. Structural biology has benefited greatly from previously observed degeneracies in structure. The decomposition of the known structural universe into a finite set of compact TERMs offers exciting opportunities toward better understanding, design, and prediction of protein structure. PMID:27810958

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds.

PubMed

Mak, Chi H; Phan, Ethan N H

2018-05-08

Functional RNAs can fold into intricate structures using a number of different secondary and tertiary structural motifs. Many factors contribute to the overall free energy of the target fold. This study aims at quantifying the entropic costs coming from the loss of conformational freedom when the sugar-phosphate backbone is subjected to constraints imposed by secondary and tertiary contacts. Motivated by insights from topology theory, we design a diagrammatic scheme to represent different types of RNA structures so that constraints associated with a folded structure may be segregated into mutually independent subsets, enabling the total conformational entropy loss to be easily calculated as a sum of independent terms. We used high-throughput Monte Carlo simulations to simulate large ensembles of single-stranded RNA sequences in solution to validate the assumptions behind our diagrammatic scheme, examining the entropic costs for hairpin initiation and formation of many multiway junctions. Our diagrammatic scheme aids in the factorization of secondary/tertiary constraints into distinct topological classes and facilitates the discovery of interrelationships among multiple constraints on RNA folds. This perspective, which to our knowledge is novel, leads to useful insights into the inner workings of some functional RNA sequences, demonstrating how they might operate by transforming their structures among different topological classes. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Alteration of human serum albumin tertiary structure induced by glycation. Spectroscopic study

NASA Astrophysics Data System (ADS)

Szkudlarek, A.; Maciążek-Jurczyk, M.; Chudzik, M.; Równicka-Zubik, J.; Sułkowska, A.

2016-01-01

The modification of human serum albumin (HSA) structure by non-enzymatic glycation is one of the underlying factors that contribute to the development of complications of diabetes and neurodegenerative diseases. The aim of the present work was to estimate how glycation of HSA altered its tertiary structure. Changes of albumin conformation were investigated by comparison of glycated (gHSA) and non-glycated human serum albumin (HSA) absorption spectra, red edge excitation shift (REES) and synchronous spectra. Effect of glycation on human serum albumin tertiary structure was also investigated by 1H NMR spectroscopy. Formation of gHSA Advanced Glycation End-products (AGEs) caused absorption of UV-VIS light between 310 nm and 400 nm while for non-glycated HSA in this region no absorbance has been registered. Analysis of red edge excitation shift effect allowed for observation of structural changes of gHSA in the hydrophobic pocket containing the tryptophanyl residue. Moreover changes in the microenvironment of tryptophanyl and tyrosyl residues brought about AGEs on the basis of synchronous fluorescence spectroscopy have been confirmed. The influence of glycation process on serum albumin binding to 5-dimethylaminonaphthalene-1-sulfonamide (DNSA), 2-(p-toluidino) naphthalene-6-sulfonic acid (TNS), has been studied. Fluorescence analysis showed that environment of both binding site I and II is modified by galactose glycation.

Maori in Partnership: A Peer Mentoring Model for Tertiary Indigenous Staff in New Zealand

ERIC Educational Resources Information Center

Kensington-Miller, Barbara; Ratima, Matiu

2015-01-01

This article presents a professional development programme which brought an indigenous minority group of tertiary staff together. We describe a peer-mentoring model, piloted in 2009 at The University of Auckland, New Zealand with university staff in order to promote staff advancement. The participants were all Maori, the indigenous people of New…

Recognition of coarse-grained protein tertiary structure.

PubMed

Lezon, Timothy; Banavar, Jayanth R; Maritan, Amos

2004-05-15

A model of the protein backbone is considered in which each residue is characterized by the location of its C(alpha) atom and one of a discrete set of conformal (phi, psi) states. We investigate the key differences between a description that offers a locally precise fit to known backbone structures and one that provides a globally accurate fit to protein structures. Using a statistical scoring scheme and threading, a protein's local best-fit conformation is highly recognizable, but its global structure cannot be directly determined from an amino acid sequence. The incorporation of information about the conformal states of neighboring residues along the chain allows one to accurately translate the local structure into a global structure. We present a two-step algorithm, which recognizes up to 95% of the tested protein native-state structures to within a 2.5 A root mean square deviation. Copyright 2004 Wiley-Liss, Inc.

The Relevance of English Language Instruction in a Changing Linguistic Environment in Iceland: The L2 Self of Young Icelanders

ERIC Educational Resources Information Center

Jeeves, Anna

2014-01-01

In this study perceptions of post-compulsory school studies in Iceland were investigated through semi-structured interviews. While colloquial English suffices for entertainment, hobbies and Internet use in Iceland, a high level of proficiency is required for employment and tertiary study. School learners and young people in tertiary study and…

Geology of drill hole UE25p No. 1: A test hole into pre-Tertiary rocks near Yucca Mountain, southern Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carr, M.D.; Waddell, S.J.; Vick, G.S.

1986-12-31

Yucca Mountain in southern Nye County, Nevada, has been proposed as a potential site for the underground disposal of high-level nuclear waste. An exploratory drill hole designated UE25p No. 1 was drilled 3 km east of the proposed repository site to investigate the geology and hydrology of the rocks that underlie the Tertiary volcanic and sedimentary rock sequence forming Yucca Mountain. Silurian dolomite assigned to the Roberts Mountain and Lone Mountain Formations was intersected below the Tertiary section between a depth of approximately 1244 m (4080 ft) and the bottom of the drill hole at 1807 m (5923 ft). Thesemore » formations are part of an important regional carbonate aquifer in the deep ground-water system. Tertiary units deeper than 1139 m (3733 ft) in drill hole UE25p No. 1 are stratigraphically older than any units previously penetrated by drill holes at Yucca Mountain. These units are, in ascending order, the tuff of Yucca Flat, an unnamed calcified ash-flow tuff, and a sequence of clastic deposits. The upper part of the Tertiary sequence in drill hole UE25p No. 1 is similar to that found in other drill holes at Yucca Mountain. The Tertiary sequence is in fault contact with the Silurian rocks. This fault between Tertiary and Paleozoic rocks may correlate with the Fran Ridge fault, a steeply westward-dipping fault exposed approximately 0.5 km east of the drill hole. Another fault intersects UE25p No. 1 at 873 m (2863 ft), but its surface trace is concealed beneath the valley west of the Fran Ridge fault. The Paintbrush Canyon fault, the trace of which passes less than 100 m (330 ft) east of the drilling site, intersects drill hole UE25p No. 1 at a depth of approximately 78 m (255 ft). The drill hole apparently intersected the west flank of a structural high of pre-Tertiary rocks, near the eastern edge of the Crater Flat structural depression.« less

Stratigraphy and structure of coalbed methane reservoirs in the United States: an overview

USGS Publications Warehouse

Pashin, J.C.

1998-01-01

Stratigraphy and geologic structure determine the shape, continuity and permeability of coal and are therefore critical considerations for designing exploration and production strategies for coalbed methane. Coal in the United states is dominantly of Pennsylvanian, Cretaceous and Tertiary age, and to date, more than 90% of the coalbed methane produced is from Pennsylvanian and cretaceous strata of the Black Warrior and San Juan Basins. Investigations of these basins establish that sequence stratigraphy is a promising approach for regional characterization of coalbed methane reservoirs. Local stratigraphic variation within these strata is the product of sedimentologic and tectonic processes and is a consideration for selecting completion zones. Coalbed methane production in the United States is mainly from foreland and intermontane basins containing diverse compression and extensional structures. Balanced structural models can be used to construct and validate cross sections as well as to quantify layer-parallel strain and predict the distribution of fractures. Folds and faults influence gas and water production in diverse ways. However, interwell heterogeneity related to fractures and shear structures makes the performance of individual wells difficult to predict.Stratigraphy and geologic structure determine the shape, continuity and permeability of coal and are therefore critical considerations for designing exploration and production strategies for coalbed methane. Coal in the United States is dominantly of Pennsylvanian, Cretaceous and Tertiary age, and to date, more than 90% of the coalbed methane produced is from Pennsylvanian and Cretaceous strata of the Black Warrior and San Juan Basins. Investigations of these basins establish that sequence stratigraphy is a promising approach for regional characterization of coalbed methane reservoirs. Local stratigraphic variation within these strata is the product of sedimentologic and tectonic processes and is a consideration for selecting completion zones. Coalbed methane production in the United States is mainly from foreland and intermontane basins containing diverse compressional and extensional structures. Balanced structural models can be used to construct and validate cross sections as well as to quantify layer-parallel strain and predict the distribution of fractures. Folds and faults influence gas and water production in diverse ways. However, interwell heterogeneity related to fractures and shear structures makes the performance of individual wells difficult to predict.

Protein sectors: evolutionary units of three-dimensional structure

PubMed Central

Halabi, Najeeb; Rivoire, Olivier; Leibler, Stanislas; Ranganathan, Rama

2011-01-01

Proteins display a hierarchy of structural features at primary, secondary, tertiary, and higher-order levels, an organization that guides our current understanding of their biological properties and evolutionary origins. Here, we reveal a structural organization distinct from this traditional hierarchy by statistical analysis of correlated evolution between amino acids. Applied to the S1A serine proteases, the analysis indicates a decomposition of the protein into three quasi-independent groups of correlated amino acids that we term “protein sectors”. Each sector is physically connected in the tertiary structure, has a distinct functional role, and constitutes an independent mode of sequence divergence in the protein family. Functionally relevant sectors are evident in other protein families as well, suggesting that they may be general features of proteins. We propose that sectors represent a structural organization of proteins that reflects their evolutionary histories. PMID:19703402

A tertiary care-primary care partnership model for medically complex and fragile children and youth with special health care needs.

PubMed

Gordon, John B; Colby, Holly H; Bartelt, Tera; Jablonski, Debra; Krauthoefer, Mary L; Havens, Peter

2007-10-01

To evaluate the impact of a tertiary care center special needs program that partners with families and primary care physicians to ensure seamless inpatient and outpatient care and assist in providing medical homes. Up to 3 years of preenrollment and postenrollment data were compared for patients in the special needs program from July 1, 2002, through June 30, 2005. A tertiary care center pediatric hospital and medical school serving urban and rural patients. A total of 227 of 230 medically complex and fragile children and youth with special needs who had a wide range of chronic disorders and were enrolled in the special needs program. Care coordination provided by a special needs program pediatric nurse case manager with or without a special needs program physician. Preenrollment and postenrollment tertiary care center resource utilization, charges, and payments. A statistically significant decrease was found in the number of hospitalizations, number of hospital days, and tertiary care center charges and payments, and an increase was found in the use of outpatient services. Aggregate data revealed a decrease in hospital days from 7926 to 3831, an increase in clinic visits from 3150 to 5420, and a decrease in tertiary care center payments of $10.7 million. The special needs program budget for fiscal year 2005 had a deficit of $400,000. This tertiary care-primary care partnership model improved health care and reduced costs with relatively modest institutional support.

Integrated use of remotely sensed imagery and other data sets to infer the tectonics, structural style, and hydrocarbon habitats of the basins of the Tien Shan orogenic belt, Western China: A case study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berry, J.L.; Nishidai, T.

1996-08-01

Remotely sensed imagery and various other published regional data sets (gravity, magnetics, earthquake data) were integrated in order to interpret the structural style, both at deep crustal levels and at the relatively shallow levels of interest to explorationists, of the Tien Shan. Cross-sections through the range were systematically prepared, and then palinspastically restored, constrained by the remote sensing interpretation, potential fields data, and published microplate movement vectors. Since large portions of the area are covered by late Tertiary orogenic sediments, the resulting interpretation focused on these areas, and what and how much geology lies concealed beneath them. We were ablemore » to demonstrate the likely consumption in the late Tertiary of over 100 km of Tarim Basin west along a broad front south of the Tien Shan, as well as within the Kuruktag area, where basins are compressional rather than extensional. There are also local areas of extension within the orogenic zone, and these can be explained using the known microplate boundaries, backward extrapolation of present microplate motions, and the type and extent of late Tertiary deformation within the plates as constraints. Relative and absolute microplate motions have to change greatly through Tertiary time in order to comply with these constraints. The results of this work allow one to infer the affinities, and hence something of the hydrocarbon potential, of fragmentary plates by reconstructing their motions. They also allow one to infer the nature of the stratigraphy, the likely depth of burial, and something of the maturation history of pre-Tertiary rocks buried by Tertiary sediments deposited in both compressional and extensional regimes.« less

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.

PubMed

Sugumar, Ramya; Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-03-01

Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87. Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies.

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools

PubMed Central

Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-01-01

Introduction Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. Aim To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. Materials and Methods The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski’s Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Results Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87. Conclusion Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies. PMID:27134887

Brittle extension of the continental crust along a rooted system of low-angle normal faults: Colorado River extensional corridor

NASA Technical Reports Server (NTRS)

John, B. E.; Howard, K. A.

1985-01-01

A transect across the 100 km wide Colorado River extensional corridor of mid-Tertiary age shows that the upper 10 to 15 km of crystalline crust extended along an imbricate system of brittle low-angle normal faults. The faults cut gently down a section in the NE-direction of tectonic transport from a headwall breakaway in the Old Woman Mountains, California. Successively higher allochthons above a basal detachment fault are futher displaced from the headwall, some as much as tens of kilometers. Allochthonous blocks are tilted toward the headwall as evidenced by the dip of the cappoing Tertiary strata and originally horizontal Proterozoic diabase sheets. On the down-dip side of the corridor in Arizona, the faults root under the unbroken Hualapai Mountains and the Colorado Plateau. Slip on faults at all exposed levels of the crust was unidirectional. Brittle thinning above these faults affected the entire upper crust, and wholly removed it locally along the central corridor or core complex region. Isostatic uplift exposed metamorphic core complexes in the domed footwall. These data support a model that the crust in California moved out from under Arizona along an asymmetric, rooted normal-slip shear system. Ductile deformation must have accompanied mid-Tertiary crustal extension at deeper structural levels in Arizona.

Assemble: an interactive graphical tool to analyze and build RNA architectures at the 2D and 3D levels.

PubMed

Jossinet, Fabrice; Ludwig, Thomas E; Westhof, Eric

2010-08-15

Assemble is an intuitive graphical interface to analyze, manipulate and build complex 3D RNA architectures. It provides several advanced and unique features within the framework of a semi-automated modeling process that can be performed by homology and ab initio with or without electron density maps. Those include the interactive editing of a secondary structure and a searchable, embedded library of annotated tertiary structures. Assemble helps users with performing recurrent and otherwise tedious tasks in structural RNA research. Assemble is released under an open-source license (MIT license) and is freely available at http://bioinformatics.org/assemble. It is implemented in the Java language and runs on MacOSX, Linux and Windows operating systems.

Major structural controls on the distribution of pre-Tertiary rocks, Nevada Test Site vicinity, southern Nevada

USGS Publications Warehouse

Cole, James C.

1997-01-01

The lateral and vertical distributions of Proterozoic and Paleozoic sedimentary rocks in southern Nevada are the combined products of original stratigraphic relationships and post-depositional faults and folds. This map compilation shows the distribution of these pre-Tertiary rocks in the region including and surrounding the Nevada Test Site. It is based on considerable new evidence from detailed geologic mapping, biostratigraphic control, sedimentological analysis, and a review of regional map relationships.Proterozoic and Paleozoic rocks of the region record paleogeographic transitions between continental shelf depositional environments on the east and deeper-water slopefacies depositional environments on the west. Middle Devonian and Mississippian sequences, in particular, show strong lateral facies variations caused by contemporaneous changes in the western margin of North America during the Antler orogeny. Sections of rock that were originally deposited in widely separated facies localities presently lie in close proximity. These spatial relationships chiefly result from major east- and southeastdirected thrusts that deformed the region in Permian or later time.Somewhat younger contractional structures are identified within two irregular zones that traverse the region. These folds and thrusts typically verge toward the west and northwest and overprint the relatively simple pattern of the older contractional terranes. Local structural complications are significant near these younger structures due to the opposing vergence and due to irregularities in the previously folded and faulted crustal section.Structural and stratigraphic discontinuities are identified on opposing sides of two north-trending fault zones in the central part of the compilation region north of Yucca Flat. The origin and significance of these zones are enigmatic because they are largely covered by Tertiary and younger deposits. These faults most likely result from significant lateral offset, most likely in the sinistral sense.Low-angle normal faults that are at least older than Oligocene, and may pre-date Late Cretaceous time, are also present in the region. These faults are shown to locally displace blocks of pre-Tertiary rock by several kilometers. However, none of these structures can be traced for significant distances beyond its outcrop extent, and the inference is made that they do not exert regional influence on the distribution of pre-Tertiary rocks. The extensional strain accommodated by these low-angle normal faults appears to be local and highly irregular.

Tectonic history of Sweetgrass Arch, Montana and Alberta-key to finding new hydrocarbons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shepard, W. Shepard, B.

1985-05-01

The Sweetgrass arch of northwestern Montana and southern Alberta is a major ancient structural feature. Initial anticlinal emplacement occurred during the early Paleozoic and was parallel with the cratonic margin. Strong uplift followed by peneplanation occurred during the Late Jurassic and basal Cretaceous during the westward drifting of the North American plate following the breakup of Pangea. During Cretaceous and early Tertiary times, the Sweetgrass arch was quiescent, but was rejuvenated in mid to late Tertiary, upwarped by a basement flexure to its present structural configuration: a 200 mi (322 km) long, north-plunging anticline showing 10,000 ft (350 m) ofmore » structural relief. Midway down its plunge, the anticline is offset 30 mi (48 km) by a right-lateral transcurrent fault. During Late Cretaceous and early Tertiary, plutonic uplifts were emplaced on the east flank, forming traps for oil then migrating updip from the Williston and Alberta basins. Oil and gas accumulated in Mississippian, Jurassic, and basal Cretaceous reservoirs in structural and stratigraphic traps around these plutonic uplifts. Subsequent late Tertiary doming of the Sweetgrass arch tilted the earlier structural traps and drained them, resulting in remigration of much of the oil and gas to the crest of the arch. The tilting failed to destroy many of the stratigraphic traps. As a result, down the flanks of the Sweetgrass arch are many frozen stratigraphic traps including Cut Bank field, the largest single-pay stratigraphic trap in the north Rockies. On the crest are large structure accumulations of remigrated oil at Kevin Sunburst and Pondera. Evidence of remigration is recorded by live oil show tracks in the reservoirs and remnant gas caps throughout the area of earlier accumulations. A potential exists for finding new frozen traps on the flanks and remigrated oil accumulations on or near the crest of the Sweetgrass arch.« less

Entropy-Driven Folding of an RNA Helical Junction: An Isothermal Titration Calorimetric Analysis of the Hammerhead Ribozyme†

PubMed Central

Mikulecky, Peter J.; Takach, Jennifer C.; Feig, Andrew L.

2008-01-01

Helical junctions are extremely common motifs in naturally occurring RNAs, but little is known about the thermodynamics that drive their folding. Studies of junction folding face several challenges: non-two-state folding behavior, superposition of secondary and tertiary structural energetics, and drastically opposing enthalpic and entropic contributions to folding. Here we describe a thermodynamic dissection of the folding of the hammerhead ribozyme, a three-way RNA helical junction, by using isothermal titration calorimetry of bimolecular RNA constructs. By using this method, we show that tertiary folding of the hammerhead core occurs with a highly unfavorable enthalpy change, and is therefore entropically driven. Furthermore, the enthalpies and heat capacities of core folding are the same whether supported by monovalent or divalent ions. These properties appear to be general to the core sequence of bimolecular hammerhead constructs. We present a model for the ion-induced folding of the hammerhead core that is similar to those advanced for the folding of much larger RNAs, involving ion-induced collapse to a structured, non-native state accompanied by rearrangement of core residues to produce the native fold. In agreement with previous enzymological and structural studies, our thermodynamic data suggest that the hammerhead structure is stabilized in vitro predominantly by diffusely bound ions. Our approach addresses several significant challenges that accompany the study of junction folding, and should prove useful in defining the thermodynamic determinants of stability in these important RNA motifs. PMID:15134461

The Design and Characterization of Multifunctional Aptamer Nanopore Sensors.

PubMed

Mayne, Laura; Lin, Chih-Yuan; Christie, Steven D R; Siwy, Zuzanna S; Platt, Mark

2018-05-22

Aptamer-modified nanomaterials provide a simple, yet powerful sensing platform when combined with resistive pulse sensing technologies. Aptamers adopt a more stable tertiary structure in the presence of a target analyte, which results in a change in charge density and velocity of the carrier particle. In practice the tertiary structure is specific for each aptamer and target, and the strength of the signal varies with different applications and experimental conditions. Resistive pulse sensors (RPS) have single particle resolution, allowing for the detailed characterization of the sample. Measuring the velocity of aptamer-modified nanomaterials as they traverse the RPS provides information on their charge state and densities. To help understand how the aptamer structure and charge density effects the sensitivity of aptamer-RPS assays, here we study two metal binding aptamers. This creates a sensor for mercury and lead ions that is capable of being run in a range of electrolyte concentrations, equivalent to river to seawater conditions. The observed results are in excellent agreement with our proposed model. Building on this we combine two aptamers together in an attempt to form a dual sensing strand of DNA for the simultaneous detection of two metal ions. We show experimental and theoretical responses for the aptamer which creates layers of differing charge densities around the nanomaterial. The density and diameter of these zones effects both the viability and sensitivity of the assay. While this approach allows the interrogation of the DNA structure, the data also highlight the limitations and considerations for future assays.

Methods for selecting fixed-effect models for heterogeneous codon evolution, with comments on their application to gene and genome data.

PubMed

Bao, Le; Gu, Hong; Dunn, Katherine A; Bielawski, Joseph P

2007-02-08

Models of codon evolution have proven useful for investigating the strength and direction of natural selection. In some cases, a priori biological knowledge has been used successfully to model heterogeneous evolutionary dynamics among codon sites. These are called fixed-effect models, and they require that all codon sites are assigned to one of several partitions which are permitted to have independent parameters for selection pressure, evolutionary rate, transition to transversion ratio or codon frequencies. For single gene analysis, partitions might be defined according to protein tertiary structure, and for multiple gene analysis partitions might be defined according to a gene's functional category. Given a set of related fixed-effect models, the task of selecting the model that best fits the data is not trivial. In this study, we implement a set of fixed-effect codon models which allow for different levels of heterogeneity among partitions in the substitution process. We describe strategies for selecting among these models by a backward elimination procedure, Akaike information criterion (AIC) or a corrected Akaike information criterion (AICc). We evaluate the performance of these model selection methods via a simulation study, and make several recommendations for real data analysis. Our simulation study indicates that the backward elimination procedure can provide a reliable method for model selection in this setting. We also demonstrate the utility of these models by application to a single-gene dataset partitioned according to tertiary structure (abalone sperm lysin), and a multi-gene dataset partitioned according to the functional category of the gene (flagellar-related proteins of Listeria). Fixed-effect models have advantages and disadvantages. Fixed-effect models are desirable when data partitions are known to exhibit significant heterogeneity or when a statistical test of such heterogeneity is desired. They have the disadvantage of requiring a priori knowledge for partitioning sites. We recommend: (i) selection of models by using backward elimination rather than AIC or AICc, (ii) use a stringent cut-off, e.g., p = 0.0001, and (iii) conduct sensitivity analysis of results. With thoughtful application, fixed-effect codon models should provide a useful tool for large scale multi-gene analyses.

Numerical Modelling of Tertiary Tides

NASA Astrophysics Data System (ADS)

Gao, Yan; Correia, Alexandre C. M.; Eggleton, Peter P.; Han, Zhanwen

2018-06-01

Stellar systems consisting of multiple stars tend to undergo tidal interactions when the separations between the stars are short. While tidal phenomena have been extensively studied, a certain tidal effect exclusive to hierarchical triples (triples in which one component star has a much wider orbit than the others) has hardly received any attention, mainly due to its complexity and consequent resistance to being modelled. This tidal effect is the tidal perturbation of the tertiary by the inner binary, which in turn depletes orbital energy from the inner binary, causing the inner binary separation to shrink. In this paper, we develop a fully numerical simulation of these "tertiary tides" by modifying established tidal models. We also provide general insight as to how close a hierarchical triple needs to be in order for such an effect to take place, and demonstrate that our simulations can effectively retrieve the orbital evolution for such systems. We conclude that tertiary tides are a significant factor in the evolution of close hierarchical triples, and strongly influence at least ˜1% of all multiple star systems.

About Student's Media Use for Learning in Tertiary Education Influence Factors and Structures of Usage Behavior

ERIC Educational Resources Information Center

Grosch, Michael

2014-01-01

The rise of the web 2.0 led to dramatic changes in media usage behavior of students in tertiary education. Services such as Google and Facebook are most accepted amongst students not only in pastime but also for learning. A representative survey was made at Karlsruhe Institute of Technology (KIT). About 1,400 students were asked 150 questions to…

Genetic diversity, genetic structure, and mating system of brewer spruce (Pinaceae), a relict of the acto-tertiary forest

Treesearch

F. Thomas Ledig; Paul D. Hodgskiss; David R. Johnson

2005-01-01

Brewer spruce (Picea breweriana), a relict of the widespread Arcto-Tertiary forests, is now restricted to a highly fragmented range in the Klamath Region of California and Oregon. Expected heterozygosity for 26 isozyme loci, averaged over 10 populations, was 0.121. More notable than the relatively high level of diversity when compared to other woody...

Equilibrium Ensembles for Insulin Folding from Bias-Exchange Metadynamics.

PubMed

Singh, Richa; Bansal, Rohit; Rathore, Anurag Singh; Goel, Gaurav

2017-04-25

Earliest events in the aggregation process, such as single molecule reconfiguration, are extremely important and the most difficult to characterize in experiments. To this end, we have used well-tempered bias exchange metadynamics simulations to determine the equilibrium ensembles of an insulin molecule under amyloidogenic conditions of low pH and high temperature. A bin-based clustering method that uses statistics accumulated in bias exchange metadynamics trajectories was employed to construct a detailed thermodynamic and kinetic model of insulin folding. The highest lifetime, lowest free-energy ensemble identified consisted of native conformations adopted by a folded insulin monomer in solution, namely, the R-, the R f -, and the T-states of insulin. The lowest free-energy structure had a root mean square deviation of only 0.15 nm from native x-ray structure. The second longest-lived metastable state was an unfolded, compact monomer with little similarity to the native structure. We have identified three additional long-lived, metastable states from the bin-based model. We then carried out an exhaustive structural characterization of metastable states on the basis of tertiary contact maps and per-residue accessible surface areas. We have also determined the lowest free-energy path between two longest-lived metastable states and confirm earlier findings of non-two-state folding for insulin through a folding intermediate. The ensemble containing the monomeric intermediate retained 58% of native hydrophobic contacts, however, accompanied by a complete loss of native secondary structure. We have discussed the relative importance of nativelike versus nonnative tertiary contacts for the folding transition. We also provide a simple measure to determine the importance of an individual residue for folding transition. Finally, we have compared and contrasted this intermediate with experimental data obtained in spectroscopic, crystallographic, and calorimetric measurements during early stages of insulin aggregation. We have also determined stability of monomeric insulin by incubation at a very low concentration to isolate protein-protein interaction effects. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Algeria: structural evolution and hydrocarbon potential of a complicated Tectonic province

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knudsen, H.W.

1985-02-01

During most of the pre-Carboniferous, Algeria was part of a stable foreland platform on which a thick clastic sequence was deposited. Caledonian tectonics were primarily epeirogenic, but they established structural alignments that were further reinforced by the much stronger movements of the Carboniferous Hercynian orogeny. In northern and eastern Algeria, a variable basal sandstone and a thick sequence of Triassic and Lower Jurassic evaporites were deposited over the eroded Hercynian surface. This provided a seal for subsequent hydrocarbon migration from the underlying Silurian and Devonian source rocks. Important epeirogenic events and tensional faulting occurred during the Jurassic and Cretaceous. Compressionalmore » forces in the tertiary culminated in the Alpine orogeny. A broad zone of uplift and southward-directed imbricate thrusting formed along the northern margins of Algeria obscuring much of the sub-Tertiary depositional and structural features. Hydrocarbon accumulation in Algeria has been predominantly controlled by the relationships among the Silurian-Devonian source rocks, the Hercynian unconformity, and the distribution of the overlying Triassic clastic and evaporite sequence. More than 65% of the recoverable oil reserves and 90% of the gas reserves are trapped immediately below or above the Hercynian unconformity, with the evaporites providing the seal. Heretofore, the complex geology of the Tertiary overthrust zone has been a deterrent to exploration in both the autochthonous Miocene basins and the sub-Tertiary sequence. However, improved seismic techniques and renewed interest in the potential of overthrust provinces point to increased activity in this area.« less

The tolerance to exchanges of the Watson–Crick base pair in the hammerhead ribozyme core is determined by surrounding elements

PubMed Central

Przybilski, Rita; Hammann, Christian

2007-01-01

Tertiary interacting elements are important features of functional RNA molecules, for example, in all small nucleolytic ribozymes. The recent crystal structure of a tertiary stabilized type I hammerhead ribozyme revealed a conventional Watson–Crick base pair in the catalytic core, formed between nucleotides C3 and G8. We show that any Watson–Crick base pair between these positions retains cleavage competence in two type III ribozymes. In the Arabidopsis thaliana sequence, only moderate differences in cleavage rates are observed for the different base pairs, while the peach latent mosaic viroid (PLMVd) ribozyme exhibits a preference for a pyrimidine at position 3 and a purine at position 8. To understand these differences, we created a series of chimeric ribozymes in which we swapped sequence elements that surround the catalytic core. The kinetic characterization of the resulting ribozymes revealed that the tertiary interacting loop sequences of the PLMVd ribozyme are sufficient to induce the preference for Y3–R8 base pairs in the A. thaliana hammerhead ribozyme. In contrast to this, only when the entire stem–loops I and II of the A. thaliana sequences are grafted on the PLMVd ribozyme is any Watson–Crick base pair similarly tolerated. The data provide evidence for a complex interplay of secondary and tertiary structure elements that lead, mediated by long-range effects, to an individual modulation of the local structure in the catalytic core of different hammerhead ribozymes. PMID:17666711

Teaching Mathematics with Intelligent Support in Natural Language. Tertiary Education Students Working with Parametrized Modelling Activities

ERIC Educational Resources Information Center

Rojano, Teresa; García-Campos, Montserrat

2017-01-01

This article reports the outcomes of a study that seeks to investigate the role of feedback, by way of an intelligent support system in natural language, in parametrized modelling activities carried out by a group of tertiary education students. With such a system, it is possible to simultaneously display on a computer screen a dialogue window and…

Molecular surface representation using 3D Zernike descriptors for protein shape comparison and docking.

PubMed

Kihara, Daisuke; Sael, Lee; Chikhi, Rayan; Esquivel-Rodriguez, Juan

2011-09-01

The tertiary structures of proteins have been solved in an increasing pace in recent years. To capitalize the enormous efforts paid for accumulating the structure data, efficient and effective computational methods need to be developed for comparing, searching, and investigating interactions of protein structures. We introduce the 3D Zernike descriptor (3DZD), an emerging technique to describe molecular surfaces. The 3DZD is a series expansion of mathematical three-dimensional function, and thus a tertiary structure is represented compactly by a vector of coefficients of terms in the series. A strong advantage of the 3DZD is that it is invariant to rotation of target object to be represented. These two characteristics of the 3DZD allow rapid comparison of surface shapes, which is sufficient for real-time structure database screening. In this article, we review various applications of the 3DZD, which have been recently proposed.

Effects of topographic position and geology on shaking damage to residential wood-framed structures during the 2003 San Simeon earthquake, western San Luis obispo county, California

USGS Publications Warehouse

McCrink, T.P.; Wills, C.J.; Real, C.R.; Manson, M.W.

2010-01-01

A statistical evaluation of shaking damage to wood-framed houses caused by the 2003 M6.5 San Simeon earthquake indicates that both the rate and severity of damage, independent of structure type, are significantly greater on hilltops compared to hill slopes when underlain by Cretaceous or Tertiary sedimentary rocks. This increase in damage is interpreted to be the result of topographic amplification. An increase in the damage rate is found for all structures built on Plio-Pleistocene rocks independent of topographic position, and this is interpreted to be the result of amplified shaking caused by geologic site response. Damage rate and severity to houses built on Tertiary rocks suggest that amplification due to both topographic position and geologic site response may be occurring in these rocks, but effects from other topographic parameters cannot be ruled out. For all geologic and topographic conditions, houses with raised foundations are more frequently damaged than those with slab foundations. However, the severity of damage to houses on raised foundations is only significantly greater for those on hill slopes underlain by Tertiary rocks. Structures with some damage-resistant characteristics experienced greater damage severity on hilltops, suggesting a spectral response to topographic amplification. ?? 2010, Earthquake Engineering Research Institute.

Development, implementation, and evaluation of a community- and hospital-based respiratory syncytial virus prophylaxis program.

PubMed

Bracht, Marianne; Heffer, Michael; O'Brien, Karel

2005-02-01

To implement and deliver a respiratory syncytial virus prophylaxis (RSVP) program in response to the Canadian Pediatric Society recommendations. A novel program was designed to provide inpatient RSVP for at-risk infants cared for in 1 tertiary care newborn intensive care unit (NICU). This inpatient program was part of a coordinated approach to RSVP, designed and implemented by 3 hospitals. An RSVP program logic model was created and used by a multidisciplinary team to evaluate the in-house program and identify areas of program activity requiring improvement. Following the 2000 to 2001 RSV season, a compliance and outcomes audit was performed in the tertiary center; 193 infants were enrolled in the RSVP program and 162 infants had received RSVP in the NICU [Mean = 1.64 doses]. Telephone follow-up with the parents of discharged infants identified that 159 infants (98%) had successfully completed their full course of RSVP. Using the RSVP program logic model, 5 areas for program improvement were identified including infant recruitment, patient transfer/discharge processes, product procurement, preparation/distribution/administration of doses, and healthcare team communication. Interdisciplinary collaboration is an important factor in the success of the RSVP program and has supported a consistent model of care for the delivery of RSVP. The program logic model provided a useful structure to systematically review the RSVP program in this organization.

Mineralogy of Cretaceous/Tertiary boundary clays in the Chicxulub structure in northern Yucatan

NASA Technical Reports Server (NTRS)

Ming, D. W.; Sharpton, Virgil L.; Schuraytz, B. C.

1991-01-01

The Cretaceous/Tertiary (K/T) boundary clay layer is thought to be derived from ejecta material from meteorite impact, based on the anomalous concentrations of noble metals in the layer. Because of recent findings of a half-meter thick ejecta deposit at the K/T boundary in Haiti, efforts have focused on locating a large impact feature in the Caribbean and the Gulf of Mexico. One of the leading candidates for the site of a large impact is the Chicxulub structure located on the northern Yucatan Peninsula in Mexico. The Chicxulub structure is a subsurface zone of upper Cretaceous igneous rocks, carbonates, and breccias. The structure has been interpreted to be a 200 km diameter; however, there is some question to the size of the structure or to the fact that it even is an impact feature. Little is known about the mineralogy of this structure; the objective of this study was to determine the clay mineralogy of core samples from within the Chicxulub structure.

Disruptive innovation in academic medical centers: balancing accountable and academic care.

PubMed

Stein, Daniel; Chen, Christopher; Ackerly, D Clay

2015-05-01

Numerous academic medicine leaders have argued that academic referral centers must prepare for the growing importance of accountability-driven payment models by adopting population health initiatives. Although this shift has merit, execution of this strategy will prove significantly more problematic than most observers have appreciated. The authors describe how successful implementation of an accountable care health strategy within a referral academic medical center (AMC) requires navigating a critical tension: The academic referral business model, driven by tertiary-level care, is fundamentally in conflict with population health. Referral AMCs that create successful value-driven population health systems within their organizations will in effect disrupt their own existing tertiary care businesses. The theory of disruptive innovation suggests that balancing the push and pull of academic and accountable care within a single organization is achievable. However, it will require significant shifts in resource allocation and changes in management structure to enable AMCs to make the inherent difficult choices and trade-offs that will ensue. On the basis of the theories of disruptive innovation, the authors present recommendations for how academic health systems can successfully navigate these issues as they transition toward accountability-driven care.

Hydrogeologic Framework of the Salt Basin, New Mexico and Texas

NASA Astrophysics Data System (ADS)

Ritchie, A. B.; Phillips, F. M.

2010-12-01

The Salt Basin is a closed drainage basin located in southeastern New Mexico (Otero, Chaves, and Eddy Counties), and northwestern Texas (Hudspeth, Culberson, Jeff Davis, and Presidio Counties), which can be divided into a northern and a southern system. Since the 1950s, extensive groundwater withdrawals have been associated with agricultural irrigation in the Dell City, Texas region, just south of the New Mexico-Texas border. Currently, there are three major applications over the appropriations of groundwater in the Salt Basin. Despite these factors, relatively little is known about the recharge rates and storage capacity of the basin, and the estimates that do exist are highly variable. The Salt Basin groundwater system was declared by the New Mexico State Engineer during 2002 in an attempt to regulate and control growing interest in the groundwater resources of the basin. In order to help guide long-term management strategies, a conceptual model of groundwater flow in the Salt Basin was developed by reconstructing the tectonic forcings that have affected the basin during its formation, and identifying the depositional environments that formed and the resultant distribution of facies. The tectonic history of the Salt Basin can be divided into four main periods: a) Pennsylvanian-to-Early Permian, b) Mid-to-Late Permian, c) Late Cretaceous, and d) Tertiary-to-Quaternary. Pennsylvanian-to-Permian structural features affected deposition throughout the Permian, resulting in three distinct hydrogeologic facies: basin, shelf-margin, and shelf. Permian shelf facies rocks form the primary aquifer within the northern Salt Basin, although minor aquifers occur in Cretaceous rocks and Tertiary-to-Quaternary alluvium. Subsequent tectonic activity during the Late Cretaceous resulted in the re-activation of many of the earlier structures. Tertiary-to-Quaternary Basin-and-Range extension produced the current physiographic form of the basin.

Both Reversible Self-Association and Structural Changes Underpin Molecular Viscoelasticity of mAb Solutions.

PubMed

Sarangapani, Prasad S; Weaver, Justin; Parupudi, Arun; Besong, Tabot M D; Adams, Gary G; Harding, Stephen E; Manikwar, Prakash; Castellanos, Maria M; Bishop, Steven M; Pathak, Jai A

2016-12-01

The role of antibody structure (conformation) in solution rheology is probed. It is demonstrated here that pH-dependent changes in the tertiary structure of 2 mAb solutions lead to viscoelasticity and not merely a shear viscosity (η) increase. Steady shear flow curves on mAb solutions are reported over broad pH (3.0 ≤ pH ≤ 8.7) and concentration (2 mg/mL ≤ c ≤ 120 mg/mL) ranges to comprehensively characterize their rheology. Results are interpreted using size exclusion chromatography, differential scanning calorimetry, analytical ultracentrifugation, near-UV circular dichroism, and dynamic light scattering. Changes in tertiary structure with concentration lead to elastic yield stress and increased solution viscosity in solution of "mAb1." These findings are supported by dynamic light scattering and differential scanning calorimetry, which show increased hydrodynamic radius of mAb1 at low pH and a reduced melting temperature T m , respectively. Conversely, another molecule at 120 mg/mL solution concentration is a strong viscoelastic gel due to perturbed tertiary structure (seen in circular dichroism) at pH 3.0, but the same molecule responds as a viscous liquid due to reversible self-association at pH 7.4 (verified by analytical ultracentrifugation). Both protein-protein interactions and structural perturbations govern pH-dependent viscoelasticity of mAb solutions. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Multiple-probe analysis of folding and unfolding pathways of human serum albumin. Evidence for a framework mechanism of folding.

PubMed

Santra, Manas Kumar; Banerjee, Abhijit; Krishnakumar, Shyam Sundar; Rahaman, Obaidur; Panda, Dulal

2004-05-01

The changes in the far-UV CD signal, intrinsic tryptophan fluorescence and bilirubin absorbance showed that the guanidine hydrochloride (GdnHCl)-induced unfolding of a multidomain protein, human serum albumin (HSA), followed a two-state process. However, using environment sensitive Nile red fluorescence, the unfolding and folding pathways of HSA were found to follow a three-state process and an intermediate was detected in the range 0.25-1.5 m GdnHCl. The intermediate state displayed 45% higher fluorescence intensity than that of the native state. The increase in the Nile red fluorescence was found to be due to an increase in the quantum yield of the HSA-bound Nile red. Low concentrations of GdnHCl neither altered the binding affinity of Nile red to HSA nor induced the aggregation of HSA. In addition, the secondary structure of HSA was not perturbed during the first unfolding transition (<1.5 m GdnHCl); however, the secondary structure was completely lost during the second transition. The data together showed that the half maximal loss of the tertiary structure occurred at a lower GdnHCl concentration than the loss of the secondary structure. Further kinetic studies of the refolding process of HSA using multiple spectroscopic techniques showed that the folding occurred in two phases, a burst phase followed by a slow phase. An intermediate with native-like secondary structure but only a partial tertiary structure was found to form in the burst phase of refolding. Then, the intermediate slowly folded into the native state. An analysis of the refolding data suggested that the folding of HSA could be best explained by the framework model.

Superacid synthesized tertiary benzenesulfonamides and benzofuzed sultams act as selective hCA IX inhibitors: toward understanding a new mode of inhibition by tertiary sulfonamides.

PubMed

Métayer, Benoît; Martin-Mingot, Agnès; Vullo, Daniella; Supuran, Claudiu T; Thibaudeau, Sébastien

2013-11-21

A series of tertiary (fluorinated) benzenesulfonamides was synthesized in superacid HF-SbF5. To circumvent the problem of the in situ iminium ion formation, proved by low temperature NMR experiments, a tandem superacid catalysed cross-coupling reaction was employed to synthesize the benzofuzed sultams analogues. These tertiary benzenesulfonamides were tested as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). These compounds did not inhibit the widespread off target hCA II isoform and showed strong selectivity toward tumor-associated carbonic anhydrase isoform IX. A dramatic effect of the electronic and structural shape of the inhibitors on selectivity was demonstrated, confirming the non-zinc-bonding mode of inhibition of this class of sulfonamides. This work allowed identifying a highly selective hCA IX inhibitor lead in this series.

An automated method for modeling proteins on known templates using distance geometry.

PubMed

Srinivasan, S; March, C J; Sudarsanam, S

1993-02-01

We present an automated method incorporated into a software package, FOLDER, to fold a protein sequence on a given three-dimensional (3D) template. Starting with the sequence alignment of a family of homologous proteins, tertiary structures are modeled using the known 3D structure of one member of the family as a template. Homologous interatomic distances from the template are used as constraints. For nonhomologous regions in the model protein, the lower and the upper bounds for the interatomic distances are imposed by steric constraints and the globular dimensions of the template, respectively. Distance geometry is used to embed an ensemble of structures consistent with these distance bounds. Structures are selected from this ensemble based on minimal distance error criteria, after a penalty function optimization step. These structures are then refined using energy optimization methods. The method is tested by simulating the alpha-chain of horse hemoglobin using the alpha-chain of human hemoglobin as the template and by comparing the generated models with the crystal structure of the alpha-chain of horse hemoglobin. We also test the packing efficiency of this method by reconstructing the atomic positions of the interior side chains beyond C beta atoms of a protein domain from a known 3D structure. In both test cases, models retain the template constraints and any additionally imposed constraints while the packing of the interior residues is optimized with no short contacts or bond deformations. To demonstrate the use of this method in simulating structures of proteins with nonhomologous disulfides, we construct a model of murine interleukin (IL)-4 using the NMR structure of human IL-4 as the template. The resulting geometry of the nonhomologous disulfide in the model structure for murine IL-4 is consistent with standard disulfide geometry.

A Case Series of the Probability Density and Cumulative Distribution of Laryngeal Disease in a Tertiary Care Voice Center.

PubMed

de la Fuente, Jaime; Garrett, C Gaelyn; Ossoff, Robert; Vinson, Kim; Francis, David O; Gelbard, Alexander

2017-11-01

To examine the distribution of clinic and operative pathology in a tertiary care laryngology practice. Probability density and cumulative distribution analyses (Pareto analysis) was used to rank order laryngeal conditions seen in an outpatient tertiary care laryngology practice and those requiring surgical intervention during a 3-year period. Among 3783 new clinic consultations and 1380 operative procedures, voice disorders were the most common primary diagnostic category seen in clinic (n = 3223), followed by airway (n = 374) and swallowing (n = 186) disorders. Within the voice strata, the most common primary ICD-9 code used was dysphonia (41%), followed by unilateral vocal fold paralysis (UVFP) (9%) and cough (7%). Among new voice patients, 45% were found to have a structural abnormality. The most common surgical indications were laryngotracheal stenosis (37%), followed by recurrent respiratory papillomatosis (18%) and UVFP (17%). Nearly 55% of patients presenting to a tertiary referral laryngology practice did not have an identifiable structural abnormality in the larynx on direct or indirect examination. The distribution of ICD-9 codes requiring surgical intervention was disparate from that seen in clinic. Application of the Pareto principle may improve resource allocation in laryngology, but these initial results require confirmation across multiple institutions.

Rhodamine Inhibitors of P-glycoprotein: An Amide/Thioamide “Switch” for ATPase Activity

PubMed Central

Gannon, Michael K.; Holt, Jason J.; Bennett, Stephanie M.; Wetzel, Bryan R.; Loo, Tip W.; Bartlett, M. Claire; Clarke, David M.; Sawada, Geri A.; Higgins, J. William; Tombline, Gregory; Raub, Thomas J.; Detty, Michael R.

2012-01-01

We have examined 46 tetramethylrosamine/rhodamine derivatives with structural diversity in the heteroatom of the xanthylium core, the amino substituents of the 3- and 6-positions, and the alkyl, aryl, or heteroaryl group at the 9-substituent. These compounds were examined for affinity and ATPase stimulation in isolated MDR3 CL P-gp and human P-gp-His10, for their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant MDCKII-MDR1 cells, and for transport in monolayers of MDCKII-MDR1 cells. Thioamide 31-S gave KM of 0.087 μM in human P-gp. Small changes in structure among this set of compounds affected affinity as well as transport rate (or flux) even though all derivatives examined were substrates for P-gp. With isolated protein, tertiary amide groups dictate high affinity and high stimulation while tertiary thioamide groups give high affinity and inhibition of ATPase activity. In MDCKII-MDR1 cells, the tertiary thioamide-containing derivatives promote uptake of calcein AM and have very slow passive, absorptive, and secretory rates of transport relative to transport rates for tertiary amide-containing derivatives. Thioamide 31-S promoted uptake of calcein AM and inhibited efflux of vinblastine with IC50’s of ~2 μM in MDCKII-MDR1 cells. PMID:19402665

Picosecond Phase Grating Spectroscopy of Hemoglobin and Myoglobin: Vibrational Relaxation and Global Protein Motions.

NASA Astrophysics Data System (ADS)

Genberg, Laura Lynn

The vibrational energy relaxation pathways from optically excited met heme proteins have been studied using the technique of picosecond phase grating spectroscopy. Vibrational energy transfer from the porphyrin ring to the protein backbone leads to extensive delocalization of the energy in the protein matrix which is efficiently transferred to the water interface in less than 20 ps. A slower relaxation process on the nanosecond time scale is also observed. The slow relaxation component is attributed to slow conformational relaxation processes of high potential energy states of the heme proteins. These states are accessed during the high internal energy conditions of the optically excited molecules. In addition, a detailed theoretical analysis of this form of spectroscopy is presented that explains the effects of delayed thermal energy deposition on grating dynamics. The effects of optical pulse shape and duration are also treated. The observable in this technique is not an electronic polarization, but is derived from a response of the material fields to changes in the lattice temperature. Phase grating spectroscopy is also used to observe picosecond tertiary structural changes in both myoglobin and hemoglobin following CO photodissociation. The original interest in this experiment was to ascertain whether local minima are accessed during the highly exothermic conditions following photodissociation, as was observed in the met heme studies. Photodissociation of CO induces a well defined ligated to deoxy structure transition that is important to the functionality of these proteins. Using grating spectroscopy, protein driven density waves are observed on a picosecond time scale. These waves are launched by the tertiary structural changes that occur in both hemoglobin and myoglobin. The exact shape and amplitude of these waves reveal the time scale for the motion as well as the energetics for these protein motions. This result demonstrates that tertiary structure changes are global in nature and occur on an extremely fast time scale. This provides new insight into the biomechanics of conformational changes in proteins and lends support to theoretical models invoking stored strain energy as the driving force for large amplitude correlated motions.

The Phyre2 web portal for protein modelling, prediction and analysis

PubMed Central

Kelley, Lawrence A; Mezulis, Stefans; Yates, Christopher M; Wass, Mark N; Sternberg, Michael JE

2017-01-01

Summary Phyre2 is a suite of tools available on the web to predict and analyse protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a protocol. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites, and analyse the effect of amino-acid variants (e.g. nsSNPs) for a user’s protein sequence. Users are guided through results by a simple interface at a level of detail determined by them. This protocol will guide a user from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30mins and 2 hours after submission. PMID:25950237

Hydrostructural maps of the Death Valley regional flow system, Nevada and California

USGS Publications Warehouse

Potter, C.J.; Sweetkind, D.S.; Dickerson, R.P.; Killgore, M.L.

2002-01-01

The locations of principal faults and structural zones that may influence ground-water flow were compiled in support of a three-dimensional ground-water model for the Death Valley regional flow system (DVRFS), which covers 80,000 square km in southwestern Nevada and southeastern California. Faults include Neogene extensional and strike-slip faults and pre-Tertiary thrust faults. Emphasis was given to characteristics of faults and deformed zones that may have a high potential for influencing hydraulic conductivity. These include: (1) faulting that results in the juxtaposition of stratigraphic units with contrasting hydrologic properties, which may cause ground-water discharge and other perturbations in the flow system; (2) special physical characteristics of the fault zones, such as brecciation and fracturing, that may cause specific parts of the zone to act either as conduits or as barriers to fluid flow; (3) the presence of a variety of lithologies whose physical and deformational characteristics may serve to impede or enhance flow in fault zones; (4) orientation of a fault with respect to the present-day stress field, possibly influencing hydraulic conductivity along the fault zone; and (5) faults that have been active in late Pleistocene or Holocene time and areas of contemporary seismicity, which may be associated with enhanced permeabilities. The faults shown on maps A and B are largely from Workman and others (in press), and fit one or more of the following criteria: (1) faults that are more than 10 km in map length; (2) faults with more than 500 m of displacement; and (3) faults in sets that define a significant structural fabric that characterizes a particular domain of the DVRFS. The following fault types are shown: Neogene normal, Neogene strike-slip, Neogene low-angle normal, pre-Tertiary thrust, and structural boundaries of Miocene calderas. We have highlighted faults that have late Pleistocene to Holocene displacement (Piety, 1996). Areas of thick Neogene basin-fill deposits (thicknesses 1-2 km, 2-3 km, and >3 km) are shown on map A, based on gravity anomalies and depth-to-basement modeling by Blakely and others (1999). We have interpreted the positions of faults in the subsurface, generally following the interpretations of Blakely and others (1999). Where geophysical constraints are not present, the faults beneath late Tertiary and Quaternary cover have been extended based on geologic reasoning. Nearly all of these concealed faults are shown with continuous solid lines on maps A and B, in order to provide continuous structures for incorporation into the hydrogeologic framework model (HFM). Map A also shows the potentiometric surface, regional springs (25-35 degrees Celsius, D'Agnese and others, 1997), and cold springs (Turner and others, 1996).

The effects of health education on knowledge and attitudes to emergency contraception by female students of a tertiary educational institution in Enugu, South East Nigeria.

PubMed

Arinze-Onyia, S U; Onwasigwe, C N; Uzochukwu, B S C; Nwobi, E A; Ndu, A C; Nwobodo, Ed

2010-11-28

This was an intervention study to assess the effects of health education on the knowledge and attitudes to emergency contraception (EC) by female students of University of Nigeria in southeast Nigeria. A structured questionnaire was used to collect data from 337 female students of a tertiary educational institution (150 in the study group and 187 from the control group) who were selected by multistage sampling. Subsequently, health education was conducted only among students in the study institution. Three months after this intervention, its effects were assessed through a survey using the same structured questionnaire employed in the baseline survey. Unlike the pre-intervention results, knowledge of EC was significantly higher among the study group than the controls. Attitudes to EC were also more favourable at the post- intervention survey among the study group. Health education can effectively improve knowledge and attitudes to EC among female students of tertiary institutions and this should be encouraged.

Tertiary tilting and dismemberment of the laramide arc and related hydrothermal systems, Sierrita Mountain, Arizona

USGS Publications Warehouse

Stavast, W.J.A.; Butler, R.P.; Seedorff, E.; Barton, M.D.; Ferguson, C.A.

2008-01-01

Multiple lines of evidence, including new and published geologic mapping and paleomagnetic and geobarometric determinations, demonstrate that the rocks and large porphyry copper systems of the Sierrita Mountains in southern Arizona were dismembered and tilted 50?? to 60?? to the south by Tertiary normal faulting. Repetition of geologic features and geobarometry indicate that the area is segmented into at least three major structural blocks, and the present surface corresponds to oblique sections through the Laramide plutonic-hydrothermal complex, ranging in paleodepth from ???1 to ???12 km. These results add to an evolving view of a north-south extensional domain at high angles to much extension in the southern Basin and Range, contrast with earlier interpretations that the Laramide systems are largely upright and dismembered by thrust faults, highlight the necessity of restoring Tertiary rotations before interpreting Laramide structural and hydrothermal features, and add to the broader understanding of pluton emplacement and evolution of porphyry copper systems. ?? 2008 Society of Economic Geologists, Inc.

Discrete RNA libraries from pseudo-torsional space

PubMed Central

Humphris-Narayanan, Elisabeth

2012-01-01

The discovery that RNA molecules can fold into complex structures and carry out diverse cellular roles has led to interest in developing tools for modeling RNA tertiary structure. While significant progress has been made in establishing that the RNA backbone is rotameric, few libraries of discrete conformations specifically for use in RNA modeling have been validated. Here, we present six libraries of discrete RNA conformations based on a simplified pseudo-torsional notation of the RNA backbone, comparable to phi and psi in the protein backbone. We evaluate the ability of each library to represent single nucleotide backbone conformations and we show how individual library fragments can be assembled into dinucleotides that are consistent with established RNA backbone descriptors spanning from sugar to sugar. We then use each library to build all-atom models of 20 test folds and we show how the composition of a fragment library can limit model quality. Despite the limitations inherent in using discretized libraries, we find that several hundred discrete fragments can rebuild RNA folds up to 174 nucleotides in length with atomic-level accuracy (<1.5Å RMSD). We anticipate the libraries presented here could easily be incorporated into RNA structural modeling, analysis, or refinement tools. PMID:22425640

Maximizing RNA folding rates: a balancing act.

PubMed Central

Thirumalai, D; Woodson, S A

2000-01-01

Large ribozymes typically require very long times to refold into their active conformation in vitro, because the RNA is easily trapped in metastable misfolded structures. Theoretical models show that the probability of misfolding is reduced when local and long-range interactions in the RNA are balanced. Using the folding kinetics of the Tetrahymena ribozyme as an example, we propose that folding rates are maximized when the free energies of forming independent domains are similar to each other. A prediction is that the folding pathway of the ribozyme can be reversed by inverting the relative stability of the tertiary domains. This result suggests strategies for optimizing ribozyme sequences for therapeutics and structural studies. PMID:10864039

Optical spectroscopic methods for probing the conformational stability of immobilised enzymes.

PubMed

Ganesan, Ashok; Moore, Barry D; Kelly, Sharon M; Price, Nicholas C; Rolinski, Olaf J; Birch, David J S; Dunkin, Ian R; Halling, Peter J

2009-07-13

We report the development of biophysical techniques based on circular dichroism (CD), diffuse reflectance infrared Fourier transform (DRIFT) and tryptophan (Trp) fluorescence to investigate in situ the structure of enzymes immobilised on solid particles. Their applicability is demonstrated using subtilisin Carlsberg (SC) immobilised on silica gel and Candida antartica lipase B immobilised on Lewatit VP.OC 1600 (Novozyme 435). SC shows nearly identical secondary structure in solution and in the immobilised state as evident from far UV CD spectra and amide I vibration bands. Increased near UV CD intensity and reduced Trp fluorescence suggest a more rigid tertiary structure on the silica surface. After immobilised SC is inactivated, these techniques reveal: a) almost complete loss of near UV CD signal, suggesting loss of tertiary structure; b) a shift in the amide I vibrational band from 1658 cm(-1) to 1632 cm(-1), indicating a shift from alpha-helical structure to beta-sheet; c) a substantial blue shift and reduced dichroism in the far UV CD, supporting a shift to beta-sheet structure; d) strong increase in Trp fluorescence intensity, which reflects reduced intramolecular quenching with loss of tertiary structure; and e) major change in fluorescence lifetime distribution, confirming a substantial change in Trp environment. DRIFT measurements suggest that pressing KBr discs may perturb protein structure. With the enzyme on organic polymer it was possible to obtain near UV CD spectra free of interference by the carrier material. However, far UV CD, DRIFT and fluorescence measurements showed strong signals from the organic support. In conclusion, the spectroscopic methods described here provide structural information hitherto inaccessible, with their applicability limited by interference from, rather than the particulate nature of, the support material.

Structural specificity of Rn nuclease I as probed on yeast tRNA(Phe) and tRNA(Asp).

PubMed Central

Przykorska, A; el Adlouni, C; Keith, G; Szarkowski, J W; Dirheimer, G

1992-01-01

A single-strand-specific nuclease from rye germ (Rn nuclease I) was characterized as a tool for secondary and tertiary structure investigation of RNAs. To test the procedure, yeast tRNA(Phe) and tRNA(Asp) for which the tertiary structures are known, as well as the 3'-half of tRNA(Asp) were used as substrates. In tRNA(Phe) the nuclease introduced main primary cuts at positions U33 and A35 of the anticodon loop and G18 and G19 of the D loop. No primary cuts were observed within the double stranded stems. In tRNA(Asp) the main cuts occurred at positions U33, G34, U35, C36 of the anticodon loop and G18 and C20:1 positions in the D loop. No cuts were observed in the T loop in intact tRNA(Asp) but strong primary cleavages occurred at positions psi 55, C56, A57 within that loop in the absence of the tertiary interactions between T and D loops (use of 3'-half tRNA(Asp)). These results show that Rn nuclease I is specific for exposed single-stranded regions. Images PMID:1542562

Geologic Map of the Gold Creek Gold District, Elko County, Nevada

USGS Publications Warehouse

Ketner, Keith B.

2007-01-01

The Gold Creek, Nev. area displays important stratigraphic and structural relationships between Paleozoic and early Tertiary sedimentary strata in an area dominated by large intrusive bodies of Mesozoic age and extensive volcanic fields of middle to late Tertiary age. An autochthonous sequence includes the Cambrian and Proterozoic(?) Prospect Mountain Quartzite and the overlying Cambrian and Ordovician Tennessee Mountain Formation. This autochthon is overlain by three allochthonous plates each composed of a distinctive sequence of strata and having a distinctive internal structure. The structurally lowest plate is composed of the Havallah sequence, locally of Mississippian and Pennsylvanian age, which is folded on north-south trending axes. The next higher plate is composed of somewhat younger Pennsylvanian and Permian strata cut by east-west trending low-angle faults. The highest plate is composed of early Tertiary non-marine sedimentary and igneous rocks folded on varied but mainly north-south trending axes. The question of whether the allochthonous plates were emplaced by contractional or extensional forces is indeterminate from the local evidence. Mineral deposits include gold placers of moderate size and small pockets of base metals, none of which is currently being exploited.

Final acceptance testing of the LSST monolithic primary/tertiary mirror

NASA Astrophysics Data System (ADS)

Tuell, Michael T.; Burge, James H.; Cuerden, Brian; Gressler, William; Martin, Hubert M.; West, Steven C.; Zhao, Chunyu

2014-07-01

The Large Synoptic Survey Telescope (LSST) is a three-mirror wide-field survey telescope with the primary and tertiary mirrors on one monolithic substrate1. This substrate is made of Ohara E6 borosilicate glass in a honeycomb sandwich, spin cast at the Steward Observatory Mirror Lab at The University of Arizona2. Each surface is aspheric, with the specification in terms of conic constant error, maximum active bending forces and finally a structure function specification on the residual errors3. There are high-order deformation terms, but with no tolerance, any error is considered as a surface error and is included in the structure function. The radii of curvature are very different, requiring two independent test stations, each with instantaneous phase-shifting interferometers with null correctors. The primary null corrector is a standard two-element Offner null lens. The tertiary null corrector is a phase-etched computer-generated hologram (CGH). This paper details the two optical systems and their tolerances, showing that the uncertainty in measuring the figure is a small fraction of the structure function specification. Additional metrology includes the radii of curvature, optical axis locations, and relative surface tilts. The methods for measuring these will also be described along with their tolerances.

Amphibian and reptile road-kills on tertiary roads in relation to landscape structure: using a citizen science approach with open-access land cover data.

PubMed

Heigl, Florian; Horvath, Kathrin; Laaha, Gregor; Zaller, Johann G

2017-06-26

Amphibians and reptiles are among the most endangered vertebrate species worldwide. However, little is known how they are affected by road-kills on tertiary roads and whether the surrounding landscape structure can explain road-kill patterns. The aim of our study was to examine the applicability of open-access remote sensing data for a large-scale citizen science approach to describe spatial patterns of road-killed amphibians and reptiles on tertiary roads. Using a citizen science app we monitored road-kills of amphibians and reptiles along 97.5 km of tertiary roads covering agricultural, municipal and interurban roads as well as cycling paths in eastern Austria over two seasons. Surrounding landscape was assessed using open access land cover classes for the region (Coordination of Information on the Environment, CORINE). Hotspot analysis was performed using kernel density estimation (KDE+). Relations between land cover classes and amphibian and reptile road-kills were analysed with conditional probabilities and general linear models (GLM). We also estimated the potential cost-efficiency of a large scale citizen science monitoring project. We recorded 180 amphibian and 72 reptile road-kills comprising eight species mainly occurring on agricultural roads. KDE+ analyses revealed a significant clustering of road-killed amphibians and reptiles, which is an important information for authorities aiming to mitigate road-kills. Overall, hotspots of amphibian and reptile road-kills were next to the land cover classes arable land, suburban areas and vineyards. Conditional probabilities and GLMs identified road-kills especially next to preferred habitats of green toad, common toad and grass snake, the most often found road-killed species. A citizen science approach appeared to be more cost-efficient than monitoring by professional researchers only when more than 400 km of road are monitored. Our findings showed that freely available remote sensing data in combination with a citizen science approach would be a cost-efficient method aiming to identify and monitor road-kill hotspots of amphibians and reptiles on a larger scale.

GeneSilico protein structure prediction meta-server.

PubMed

Kurowski, Michal A; Bujnicki, Janusz M

2003-07-01

Rigorous assessments of protein structure prediction have demonstrated that fold recognition methods can identify remote similarities between proteins when standard sequence search methods fail. It has been shown that the accuracy of predictions is improved when refined multiple sequence alignments are used instead of single sequences and if different methods are combined to generate a consensus model. There are several meta-servers available that integrate protein structure predictions performed by various methods, but they do not allow for submission of user-defined multiple sequence alignments and they seldom offer confidentiality of the results. We developed a novel WWW gateway for protein structure prediction, which combines the useful features of other meta-servers available, but with much greater flexibility of the input. The user may submit an amino acid sequence or a multiple sequence alignment to a set of methods for primary, secondary and tertiary structure prediction. Fold-recognition results (target-template alignments) are converted into full-atom 3D models and the quality of these models is uniformly assessed. A consensus between different FR methods is also inferred. The results are conveniently presented on-line on a single web page over a secure, password-protected connection. The GeneSilico protein structure prediction meta-server is freely available for academic users at http://genesilico.pl/meta.

GeneSilico protein structure prediction meta-server

PubMed Central

Kurowski, Michal A.; Bujnicki, Janusz M.

2003-01-01

Rigorous assessments of protein structure prediction have demonstrated that fold recognition methods can identify remote similarities between proteins when standard sequence search methods fail. It has been shown that the accuracy of predictions is improved when refined multiple sequence alignments are used instead of single sequences and if different methods are combined to generate a consensus model. There are several meta-servers available that integrate protein structure predictions performed by various methods, but they do not allow for submission of user-defined multiple sequence alignments and they seldom offer confidentiality of the results. We developed a novel WWW gateway for protein structure prediction, which combines the useful features of other meta-servers available, but with much greater flexibility of the input. The user may submit an amino acid sequence or a multiple sequence alignment to a set of methods for primary, secondary and tertiary structure prediction. Fold-recognition results (target-template alignments) are converted into full-atom 3D models and the quality of these models is uniformly assessed. A consensus between different FR methods is also inferred. The results are conveniently presented on-line on a single web page over a secure, password-protected connection. The GeneSilico protein structure prediction meta-server is freely available for academic users at http://genesilico.pl/meta. PMID:12824313

A Stochastic Point Cloud Sampling Method for Multi-Template Protein Comparative Modeling.

PubMed

Li, Jilong; Cheng, Jianlin

2016-05-10

Generating tertiary structural models for a target protein from the known structure of its homologous template proteins and their pairwise sequence alignment is a key step in protein comparative modeling. Here, we developed a new stochastic point cloud sampling method, called MTMG, for multi-template protein model generation. The method first superposes the backbones of template structures, and the Cα atoms of the superposed templates form a point cloud for each position of a target protein, which are represented by a three-dimensional multivariate normal distribution. MTMG stochastically resamples the positions for Cα atoms of the residues whose positions are uncertain from the distribution, and accepts or rejects new position according to a simulated annealing protocol, which effectively removes atomic clashes commonly encountered in multi-template comparative modeling. We benchmarked MTMG on 1,033 sequence alignments generated for CASP9, CASP10 and CASP11 targets, respectively. Using multiple templates with MTMG improves the GDT-TS score and TM-score of structural models by 2.96-6.37% and 2.42-5.19% on the three datasets over using single templates. MTMG's performance was comparable to Modeller in terms of GDT-TS score, TM-score, and GDT-HA score, while the average RMSD was improved by a new sampling approach. The MTMG software is freely available at: http://sysbio.rnet.missouri.edu/multicom_toolbox/mtmg.html.

A Stochastic Point Cloud Sampling Method for Multi-Template Protein Comparative Modeling

PubMed Central

Li, Jilong; Cheng, Jianlin

2016-01-01

Generating tertiary structural models for a target protein from the known structure of its homologous template proteins and their pairwise sequence alignment is a key step in protein comparative modeling. Here, we developed a new stochastic point cloud sampling method, called MTMG, for multi-template protein model generation. The method first superposes the backbones of template structures, and the Cα atoms of the superposed templates form a point cloud for each position of a target protein, which are represented by a three-dimensional multivariate normal distribution. MTMG stochastically resamples the positions for Cα atoms of the residues whose positions are uncertain from the distribution, and accepts or rejects new position according to a simulated annealing protocol, which effectively removes atomic clashes commonly encountered in multi-template comparative modeling. We benchmarked MTMG on 1,033 sequence alignments generated for CASP9, CASP10 and CASP11 targets, respectively. Using multiple templates with MTMG improves the GDT-TS score and TM-score of structural models by 2.96–6.37% and 2.42–5.19% on the three datasets over using single templates. MTMG’s performance was comparable to Modeller in terms of GDT-TS score, TM-score, and GDT-HA score, while the average RMSD was improved by a new sampling approach. The MTMG software is freely available at: http://sysbio.rnet.missouri.edu/multicom_toolbox/mtmg.html. PMID:27161489

Replica exchange molecular dynamics simulation of structure variation from α/4β-fold to 3α-fold protein.

PubMed

Lazim, Raudah; Mei, Ye; Zhang, Dawei

2012-03-01

Replica exchange molecular dynamics (REMD) simulation provides an efficient conformational sampling tool for the study of protein folding. In this study, we explore the mechanism directing the structure variation from α/4β-fold protein to 3α-fold protein after mutation by conducting REMD simulation on 42 replicas with temperatures ranging from 270 K to 710 K. The simulation began from a protein possessing the primary structure of GA88 but the tertiary structure of GB88, two G proteins with "high sequence identity." Albeit the large Cα-root mean square deviation (RMSD) of the folded protein (4.34 Å at 270 K and 4.75 Å at 304 K), a variation in tertiary structure was observed. Together with the analysis of secondary structure assignment, cluster analysis and principal component, it provides insights to the folding and unfolding pathway of 3α-fold protein and α/4β-fold protein respectively paving the way toward the understanding of the ongoings during conformational variation.

Structure of an E. coli integral membrane sulfurtransferase and its structural transition upon SCN- binding defined by EPR-based hybrid method

NASA Astrophysics Data System (ADS)

Ling, Shenglong; Wang, Wei; Yu, Lu; Peng, Junhui; Cai, Xiaoying; Xiong, Ying; Hayati, Zahra; Zhang, Longhua; Zhang, Zhiyong; Song, Likai; Tian, Changlin

2016-01-01

Electron paramagnetic resonance (EPR)-based hybrid experimental and computational approaches were applied to determine the structure of a full-length E. coli integral membrane sulfurtransferase, dimeric YgaP, and its structural and dynamic changes upon ligand binding. The solution NMR structures of the YgaP transmembrane domain (TMD) and cytosolic catalytic rhodanese domain were reported recently, but the tertiary fold of full-length YgaP was not yet available. Here, systematic site-specific EPR analysis defined a helix-loop-helix secondary structure of the YagP-TMD monomers using mobility, accessibility and membrane immersion measurements. The tertiary folds of dimeric YgaP-TMD and full-length YgaP in detergent micelles were determined through inter- and intra-monomer distance mapping and rigid-body computation. Further EPR analysis demonstrated the tight packing of the two YgaP second transmembrane helices upon binding of the catalytic product SCN-, which provides insight into the thiocyanate exportation mechanism of YgaP in the E. coli membrane.

Micro-Macro Analysis and Phenomenological Modelling of Salt Viscous Damage and Application to Salt Caverns

NASA Astrophysics Data System (ADS)

Zhu, Cheng; Pouya, Ahmad; Arson, Chloé

2015-11-01

This paper aims to gain fundamental understanding of the microscopic mechanisms that control the transition between secondary and tertiary creep around salt caverns in typical geological storage conditions. We use a self-consistent inclusion-matrix model to homogenize the viscoplastic deformation of halite polycrystals and predict the number of broken grains in a Representative Elementary Volume of salt. We use this micro-macro modeling framework to simulate creep tests under various axial stresses, which gives us the critical viscoplastic strain at which grain breakage (i.e., tertiary creep) is expected to occur. The comparison of simulation results for short-term and long-term creep indicates that the initiation of tertiary creep depends on the stress and the viscoplastic strain. We use the critical viscoplastic deformation as a yield criterion to control the transition between secondary and tertiary creep in a phenomenological viscoplastic model, which we implement into the Finite Element Method program POROFIS. We model a 850-m-deep salt cavern of irregular shape, in axis-symmetric conditions. Simulations of cavern depressurization indicate that a strain-dependent damage evolution law is more suitable than a stress-dependent damage evolution law, because it avoids high damage concentrations and allows capturing the formation of a damaged zone around the cavity. The modeling framework explained in this paper is expected to provide new insights to link grain breakage to phenomenological damage variables used in Continuum Damage Mechanics.

Awareness about basic life support and emergency medical services and its associated factors among students in a tertiary care hospital in South India.

PubMed

Aroor, Akshatha Rao; Saya, Rama Prakash; Attar, Nazir Rahim; Saya, Ganesh Kumar; Ravinanthanan, Manikandan

2014-07-01

The knowledge and skills about the basic life support (BLS) and the advanced life support are the most important determining factors of the cardiopulmonary resuscitation (CPR) success rates. To determine the level of awareness on BLS and skills among undergraduate and postgraduate students of medical and dental profession, as well as nursing students and interns in a tertiary care hospital. This descriptive cross-sectional study was conducted in a tertiary care hospital in South India. The awareness level on BLS and factors associated which include age, sex, level of training (undergraduate, internship, and postgraduate groups), course of study (nursing, dental, and medical groups), and previous exposure to BLS were assessed by using a structured questionnaire. The association of these variables with awareness level was assessed by independent t test, analysis of variance, and linear regression analysis. Among 520 study subjects, 229 were students, 171 were interns, and 120 were postgraduate students. The overall mean score of awareness was 4.16 ± 1.40 (score range: 0-10). Age, sex, level of training, course of study, and previous exposure to BLS were significantly associated with awareness level in univariate analysis (P < 0.05). Linear regression model also showed that all the above variables were significantly associated with awareness level (P < 0.05). About 322 (61.9%) subjects attributed lack of awareness about BLS to lack of available professional training. About 479 (92.1%) responded that BLS training should be a part of medical curriculum. Awareness level on BLS is below average indicating the importance of professional training at all levels in a tertiary care health institution.

Geologic framework of lower Cook Inlet, Alaska

USGS Publications Warehouse

Fisher, M.A.; Magoon, L.B.

1978-01-01

Three seismic reflectors are present throughout the lower Cook Inlet basin and can be correlated with onshore geologic features. The reflections come from unconformities at the base of the Tertiary sequence, at the base of Upper Cretaceous rocks, and near the base of Upper Jurassic strata. A contour map of the deepest horizon shows that Mesozoic rocks are formed into a northeast-trending syncline. Along the southeast flank of the basin, the northwest-dipping Mesozoic rocks are truncated at the base of Tertiary rocks. The Augustine-Seldovia arch trends across the basin axis between Augustine Island and Seldovia. Tertiary rocks thin onto the arch from the north and south. Numerous anticlines, smaller in structural relief and breadth than the Augustine-Seldovia arch, trend northeast parallel with the basin, and intersect the arch at oblique angles. The stratigraphic record shows four cycles of sedimentation and tectonism that are bounded by three regional unconformities in lower Cook Inlet and by four thrust faults and the modern Benioff zone in flysch rocks of the Kenai Peninsula and the Gulf of Alaska. The four cycles of sedimentation are, from oldest to youngest, the early Mesozoic, late Mesozoic, early Cenozoic, and late Cenozoic. Data on organic geochemistry of the rocks from one well suggest that Middle Jurassic strata may be a source of hydrocarbons. Seismic data show that structural traps are formed by northeast-trending anticlines and by structures formed at the intersections of these anticlines with the transbasin arch. Stratigraphic traps may be formed beneath the unconformity at the base of Tertiary strata and beneath unconformities within Mesozoic strata.

Long-range tertiary interactions in single hammerhead ribozymes bias motional sampling toward catalytically active conformations

PubMed Central

McDowell, S. Elizabeth; Jun, Jesse M.; Walter, Nils G.

2010-01-01

Enzymes generally are thought to derive their functional activity from conformational motions. The limited chemical variation in RNA suggests that such structural dynamics may play a particularly important role in RNA function. Minimal hammerhead ribozymes are known to cleave efficiently only in ∼10-fold higher than physiologic concentrations of Mg2+ ions. Extended versions containing native loop–loop interactions, however, show greatly enhanced catalytic activity at physiologically relevant Mg2+ concentrations, for reasons that are still ill-understood. Here, we use Mg2+ titrations, activity assays, ensemble, and single molecule fluorescence resonance energy transfer (FRET) approaches, combined with molecular dynamics (MD) simulations, to ask what influence the spatially distant tertiary loop–loop interactions of an extended hammerhead ribozyme have on its structural dynamics. By comparing hammerhead variants with wild-type, partially disrupted, and fully disrupted loop–loop interaction sequences we find that the tertiary interactions lead to a dynamic motional sampling that increasingly populates catalytically active conformations. At the global level the wild-type tertiary interactions lead to more frequent, if transient, encounters of the loop-carrying stems, whereas at the local level they lead to an enrichment in favorable in-line attack angles at the cleavage site. These results invoke a linkage between RNA structural dynamics and function and suggest that loop–loop interactions in extended hammerhead ribozymes—and Mg2+ ions that bind to minimal ribozymes—may generally allow more frequent access to a catalytically relevant conformation(s), rather than simply locking the ribozyme into a single active state. PMID:20921269

Tertiary instability of zonal flows within the Wigner-Moyal formulation of drift turbulence

NASA Astrophysics Data System (ADS)

Zhu, Hongxuan; Ruiz, D. E.; Dodin, I. Y.

2017-10-01

The stability of zonal flows (ZFs) is analyzed within the generalized-Hasegawa-Mima model. The necessary and sufficient condition for a ZF instability, which is also known as the tertiary instability, is identified. The qualitative physics behind the tertiary instability is explained using the recently developed Wigner-Moyal formulation and the corresponding wave kinetic equation (WKE) in the geometrical-optics (GO) limit. By analyzing the drifton phase space trajectories, we find that the corrections proposed in Ref. to the WKE are critical for capturing the spatial scales characteristic for the tertiary instability. That said, we also find that this instability itself cannot be adequately described within a GO formulation in principle. Using the Wigner-Moyal equations, which capture diffraction, we analytically derive the tertiary-instability growth rate and compare it with numerical simulations. The research was sponsored by the U.S. Department of Energy.

Construction of topological structure of 3D coronary vessels for analysis of catheter navigation in interventional cardiology simulation

NASA Astrophysics Data System (ADS)

Wang, Yaoping; Chui, Cheekong K.; Cai, Yiyu; Mak, KoonHou

1998-06-01

This study presents an approach to build a 3D vascular system of coronary for the development of a virtual cardiology simulator. The 3D model of the coronary arterial tree is reconstructed from the geometric information segmented from the Visible Human data set for physical analysis of catheterization. The process of segmentation is guided by a 3D topologic hierarchy structure of coronary vessels which is obtained from a mechanical model by using Coordinate Measuring Machine (CMM) probing. This mechanical professional model includes all major coronary arterials ranging from right coronary artery to atrioventricular branch and from left main trunk to left anterior descending branch. All those branches are considered as the main operating sites for cardiology catheterization. Along with the primary arterial vasculature and accompanying secondary and tertiary networks obtained from a previous work, a more complete vascular structure can then be built for the simulation of catheterization. A novel method has been developed for real time Finite Element Analysis of catheter navigation based on this featured vasculature of vessels.

High-Resolution 3D P-Wave Velocity Model in the Trans-European Suture Zone in Poland

NASA Astrophysics Data System (ADS)

Polkowski, M.; Grad, M.; Ostaficzuk, S.

2014-12-01

Poland is located on conjunction of major European tectonic units - the Precambrian East European Craton and the Paleozoic Platform of Central and Western Europe. This conjunction is known as Trans-European Suture Zone (TESZ). Geological and seismic structure under area of Poland is well studied by over one hundred thousand boreholes, over thirty deep seismic refraction and wide angle reflection profiles and other methods: vertical seismic profiling, magnetic, gravity, magnetotelluric, thermal. Compilation of these studies allows creation of detailed, high-resolution 3D P-wave velocity model for entire Earth's crust in the area of Poland. Model provides detailed six layer sediments (Tertiary and Quaternary, Cretaceous, Jurassic, Triassic, Permian, old Paleozoic), consolidated / crystalline crust and uppermost mantle. Continental suturing is a fundamental part of the plate tectonic cycle, and knowing its detailed structure allows understanding plate tectonic cycle. We present a set of crustal cross sections through the TESZ, illustrating differentiation in the structure between Precambrian and Wariscan Europe. National Science Centre Poland provided financial support for this work by NCN grant DEC- 2011/02/A/ST10/00284.

Seismic Expression of Fault Related Folding in Southeastern Turkey

NASA Astrophysics Data System (ADS)

Beauchamp, W.; McDonald, D.

2009-12-01

Weldon Beauchamp, and David McDonald,TransAtlantic Petroleum Corp. 5910 N. Central Expressway, Suite 1755, Dallas, TX 75206 weldon@tapcor.com, 214-395-7125 The Zagros fold belt extends northwest from Iran and Iraq into southeastern Turkey. Large scale fault related folds control the topography of this region and the path of the Tigris river. Large surface anticlines in the Zagros Mountains provide traps for giant oil and gas fields in Iran and Iraq. Similar scale folds extend into southeast Turkey. These southward verging fault related folds are believed to detach in the Paleozoic. Borehole data, surface geological maps, satellite data and digital topographic models were used to create models to constrain structure at depth. Structural modeling of these folds was used to design, acquire and process seismic reflection data in the region. The seismic reflection data confirmed the presence of asymmetrical, south verging complex fault related folding. Faults related to these folds detach in the Lower Ordovician to Cambrian age shales. These folds are believed to form doubly plunging structures that fold Tertiary through Paleozoic age rocks forming multiple levels of possible hydrocarbon entrapment.

Predicting change in epistemological beliefs, reflective thinking and learning styles: a longitudinal study.

PubMed

Phan, Huy P

2008-03-01

Although extensive research has examined epistemological beliefs, reflective thinking and learning approaches, very few studies have looked at these three theoretical frameworks in their totality. This research tested two separate structural models of epistemological beliefs, learning approaches, reflective thinking and academic performance among tertiary students over a period of 12 months. Participants were first-year Arts (N=616; 271 females, 345 males) and second-year Mathematics (N=581; 241 females, 341 males) university students. Students' epistemological beliefs were measured with the Schommer epistemological questionnaire (EQ, Schommer, 1990). Reflective thinking was measured with the reflective thinking questionnaire (RTQ, Kember et al., 2000). Student learning approaches were measured with the revised study process questionnaire (R-SPQ-2F, Biggs, Kember, & Leung, 2001). LISREL 8 was used to test two structural equation models - the cross-lag model and the causal-mediating model. In the cross-lag model involving Arts students, structural equation modelling showed that epistemological beliefs influenced student learning approaches rather than the contrary. In the causal-mediating model involving Mathematics students, the results indicate that both epistemological beliefs and learning approaches predicted reflective thinking and academic performance. Furthermore, learning approaches mediated the effect of epistemological beliefs on reflective thinking and academic performance. Results of this study are significant as they integrated the three theoretical frameworks within the one study.

Reduction in lipophilicity improved the solubility, plasma–protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fauber, Benjamin P.; René, Olivier; de Leon Boenig, Gladys

2014-08-01

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma–protein unbound fraction and improvements in cellular permeability and aqueous solubility.

Concerning the production of free radicals in proteins by ultraviolet light.

NASA Technical Reports Server (NTRS)

Androes, G. M.; Gloria, H. R.; Reinisch, R. F.

1972-01-01

The response to UV light of several solid proteins and model compounds has been studied in vacuum and at low temperature, using electron paramagnetic resonance techniques. The results indicate that the details of amino acid composition and sequence, and the tertiary structure of a protein are important in determining both the rate of, and the mechanism for, the production of free radicals, and in determining the conditions under which sulfur-type radicals can be produced. The results presented are related to enzyme inactivation and to the UV stability of proteins generally.

Data set for phylogenetic tree and RAMPAGE Ramachandran plot analysis of SODs in Gossypium raimondii and G. arboreum.

PubMed

Wang, Wei; Xia, Minxuan; Chen, Jie; Deng, Fenni; Yuan, Rui; Zhang, Xiaopei; Shen, Fafu

2016-12-01

The data presented in this paper is supporting the research article "Genome-Wide Analysis of Superoxide Dismutase Gene Family in Gossypium raimondii and G. arboreum" [1]. In this data article, we present phylogenetic tree showing dichotomy with two different clusters of SODs inferred by the Bayesian method of MrBayes (version 3.2.4), "Bayesian phylogenetic inference under mixed models" [2], Ramachandran plots of G. raimondii and G. arboreum SODs, the protein sequence used to generate 3D sructure of proteins and the template accession via SWISS-MODEL server, "SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information." [3] and motif sequences of SODs identified by InterProScan (version 4.8) with the Pfam database, "Pfam: the protein families database" [4].

Assembly and analysis of eukaryotic Argonaute–RNA complexes in microRNA-target recognition

PubMed Central

Gan, Hin Hark; Gunsalus, Kristin C.

2015-01-01

Experimental studies have uncovered a variety of microRNA (miRNA)–target duplex structures that include perfect, imperfect and seedless duplexes. However, non-canonical binding modes from imperfect/seedless duplexes are not well predicted by computational approaches, which rely primarily on sequence and secondary structural features, nor have their tertiary structures been characterized because solved structures to date are limited to near perfect, straight duplexes in Argonautes (Agos). Here, we use structural modeling to examine the role of Ago dynamics in assembling viable eukaryotic miRNA-induced silencing complexes (miRISCs). We show that combinations of low-frequency, global modes of motion of Ago domains are required to accommodate RNA duplexes in model human and C. elegans Ago structures. Models of viable miRISCs imply that Ago adopts variable conformations at distinct target sites that generate distorted, imperfect miRNA-target duplexes. Ago's ability to accommodate a duplex is dependent on the region where structural distortions occur: distortions in solvent-exposed seed and 3′-end regions are less likely to produce steric clashes than those in the central duplex region. Energetic analyses of assembled miRISCs indicate that target recognition is also driven by favorable Ago-duplex interactions. Such structural insights into Ago loading and target recognition mechanisms may provide a more accurate assessment of miRNA function. PMID:26432829

The attachment of α -synuclein to a fiber: A coarse-grain approach

NASA Astrophysics Data System (ADS)

Ilie, Ioana M.; den Otter, Wouter K.; Briels, Wim J.

2017-03-01

We present simulations of the amyloidogenic core of α-synuclein, the protein causing Parkinson's disease, as a short chain of coarse-grain patchy particles. Each particle represents a sequence of about a dozen amino acids. The fluctuating secondary structure of this intrinsically disordered protein is modelled by dynamic variations of the shape and interaction characteristics of the patchy particles, ranging from spherical with weak isotropic attractions for the disordered state to spherocylindrical with strong directional interactions for a β-sheet. Flexible linkers between the particles enable sampling of the tertiary structure. This novel model is applied here to study the growth of an amyloid fibril, by calculating the free energy profile of a protein attaching to the end of a fibril. The simulation results suggest that the attaching protein readily becomes trapped in a mis-folded state, thereby inhibiting further growth of the fibril until the protein has readjusted to conform to the fibril structure, in line with experimental findings and previous simulations on small fragments of other proteins.

Structural model of an mRNA in complex with the bacterial chaperone Hfq

DOE PAGES

Peng, Yi; Curtis, Joseph E.; Fang, Xianyang; ...

2014-11-17

The Sm-like protein Hfq (host factor Q-beta phage) facilitates regulation by bacterial small noncoding RNAs (sRNAs) in response to stress and other environmental signals. In this paper, we present a low-resolution model of Escherichia coli Hfq bound to the rpoS mRNA, a bacterial stress response gene that is targeted by three different sRNAs. Selective 2'-hydroxyl acylation and primer extension, small-angle X-ray scattering, and Monte Carlo molecular dynamics simulations show that the distal face and lateral rim of Hfq interact with three sites in the rpoS leader, folding the RNA into a compact tertiary structure. These interactions are needed for sRNAmore » regulation of rpoS translation and position the sRNA target adjacent to an sRNA binding region on the proximal face of Hfq. Finally, our results show how Hfq specifically distorts the structure of the rpoS mRNA to enable sRNA base pairing and translational control.« less

An Amino Acid Code for β-sheet Packing Structure

PubMed Central

Joo, Hyun; Tsai, Jerry

2014-01-01

To understand the relationship between protein sequence and structure, this work extends the knob-socket model in an investigation of β-sheet packing. Over a comprehensive set of β-sheet folds, the contacts between residues were used to identify packing cliques: sets of residues that all contact each other. These packing cliques were then classified based on size and contact order. From this analysis, the 2 types of 4 residue packing cliques necessary to describe β-sheet packing were characterized. Both occur between 2 adjacent hydrogen bonded β-strands. First, defining the secondary structure packing within β-sheets, the combined socket or XY:HG pocket consists of 4 residues i,i+2 on one strand and j,j+2 on the other. Second, characterizing the tertiary packing between β-sheets, the knob-socket XY:H+B consists of a 3 residue XY:H socket (i,i+2 on one strand and j on the other) packed against a knob B residue (residue k distant in sequence). Depending on the packing depth of the knob B residue, 2 types of knob-sockets are found: side-chain and main-chain sockets. The amino acid composition of the pockets and knob-sockets reveal the sequence specificity of β-sheet packing. For β-sheet formation, the XY:HG pocket clearly shows sequence specificity of amino acids. For tertiary packing, the XY:H+B side-chain and main-chain sockets exhibit distinct amino acid preferences at each position. These relationships define an amino acid code for β-sheet structure and provide an intuitive topological mapping of β-sheet packing. PMID:24668690

Molecular dynamics study of unfolding of lysozyme in water and its mixtures with dimethyl sulfoxide.

PubMed

Sedov, Igor A; Magsumov, Timur I

2017-09-01

All-atom explicit solvent molecular dynamics was used to study the process of unfolding of hen egg white lysozyme in water and mixtures of water with dimethyl sulfoxide at different compositions. We have determined the kinetic parameters of unfolding at a constant temperature 450K. For each run, the time of disruption of the tertiary structure of lysozyme t u was defined as the moment when a certain structural criterion computed from the trajectory reaches its critical value. A good agreement is observed between the results obtained using several different criteria. The secondary structure according to DSSP calculations is found to be partially unfolded to the moment of disruption of tertiary structure, but some of its elements keep for a long time after that. The values of t u averaged over ten 30ns-long trajectories for each solvent composition are shown to decrease very rapidly with addition of dimethyl sulfoxide, and rather small amounts of dimethyl sulfoxide are found to change the pathway of unfolding. In pure water, despite the loss of tertiary contacts and disruption of secondary structure elements, the protein preserves its compact globular state at least over 130ns of simulation, while even at 5mol percents of dimethyl sulfoxide it loses its compactness within 30ns. The proposed methodology is a generally applicable tool to quantify the rate of protein unfolding in simulation studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Computational Analysis of the Ligand Binding Site of the Extracellular ATP Receptor, DORN1

DOE PAGES

Nguyen, Cuong The; Tanaka, Kiwamu; Cao, Yangrong; ...

2016-09-01

DORN1 (also known as P2K1) is a plant receptor for extracellular ATP, which belongs to a large gene family of legume-type (L-type) lectin receptor kinases. Extracellular ATP binds to DORN1 with strong affinity through its lectin domain, and the binding triggers a variety of intracellular activities in response to biotic and abiotic stresses. However, information on the tertiary structure of the ligand binding site of DORN1is lacking, which hampers efforts to fully elucidate the mechanism of receptor action. Available data of the crystal structures from more than 50 L-type lectins enable us to perform an in silico study of molecularmore » interaction between DORN1 and ATP. In this study, we employed a computational approach to develop a tertiary structure model of the DORN1 lectin domain. A blind docking analysis demonstrated that ATP binds to a cavity made by four loops (defined as loops A B, C and D) of the DORN1 lectin domain with high affinity. In silico target docking of ATP to the DORN1 binding site predicted interaction with 12 residues, located on the four loops, via hydrogen bonds and hydrophobic interactions. The ATP binding pocket is structurally similar in location to the carbohydrate binding pocket of the canonical L-type lectins. However, four of the residues predicted to interact with ATP are not conserved between DORN1 and the other carbohydrate-binding lectins, suggesting that diversifying selection acting on these key residues may have led to the ATP binding activity of DORN1. Finally, the in silico model was validated by in vitro ATP binding assays using the purified extracellular lectin domain of wild-type DORN1, as well as mutated DORN1 lacking key ATP binding residues.« less

Computational Analysis of the Ligand Binding Site of the Extracellular ATP Receptor, DORN1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Cuong The; Tanaka, Kiwamu; Cao, Yangrong

DORN1 (also known as P2K1) is a plant receptor for extracellular ATP, which belongs to a large gene family of legume-type (L-type) lectin receptor kinases. Extracellular ATP binds to DORN1 with strong affinity through its lectin domain, and the binding triggers a variety of intracellular activities in response to biotic and abiotic stresses. However, information on the tertiary structure of the ligand binding site of DORN1is lacking, which hampers efforts to fully elucidate the mechanism of receptor action. Available data of the crystal structures from more than 50 L-type lectins enable us to perform an in silico study of molecularmore » interaction between DORN1 and ATP. In this study, we employed a computational approach to develop a tertiary structure model of the DORN1 lectin domain. A blind docking analysis demonstrated that ATP binds to a cavity made by four loops (defined as loops A B, C and D) of the DORN1 lectin domain with high affinity. In silico target docking of ATP to the DORN1 binding site predicted interaction with 12 residues, located on the four loops, via hydrogen bonds and hydrophobic interactions. The ATP binding pocket is structurally similar in location to the carbohydrate binding pocket of the canonical L-type lectins. However, four of the residues predicted to interact with ATP are not conserved between DORN1 and the other carbohydrate-binding lectins, suggesting that diversifying selection acting on these key residues may have led to the ATP binding activity of DORN1. Finally, the in silico model was validated by in vitro ATP binding assays using the purified extracellular lectin domain of wild-type DORN1, as well as mutated DORN1 lacking key ATP binding residues.« less

Massification and Diversification as Complementary Strategies for Economic Growth in Developed and Developing Countries

ERIC Educational Resources Information Center

Tyndorf, Darryl; Glass, Chris R.

2016-01-01

Numerous microeconomic studies demonstrate the significant individual returns to tertiary education; however, little empirical evidence exists regarding the effects of higher education massification and diversification agendas on long-term macroeconomic growth. The researchers used the Uzawa-Lucas endogenous growth model to tertiary education…

Improving mental health service users' with medical co-morbidity transition between tertiary medical hospital and primary care services: a qualitative study.

PubMed

Cranwell, Kate; Polacsek, Meg; McCann, Terence V

2016-07-26

Mental health service users have high rates of medical co-morbidity but frequently experience problems accessing and transitioning between tertiary medical and primary care services. The aim of this study was to identify ways to improve service users' with medical co-morbidity care and experience during their transition between tertiary medical hospitals and primary care services. Experience-based co-design (EBCD) qualitative study incorporating a focus group discussion. The study took place in a large tertiary medical service, incorporating three medical hospitals, and primary care services, in Melbourne, Australia. A purposive sample of service users and their caregivers and tertiary medical and primary care clinicians participated in the focus group discussion, in August 2014. A semi-structured interview guide was used to inform data collection. A thematic analysis of the data was undertaken. Thirteen participants took part in the focus group interview, comprising 5 service users, 2 caregivers and 6 clinicians. Five themes were abstracted from the data, illustrating participants' perspectives about factors that facilitated (clinicians' expertise, engagement and accessibility enhancing transition) and presented as barriers (improving access pathways; enhancing communication and continuity of care; improving clinicians' attitudes; and increasing caregiver participation) to service users' progress through tertiary medical and primary care services. A sixth theme, enhancing service users' transition, incorporated three strategies to enhance their transition through tertiary medical and primary care services. EBCD is a useful approach to collaboratively develop strategies to improve service users' with medical co-morbidity and their caregivers' transition between tertiary medical and primary care services. A whole-of-service approach, incorporating policy development and implementation, change of practice philosophy, professional development education and support for clinicians, and acceptance of the need for caregiver participation, is required to improve service users' transition.

Structural rearrangements at the translocation pore of the human glutamate transporter, EAAT1.

PubMed

Leighton, Barbara H; Seal, Rebecca P; Watts, Spencer D; Skyba, Mary O; Amara, Susan G

2006-10-06

Structure-function studies of mammalian and bacterial excitatory amino acid transporters (EAATs), as well as the crystal structure of a related archaeal glutamate transporter, support a model in which TM7, TM8, and the re-entrant loops HP1 and HP2 participate in forming a substrate translocation pathway within each subunit of a trimer. However, the transport mechanism, including precise binding sites for substrates and co-transported ions and changes in the tertiary structure underlying transport, is still not known. In this study, we used chemical cross-linking of introduced cysteine pairs in a cysteine-less version of EAAT1 to examine the dynamics of key domains associated with the translocation pore. Here we show that cysteine substitution at Ala-395, Ala-367, and Ala-440 results in functional single and double cysteine transporters and that in the absence of glutamate or dl-threo-beta-benzyloxyaspartate (dl-TBOA), A395C in the highly conserved TM7 can be cross-linked to A367C in HP1 and to A440C in HP2. The formation of these disulfide bonds is reversible and occurs intra-molecularly. Interestingly, cross-linking A395C to A367C appears to abolish transport, whereas cross-linking A395C to A440C lowers the affinities for glutamate and dl-TBOA but does not change the maximal transport rate. Additionally, glutamate and dl-TBOA binding prevent cross-linking in both double cysteine transporters, whereas sodium binding facilitates cross-linking in the A395C/A367C transporter. These data provide evidence that within each subunit of EAAT1, Ala-395 in TM7 resides close to a residue at the tip of each re-entrant loop (HP1 and HP2) and that these residues are repositioned relative to one another at different steps in the transport cycle. Such behavior likely reflects rearrangements in the tertiary structure of the translocation pore during transport and thus provides constraints for modeling the structural dynamics associated with transport.

Predicting 3D structure and stability of RNA pseudoknots in monovalent and divalent ion solutions.

PubMed

Shi, Ya-Zhou; Jin, Lei; Feng, Chen-Jie; Tan, Ya-Lan; Tan, Zhi-Jie

2018-06-01

RNA pseudoknots are a kind of minimal RNA tertiary structural motifs, and their three-dimensional (3D) structures and stability play essential roles in a variety of biological functions. Therefore, to predict 3D structures and stability of RNA pseudoknots is essential for understanding their functions. In the work, we employed our previously developed coarse-grained model with implicit salt to make extensive predictions and comprehensive analyses on the 3D structures and stability for RNA pseudoknots in monovalent/divalent ion solutions. The comparisons with available experimental data show that our model can successfully predict the 3D structures of RNA pseudoknots from their sequences, and can also make reliable predictions for the stability of RNA pseudoknots with different lengths and sequences over a wide range of monovalent/divalent ion concentrations. Furthermore, we made comprehensive analyses on the unfolding pathway for various RNA pseudoknots in ion solutions. Our analyses for extensive pseudokonts and the wide range of monovalent/divalent ion concentrations verify that the unfolding pathway of RNA pseudoknots is mainly dependent on the relative stability of unfolded intermediate states, and show that the unfolding pathway of RNA pseudoknots can be significantly modulated by their sequences and solution ion conditions.

Formation Mechanism of NDMA from Ranitidine, Trimethylamine, and Other Tertiary Amines during Chloramination: A Computational Study

PubMed Central

2015-01-01

Chloramination of drinking waters has been associated with N-nitrosodimethylamine (NDMA) formation as a disinfection byproduct. NDMA is classified as a probable carcinogen and thus its formation during chloramination has recently become the focus of considerable research interest. In this study, the formation mechanisms of NDMA from ranitidine and trimethylamine (TMA), as models of tertiary amines, during chloramination were investigated by using density functional theory (DFT). A new four-step formation pathway of NDMA was proposed involving nucleophilic substitution by chloramine, oxidation, and dehydration followed by nitrosation. The results suggested that nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines. When 45 other tertiary amines were examined, the proposed mechanism was found to be more applicable to aromatic tertiary amines, and there may be still some additional factors or pathways that need to be considered for aliphatic tertiary amines. The heterolytic ONN(Me)2–R+ bond dissociation energy to release NDMA and carbocation R+ was found to be a criterion for evaluating the reactivity of aromatic tertiary amines. A structure–activity study indicates that tertiary amines with benzyl, aromatic heterocyclic ring, and diene-substituted methenyl adjacent to the DMA moiety are potentially significant NDMA precursors. The findings of this study are helpful for understanding NDMA formation mechanism and predicting NDMA yield of a precursor. PMID:24968236

Three-residue turns in alpha/beta-peptides and their application in the design of tertiary structures.

PubMed

Sharma, Gangavaram V M; Nagendar, Pendem; Ramakrishna, Kallaganti V S; Chandramouli, Nagula; Choudhary, Madavi; Kunwar, Ajit C

2008-06-02

A new three-residue turn was serendipitously discovered in alpha/beta hybrid peptides derived from alternating C-linked carbo-beta-amino acids (beta-Caa) and L-Ala residues. The three-residue beta-alpha-beta turn at the C termini, nucleated by a helix at the N termini, resulted in helix-turn (HT) supersecondary structures in these peptides. The turn in the HT motif is stabilized by two H bonds-CO(i-2)-NH(i), with a seven-membered pseudoring (gamma turn) in the backward direction, and NH(i-2)-CO(i), with a 13-membered pseudoring in the forward direction (i being the last residue)--at the C termini. The study was extended to generalize the new three-residue turn (beta-alpha-beta) by using different alpha- and beta-amino acids. Furthermore, the HT motifs were efficiently converted, by an extension with helical oligomers at the C termini, into peptides with novel helix-turn-helix (HTH) tertiary structures. However, this resulted in the destabilization of the beta-alpha-beta turn with the concomitant nucleation of another three-residue turn, alpha-beta-beta, which is stabilized by 11- and 15-membered bifurcated H bonds. Extensive NMR spectroscopic studies were carried out to delineate the secondary and tertiary structures in these peptides, which are further supported by molecular dynamics (MD) investigations.

Representing the Marginal Stability of Peptides in Coarse Grained Models

NASA Astrophysics Data System (ADS)

Sayar, Mehmet; Dalgicdir, Cahit; Ramezanghorbani, Farhad

Tertiary structure of proteins is only marginally stable; such that the folded structure is separated from local minima by as little as 10 kcal/mol. In particular for intrinsically disordered peptides, this marginal stability is key to understanding their complex behavior. Bottom-up coarse grained (CG) models for proteins/peptides which rely on structural and/or thermodynamic reference data from experiments or all atom simulations inherently focus on the equilibrium structure and fail to capture the conformational dynamics of the molecule. In this study, we present a CG model for a synthetic peptide, LK, which successfully captures the conformational flexibility of the molecule in different environments. LK peptide is composed of leucine and lysine residues and displays a stark conformational transition from a degenerate conformation in dilute solution to a fully stable alpha-helix at macroscopic and molecular interfaces. In this study we demonstrate that by carefully combining atomistic references from both the unfolded and folded states, one can create a CG model that can represent not only the folded state, but also the conformational transitions that the peptide exhibits in response to changes in the environment. M. Sayar thanks TÜBİTAK (Grant No. 212T184) and TÜBA Distinguished Young Scientist Award (2012 awardee) for financial support.

Introduction to bioinformatics.

PubMed

Can, Tolga

2014-01-01

Bioinformatics is an interdisciplinary field mainly involving molecular biology and genetics, computer science, mathematics, and statistics. Data intensive, large-scale biological problems are addressed from a computational point of view. The most common problems are modeling biological processes at the molecular level and making inferences from collected data. A bioinformatics solution usually involves the following steps: Collect statistics from biological data. Build a computational model. Solve a computational modeling problem. Test and evaluate a computational algorithm. This chapter gives a brief introduction to bioinformatics by first providing an introduction to biological terminology and then discussing some classical bioinformatics problems organized by the types of data sources. Sequence analysis is the analysis of DNA and protein sequences for clues regarding function and includes subproblems such as identification of homologs, multiple sequence alignment, searching sequence patterns, and evolutionary analyses. Protein structures are three-dimensional data and the associated problems are structure prediction (secondary and tertiary), analysis of protein structures for clues regarding function, and structural alignment. Gene expression data is usually represented as matrices and analysis of microarray data mostly involves statistics analysis, classification, and clustering approaches. Biological networks such as gene regulatory networks, metabolic pathways, and protein-protein interaction networks are usually modeled as graphs and graph theoretic approaches are used to solve associated problems such as construction and analysis of large-scale networks.

Conceptual model of the uppermost principal aquifer systems in the Williston and Powder River structural basins, United States and Canada

USGS Publications Warehouse

Long, Andrew J.; Aurand, Katherine R.; Bednar, Jennifer M.; Davis, Kyle W.; McKaskey, Jonathan D.R.G.; Thamke, Joanna N.

2014-01-01

The three uppermost principal aquifer systems of the Northern Great Plains—the glacial, lower Tertiary, and Upper Cretaceous aquifer systems—are described in this report and provide water for irrigation, mining, public and domestic supply, livestock, and industrial uses. These aquifer systems primarily are present in two nationally important fossil-fuelproducing areas: the Williston and Powder River structural basins in the United States and Canada. The glacial aquifer system is contained within glacial deposits that overlie the lower Tertiary and Upper Cretaceous aquifer systems in the northeastern part of the Williston structural basin. Productive sand and gravel aquifers exist within this aquifer system. The Upper Cretaceous aquifer system is contained within bedrock lithostratigraphic units as deep as 2,850 and 8,500 feet below land surface in the Williston and Powder River structural basins, respectively. Petroleum extraction from much deeper formations, such as the Bakken Formation, is rapidly increasing because of recently improved hydraulic fracturing methods that require large volumes of relatively freshwater from shallow aquifers or surface water. Extraction of coalbed natural gas from within the lower Tertiary aquifer system requires removal of large volumes of groundwater to allow degasification. Recognizing the importance of understanding water resources in these energy-rich basins, the U.S. Geological Survey (USGS) Groundwater Resources Program (http://water.usgs.gov/ogw/gwrp/) began a groundwater study of the Williston and Powder River structural basins in 2011 to quantify this groundwater resource, the results of which are described in this report. The overall objective of this study was to characterize, quantify, and provide an improved conceptual understanding of the three uppermost and principal aquifer systems in energy-resource areas of the Northern Great Plains to assist in groundwater-resource management for multiple uses. The study area includes parts of Montana, North Dakota, South Dakota, and Wyoming in the United States and Manitoba and Saskatchewan in Canada. The glacial aquifer system is contained within glacial drift consisting primarily of till, with smaller amounts of glacial outwash sand and gravel deposits. The lower Tertiary and Upper Cretaceous aquifer systems are contained within several formations of the Tertiary and Cretaceous geologic systems, which are hydraulically separated from underlying aquifers by a basal confining unit. The lower Tertiary and Upper Cretaceous aquifer systems each were divided into three hydrogeologic units that correspond to one or more lithostratigraphic units. The period prior to 1960 is defined as the predevelopment period when little groundwater was extracted. From 1960 through 1990, numerous flowing wells were installed near the Yellowstone, Little Missouri and Knife Rivers, resulting in local groundwater declines. Recently developed technologies for the extraction of petroleum resources, which largely have been applied in the study area since about 2005, require millions of gallons of water for construction of each well, with additional water needed for long-term operation; therefore, the potential for an increase in groundwater extraction is high. In this study, groundwater recharge and discharge components were estimated for the period 1981–2005. Groundwater recharge primarily occurs from infiltration of rainfall and snowmelt (precipitation recharge) and infiltration of streams into the ground (stream infiltration). Total estimated recharge to the Williston and Powder River control volumes is 4,560 and 1,500 cubic feet per second, respectively. Estimated precipitation recharge is 26 and 15 percent of total recharge for the Williston and Powder River control volumes, respectively. Estimated stream infiltration is 71 and 80 percent of total recharge for the Williston and Powder River control volumes, respectively. Groundwater discharge primarily is to streams and springs and is estimated to be about 97 and 92 percent of total discharge for the Williston and Powder River control volumes, respectively. Most of the remaining discharge results from pumped and flowing wells. Groundwater flow in the Williston structural basin generally is from the west and southwest toward the east, where discharge to streams occurs. Locally, in the uppermost hydrogeologic units, groundwater generally is unconfined and flows from topographically high to low areas, where discharge to streams occurs. Groundwater flow in the Powder River structural basin generally is toward the north, with local variations, particularly in the upper Fort Union aquifer, where flow is toward streams.

BindML/BindML+: Detecting Protein-Protein Interaction Interface Propensity from Amino Acid Substitution Patterns.

PubMed

Wei, Qing; La, David; Kihara, Daisuke

2017-01-01

Prediction of protein-protein interaction sites in a protein structure provides important information for elucidating the mechanism of protein function and can also be useful in guiding a modeling or design procedures of protein complex structures. Since prediction methods essentially assess the propensity of amino acids that are likely to be part of a protein docking interface, they can help in designing protein-protein interactions. Here, we introduce BindML and BindML+ protein-protein interaction sites prediction methods. BindML predicts protein-protein interaction sites by identifying mutation patterns found in known protein-protein complexes using phylogenetic substitution models. BindML+ is an extension of BindML for distinguishing permanent and transient types of protein-protein interaction sites. We developed an interactive web-server that provides a convenient interface to assist in structural visualization of protein-protein interactions site predictions. The input data for the web-server are a tertiary structure of interest. BindML and BindML+ are available at http://kiharalab.org/bindml/ and http://kiharalab.org/bindml/plus/ .

Kinact: a computational approach for predicting activating missense mutations in protein kinases.

PubMed

Rodrigues, Carlos H M; Ascher, David B; Pires, Douglas E V

2018-05-21

Protein phosphorylation is tightly regulated due to its vital role in many cellular processes. While gain of function mutations leading to constitutive activation of protein kinases are known to be driver events of many cancers, the identification of these mutations has proven challenging. Here we present Kinact, a novel machine learning approach for predicting kinase activating missense mutations using information from sequence and structure. By adapting our graph-based signatures, Kinact represents both structural and sequence information, which are used as evidence to train predictive models. We show the combination of structural and sequence features significantly improved the overall accuracy compared to considering either primary or tertiary structure alone, highlighting their complementarity. Kinact achieved a precision of 87% and 94% and Area Under ROC Curve of 0.89 and 0.92 on 10-fold cross-validation, and on blind tests, respectively, outperforming well established tools (P < 0.01). We further show that Kinact performs equally well on homology models built using templates with sequence identity as low as 33%. Kinact is freely available as a user-friendly web server at http://biosig.unimelb.edu.au/kinact/.

DeepQA: improving the estimation of single protein model quality with deep belief networks.

PubMed

Cao, Renzhi; Bhattacharya, Debswapna; Hou, Jie; Cheng, Jianlin

2016-12-05

Protein quality assessment (QA) useful for ranking and selecting protein models has long been viewed as one of the major challenges for protein tertiary structure prediction. Especially, estimating the quality of a single protein model, which is important for selecting a few good models out of a large model pool consisting of mostly low-quality models, is still a largely unsolved problem. We introduce a novel single-model quality assessment method DeepQA based on deep belief network that utilizes a number of selected features describing the quality of a model from different perspectives, such as energy, physio-chemical characteristics, and structural information. The deep belief network is trained on several large datasets consisting of models from the Critical Assessment of Protein Structure Prediction (CASP) experiments, several publicly available datasets, and models generated by our in-house ab initio method. Our experiments demonstrate that deep belief network has better performance compared to Support Vector Machines and Neural Networks on the protein model quality assessment problem, and our method DeepQA achieves the state-of-the-art performance on CASP11 dataset. It also outperformed two well-established methods in selecting good outlier models from a large set of models of mostly low quality generated by ab initio modeling methods. DeepQA is a useful deep learning tool for protein single model quality assessment and protein structure prediction. The source code, executable, document and training/test datasets of DeepQA for Linux is freely available to non-commercial users at http://cactus.rnet.missouri.edu/DeepQA/ .

Chicxulub impact basin: Gravity characteristics and implications for basin morphology and deep structure

NASA Technical Reports Server (NTRS)

Sharpton, Virgil L.; Burke, Kevin; Hall, Stuart A.; Lee, Scott; Marin, Luis E.; Suarez, Gerardo; Quezada-Muneton, Juan Manuel; Urrutia-Fucugauchi, Jaime

1993-01-01

The K-T-aged Chicxulub Impact Structure is buried beneath the Tertiary carbonate rocks of the Northern Yucatan Platform. Consequently its morphology and structure are poorly understood. Reprocessed Bouguer (onshore) and Free Air (offshore) gravity data over Northern Yucatan reveal that Chicxulub may be a 200-km-diameter multi-ring impact basin with at least three concentric basin rings. The positions of these rings follow the square root of 2 spacing rule derived empirically from analysis of multi-ring basins on other planets indicating that these rings probably correspond to now-buried topographic basin rings. A forward model of the gravity data along a radial transect from the southwest margin of the structure indicates that the Chicxulub gravity signature is compatible with this interpretation. We estimate the basin rim diameter to be 204 +/- 16 km and the central peak ring diameter (D) is 104 +/- 6 km.

Ligand-induced folding of the thiM TPP riboswitch investigated by a structure-based fluorescence spectroscopic approach

PubMed Central

Lang, Kathrin; Rieder, Renate; Micura, Ronald

2007-01-01

Riboswitches are genetic control elements within non-coding regions of mRNA. They consist of a metabolite-sensitive aptamer and an adjoining expression platform. Here, we describe ligand-induced folding of a thiamine pyrophosphate (TPP) responsive riboswitch from Escherichia coli thiM mRNA, using chemically labeled variants. Referring to a recent structure determination of the TPP/aptamer complex, each variant was synthesized with a single 2-aminopurine (AP) nucleobase replacement that was selected to monitor formation of tertiary interactions of a particular region during ligand binding in real time by fluorescence experiments. We have determined the rate constants for conformational adjustment of the individual AP sensors. From the 7-fold differentiation of these constants, it can be deduced that tertiary contacts between the two parallel helical domains (P2/J3-2/P3/L3 and P4/P5/L5) that grip the ligand's ends in two separate pockets, form significantly faster than the function-critical three-way junction with stem P1 fully developed. Based on these data, we characterize the process of ligand binding by an induced fit of the RNA and propose a folding model of the TPP riboswitch aptamer. For the full-length riboswitch domain and for shorter constructs that represent transcriptional intermediates, we have additionally evaluated ligand-induced folding via AP-modified variants and provide insights into the sequential folding pathway that involves a finely balanced equilibrium of secondary structures. PMID:17693433

Determination of Cenozoic sedimentary structures using integrated geophysical surveys: A case study in the Barkol Basin, Xinjiang, China

NASA Astrophysics Data System (ADS)

Sun, Kai; Chen, Chao; Du, Jinsong; Wang, Limin; Lei, Binhua

2018-01-01

Thickness estimation of sedimentary basin is a complex geological problem, especially in an orogenic environment. Intense and multiple tectonic movements and climate changes result in inhomogeneity of sedimentary layers and basement configurations, which making sedimentary structure modelling difficult. In this study, integrated geophysical methods, including gravity, magnetotelluric (MT) sounding and electrical resistivity tomography (ERT), were used to estimate basement relief to understand the geological structure and evolution of the eastern Barkol Basin in China. This basin formed with the uplift of the eastern Tianshan during the Cenozoic. Gravity anomaly map revealed the framework of the entire area, and ERT as well as MT sections reflected the geoelectric features of the Cenozoic two-layer distribution. Therefore, gravity data, constrained by MT, ERT and boreholes, were utilized to estimate the spatial distribution of the Quaternary layer. The gravity effect of the Quaternary layer related to the Tertiary layer was later subtracted to obtain the residual anomaly for inversion. For the Tertiary layer, the study area was divided into several parts because of lateral difference of density contrasts. Gravity data were interpreted to determine the density contrast constrained by the MT results. The basement relief can be verified by geological investigation, including the uplift process and regional tectonic setting. The agreement between geophysical survey and prior information from geology emphasizes the importance of integrated geophysical survey as a complementary means of geological studies in this region.

One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue

PubMed Central

Nury, Hugues; Poitevin, Frédéric; Van Renterghem, Catherine; Changeux, Jean-Pierre; Corringer, Pierre-Jean; Delarue, Marc; Baaden, Marc

2010-01-01

Recently discovered bacterial homologues of eukaryotic pentameric ligand-gated ion channels, such as the Gloeobacter violaceus receptor (GLIC), are increasingly used as structural and functional models of signal transduction in the nervous system. Here we present a one-microsecond-long molecular dynamics simulation of the GLIC channel pH stimulated gating mechanism. The crystal structure of GLIC obtained at acidic pH in an open-channel form is equilibrated in a membrane environment and then instantly set to neutral pH. The simulation shows a channel closure that rapidly takes place at the level of the hydrophobic furrow and a progressively increasing quaternary twist. Two major events are captured during the simulation. They are initiated by local but large fluctuations in the pore, taking place at the top of the M2 helix, followed by a global tertiary relaxation. The two-step transition of the first subunit starts within the first 50 ns of the simulation and is followed at 450 ns by its immediate neighbor in the pentamer, which proceeds with a similar scenario. This observation suggests a possible two-step domino-like tertiary mechanism that takes place between adjacent subunits. In addition, the dynamical properties of GLIC described here offer an interpretation of the paradoxical properties of a permeable A13′F mutant whose crystal structure determined at 3.15 Å shows a pore too narrow to conduct ions. PMID:20308576

Effect of pulsed light on activity and structural changes of horseradish peroxidase

USDA-ARS?s Scientific Manuscript database

The objective of this research was to investigate the effects of pulsed light (PL) on the activity and structure of horseradish peroxidase (HRP) in buffer solution. Enzyme residual activities were measured after PL. Surface topography, secondary, and tertiary structures of HRP were determined using ...

Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure.

PubMed

Katen, Sarah P; Tan, Zhenning; Chirapu, Srinivas Reddy; Finn, M G; Zlotnick, Adam

2013-08-06

Hepatitis B virus (HBV) is a major cause of liver disease. Assembly of the HBV capsid is a critical step in virus production and an attractive target for new antiviral therapies. We determined the structure of HBV capsid in complex with AT-130, a member of the phenylpropenamide family of assembly effectors. AT-130 causes tertiary and quaternary structural changes but does not disrupt capsid structure. AT-130 binds a hydrophobic pocket that also accommodates the previously characterized heteroaryldihydropyrimidine compounds but favors a unique quasiequivalent location on the capsid surface. Thus, this pocket is a promiscuous drug-binding site and a likely target for different assembly effectors with a broad range of mechanisms of activity. That AT-130 successfully decreases virus production by increasing capsid assembly rate without disrupting capsid structure delineates a paradigm in antiviral design, that disrupting reaction timing is a viable strategy for assembly effectors of HBV and other viruses. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pushing the size limit of de novo structure ensemble prediction guided by sparse SDSL-EPR restraints to 200 residues: The monomeric and homodimeric forms of BAX

PubMed Central

Fischer, Axel W.; Bordignon, Enrica; Bleicken, Stephanie; García-Sáez, Ana J.; Jeschke, Gunnar; Meiler, Jens

2016-01-01

Structure determination remains a challenge for many biologically important proteins. In particular, proteins that adopt multiple conformations often evade crystallization in all biologically relevant states. Although computational de novo protein folding approaches often sample biologically relevant conformations, the selection of the most accurate model for different functional states remains a formidable challenge, in particular, for proteins with more than about 150 residues. Electron paramagnetic resonance (EPR) spectroscopy can obtain limited structural information for proteins in well-defined biological states and thereby assist in selecting biologically relevant conformations. The present study demonstrates that de novo folding methods are able to accurately sample the folds of 192-residue long soluble monomeric Bcl-2-associated X protein (BAX). The tertiary structures of the monomeric and homodimeric forms of BAX were predicted using the primary structure as well as 25 and 11 EPR distance restraints, respectively. The predicted models were subsequently compared to respective NMR/X-ray structures of BAX. EPR restraints improve the protein-size normalized root-mean-square-deviation (RMSD100) of the most accurate models with respect to the NMR/crystal structure from 5.9 Å to 3.9 Å and from 5.7 Å to 3.3 Å, respectively. Additionally, the model discrimination is improved, which is demonstrated by an improvement of the enrichment from 5% to 15% and from 13% to 21%, respectively. PMID:27129417

Probing Protein Fold Space with a Simplified Model

PubMed Central

Minary, Peter; Levitt, Michael

2008-01-01

We probe the stability and near-native energy landscape of protein fold space using powerful conformational sampling methods together with simple reduced models and statistical potentials. Fold space is represented by a set of 280 protein domains spanning all topological classes and having a wide range of lengths (0-300 residues), amino acid composition, and number of secondary structural elements. The degrees of freedom are taken as the loop torsion angles. This choice preserves the native secondary structure but allows the tertiary structure to change. The proteins are represented by three-point per residue, three-dimensional models with statistical potentials derived from a knowledge-based study of known protein structures. When this space is sampled by a combination of Parallel Tempering and Equi-Energy Monte Carlo, we find that the three-point model captures the known stability of protein native structures with stable energy basins that are near-native (all-α: 4.77 Å, all-β: 2.93 Å, α/β: 3.09 Å, α+β: 4.89 Å on average and within 6 Å for 71.41 %, 92.85 %, 94.29 % and 64.28 % for all-α, all-β, α/β and α+β, classes respectively). Denatured structures also occur and these have interesting structural properties that shed light on the different landscape characteristics of α and β folds. We find that α/β proteins with alternating α and β segments (such as the beta-barrel) are more stable than proteins in other fold classes. PMID:18054792

[Development of an index system for the comprehensive evaluation on public health emergency events surveillance system in China].

PubMed

Hong, Zhiheng; Ni, Daxin; Cao, Yang; Meng, Ling; Tu, Wenxiao; Li, Leilei; Li, Qun; Jin, Lianmei

2015-06-01

To establish a comprehensive evaluation index system for the China Public Health Emergency Events Surveillance System (CPHEESS). A draft index system was built through literature review and under the consideration of the characteristics on CPHEESS. Delphi method was adapted to determine the final index system. The index system was divided into primary, secondary and tertiary levels. There were 4 primary indicators: System structure, Network platform, Surveillance implementation reports with Data analysis and utilization. There were 16 secondary and 70 tertiary indicators being set, with System structure including 14 tertiary indicators (accounted for 20.00%), 21 Network platforms (accounted for 30.00%). Twenty-four Surveillance implementation reports (accounted for 34.29%), 11 Data analysis and utilization (accounted for 15.71%). The average score of importance of each indicators was 4.29 (3.77-4.94), with an average coefficient variation as 0.14 (0.12-0.16). The mean Chronbach's α index was 0.84 (0.81-0.89). The adaptability of each related facilities indicator was specified. The primary indicators were set in accordance with the characteristics and goals of the surveillance systems. Secondary indicators provided key elements in the management and control of the system while the tertiary indicators were available and operative. The agreement rate of experts was high with good validity and reliability. This index system could be used for CPHEESS in future.

Near-atomic structural model for bacterial DNA replication initiation complex and its functional insights.

PubMed

Shimizu, Masahiro; Noguchi, Yasunori; Sakiyama, Yukari; Kawakami, Hironori; Katayama, Tsutomu; Takada, Shoji

2016-12-13

Upon DNA replication initiation in Escherichia coli, the initiator protein DnaA forms higher-order complexes with the chromosomal origin oriC and a DNA-bending protein IHF. Although tertiary structures of DnaA and IHF have previously been elucidated, dynamic structures of oriC-DnaA-IHF complexes remain unknown. Here, combining computer simulations with biochemical assays, we obtained models at almost-atomic resolution for the central part of the oriC-DnaA-IHF complex. This complex can be divided into three subcomplexes; the left and right subcomplexes include pentameric DnaA bound in a head-to-tail manner and the middle subcomplex contains only a single DnaA. In the left and right subcomplexes, DnaA ATPases associated with various cellular activities (AAA+) domain III formed helices with specific structural differences in interdomain orientations, provoking a bend in the bound DNA. In the left subcomplex a continuous DnaA chain exists, including insertion of IHF into the DNA looping, consistent with the DNA unwinding function of the complex. The intervening spaces in those subcomplexes are crucial for DNA unwinding and loading of DnaB helicases. Taken together, this model provides a reasonable near-atomic level structural solution of the initiation complex, including the dynamic conformations and spatial arrangements of DnaA subcomplexes.

Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.

PubMed

Metzger, Vincent T; Eun, Changsun; Kekenes-Huskey, Peter M; Huber, Gary; McCammon, J Andrew

2014-11-18

We perform Brownian dynamics simulations and Smoluchowski continuum modeling of the bifunctional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (P. falciparum DHFR-TS) with the objective of understanding the electrostatic channeling of dihydrofolate generated at the TS active site to the DHFR active site. The results of Brownian dynamics simulations and Smoluchowski continuum modeling suggest that compared to Leishmania major DHFR-TS, P. falciparum DHFR-TS has a lower but significant electrostatic-mediated channeling efficiency (?15-25%) at physiological pH (7.0) and ionic strength (150 mM). We also find that removing the electric charges from key basic residues located between the DHFR and TS active sites significantly reduces the channeling efficiency of P. falciparum DHFR-TS. Although several protozoan DHFR-TS enzymes are known to have similar tertiary and quaternary structure, subtle differences in structure, active-site geometry, and charge distribution appear to influence both electrostatic-mediated and proximity-based substrate channeling.

Revisiting the NMR structure of the ultrafast downhill folding protein gpW from bacteriophage λ.

PubMed

Sborgi, Lorenzo; Verma, Abhinav; Muñoz, Victor; de Alba, Eva

2011-01-01

GpW is a 68-residue protein from bacteriophage λ that participates in virus head morphogenesis. Previous NMR studies revealed a novel α+β fold for this protein. Recent experiments have shown that gpW folds in microseconds by crossing a marginal free energy barrier (i.e., downhill folding). These features make gpW a highly desirable target for further experimental and computational folding studies. As a step in that direction, we have re-determined the high-resolution structure of gpW by multidimensional NMR on a construct that eliminates the purification tags and unstructured C-terminal tail present in the prior study. In contrast to the previous work, we have obtained a full manual assignment and calculated the structure using only unambiguous distance restraints. This new structure confirms the α+β topology, but reveals important differences in tertiary packing. Namely, the two α-helices are rotated along their main axis to form a leucine zipper. The β-hairpin is orthogonal to the helical interface rather than parallel, displaying most tertiary contacts through strand 1. There also are differences in secondary structure: longer and less curved helices and a hairpin that now shows the typical right-hand twist. Molecular dynamics simulations starting from both gpW structures, and calculations with CS-Rosetta, all converge to our gpW structure. This confirms that the original structure has strange tertiary packing and strained secondary structure. A comparison of NMR datasets suggests that the problems were mainly caused by incomplete chemical shift assignments, mistakes in NOE assignment and the inclusion of ambiguous distance restraints during the automated procedure used in the original study. The new gpW corrects these problems, providing the appropriate structural reference for future work. Furthermore, our results are a cautionary tale against the inclusion of ambiguous experimental information in the determination of protein structures.

Network structure and concentration fluctuations in a series of elemental, binary, and tertiary liquids and glasses.

PubMed

Soper, Alan K

2010-10-13

Liquids and glasses continue to produce a lively debate about the nature of the disordered structure in these materials, and whether it is driven by longer range concentration or density fluctuations. One factor often lacking in these studies is an overview of a wide range of structures from which common features of and differences between materials can be identified. Here I examine the structure of a wide range of chain and network, elemental, binary and tertiary liquids and glasses, using available x-ray and neutron diffraction data and combining them with empirical potential structure refinement. Calculation of the Bhatia-Thornton number-number and concentration-concentration structure factors and distribution functions highlights common structural motifs that run through many of the series. It is found that the greatest structural overlap occurs where the nearest-neighbour and second-neighbour coordination numbers are similar for different materials. As these coordination numbers increase, so the structures undergo a sequence of characteristic changes involving increasingly bent bond angle distributions and increased packing fractions. In these regards liquid and amorphous phosphorus appear to be in a structural class of their own, combining both chain-like and network-like characteristics.

Tertiary lymphoid structures in cancer and beyond.

PubMed

Dieu-Nosjean, Marie-Caroline; Goc, Jérémy; Giraldo, Nicolas A; Sautès-Fridman, Catherine; Fridman, Wolf Herman

2014-11-01

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations found in inflamed, infected, or tumoral tissues. They exhibit all the characteristics of structures in the lymph nodes (LN) associated with the generation of an adaptive immune response, including a T cell zone with mature dendritic cells (DC), a germinal center with follicular dendritic cells (FDC) and proliferating B cells, and high endothelial venules (HEV). In this review, we discuss evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and address the question of whether TLS present beneficial or deleterious effects in these contexts. We examine the relationship between TLS in tumors and patient prognosis, and discuss the potential role of TLS in building and/or maintaining local immune responses and how this understanding may guide therapeutic interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Physiological Molecular Shape of Spectrin: A Compact Supercoil Resembling a Chinese Finger Trap.

PubMed

Brown, Jeffrey W; Bullitt, Esther; Sriswasdi, Sira; Harper, Sandra; Speicher, David W; McKnight, C James

2015-06-01

The primary, secondary, and tertiary structures of spectrin are reasonably well defined, but the structural basis for the known dramatic molecular shape change, whereby the molecular length can increase three-fold, is not understood. In this study, we combine previously reported biochemical and high-resolution crystallographic data with structural mass spectroscopy and electron microscopic data to derive a detailed, experimentally-supported quaternary structure of the spectrin heterotetramer. In addition to explaining spectrin's physiological resting length of ~55-65 nm, our model provides a mechanism by which spectrin is able to undergo a seamless three-fold extension while remaining a linear filament, an experimentally observed property. According to the proposed model, spectrin's quaternary structure and mechanism of extension is similar to a Chinese Finger Trap: at shorter molecular lengths spectrin is a hollow cylinder that extends by increasing the pitch of each spectrin repeat, which decreases the internal diameter. We validated our model with electron microscopy, which demonstrated that, as predicted, spectrin is hollow at its biological resting length of ~55-65 nm. The model is further supported by zero-length chemical crosslink data indicative of an approximately 90 degree bend between adjacent spectrin repeats. The domain-domain interactions in our model are entirely consistent with those present in the prototypical linear antiparallel heterotetramer as well as recently reported inter-strand chemical crosslinks. The model is consistent with all known physical properties of spectrin, and upon full extension our Chinese Finger Trap Model reduces to the ~180-200 nm molecular model currently in common use.

Coordination-Driven Dimerization of Zinc Chlorophyll Derivatives Possessing a Dialkylamino Group.

PubMed

Watanabe, Hiroaki; Kamatani, Yusuke; Tamiaki, Hitoshi

2017-04-04

Zinc chlorophyll derivatives Zn-1-3 possessing a tertiary amino group at the C3 1 position have been synthesized through reductive amination of methyl pyropheophorbide-d obtained from naturally occurring chlorophyll-a. In a dilute CH 2 Cl 2 solution as well as in a dilute 10 %(v/v) CH 2 Cl 2 /hexane solution, Zn-1 possessing a dimethylamino group at the C3 1 position showed red-shifted UV/Vis absorption and intensified exciton-coupling circular dichroism (CD) spectra at room temperature owing to its dimer formation via coordination to the central zinc by the 3 1 -N atom of the dimethylamino group. However, Zn-2/3 bearing 3 1 -ethylmethylamino/diethylamino groups did not. The difference was dependent on the steric factor of the substituents in the tertiary amino group, where an increase of the carbon numbers on the N atom reduced the intermolecular N⋅⋅⋅Zn coordination. UV/Vis, CD, and 1 H NMR spectroscopic analyses including DOSY measurements revealed that Zn-1 formed closed-type dimers via an opened dimer by single-to-double axial coordination with an increase in concentration and a temperature decrease in CH 2 Cl 2 , while Zn-2/3 gave open and flexible dimers in a concentrated CH 2 Cl 2 solution at low temperature. The supramolecular closed dimer structures of Zn-1 were estimated by molecular modelling calculations, which showed these structures were promising models for the chlorophyll dimer in a photosynthetic reaction center. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Marked variation in newborn resuscitation practice: A national survey in the UK☆

PubMed Central

Mann, Chantelle; Ward, Carole; Grubb, Mark; Hayes-Gill, Barrie; Crowe, John; Marlow, Neil; Sharkey, Don

2012-01-01

Background Although international newborn resuscitation guidance has been in force for some time, there are no UK data on current newborn resuscitation practices. Objective Establish delivery room (DR) resuscitation practices in the UK, and identify any differences between neonatal intensive care units (NICU), and other local neonatal services. Methods We conducted a structured two-stage survey of DR management, among UK neonatal units during 2009–2010 (n = 192). Differences between NICU services (tertiary level) and other local neonatal services (non-tertiary) were analysed using Fisher's exact and Student's t-tests. Results There was an 89% response rate (n = 171). More tertiary NICUs institute DR CPAP than non-tertiary units (43% vs. 16%, P = 0.0001) though there was no significant difference in frequency of elective intubation and surfactant administration for preterm babies. More tertiary units commence DR resuscitation in air (62% vs. 29%, P < 0.0001) and fewer in 100% oxygen (11% vs. 41%, P < 0.0001). Resuscitation of preterm babies in particular, commences with air in 56% of tertiary units. Significantly more tertiary units use DR pulse oximeters (58% vs. 29%, P < 0.01) and titrate oxygen based on saturations. Almost all services use occlusive wrapping to maintain temperature for preterm infants. Conclusions In the UK, there are many areas of good evidence based DR practice. However, there is marked variation in management, including between units of different designation, suggesting a need to review practice to fulfil new resuscitation guidance, which will have training and resource implications. PMID:22245743

40Ar/39Ar thermochronologic constraints on the tectonothermal evolution of the Northern East Humboldt range metamorphic core complex, Nevada

USGS Publications Warehouse

McGrew, A.J.; Snee, L.W.

1994-01-01

The northern East Humboldt Range (NEHR) of northeastern Nevada exposes a suite of complexly deformed migmatitic, upper amphibolite-facies rocks in the footwall of the Ruby Mountains-East Humboldt Range (RM-EHR) detachment fault. New 40Ar/39Ar data on hornblende, muscovite, biotite, and potassium feldspar help constrain the kinematic and thermal evolution of this terrain during Tertiary extensional exhumation. Hornblende samples from relatively high structural levels yield discordant age spectra that suggest initial cooling during early Tertiary time (63-49 Ma). When coupled with petrological constraints indicating a strongly decompressional P-T-t path above 550??C, the hornblende data suggest that exhumation of the RM-EHR may have initiated in early Tertiary time, approximately coincident with the initial phases of unroofing in the Wood Hills immediately to the east and with the end of thrusting in the late Mesozoic to early Tertiary Sevier orogenic belt of eastern Nevada and western Utah. This temporal coincidence suggests that gravitational collapse of tectonically thickened crust in the internal zone of the Sevier belt could have driven the initial phases of unroofing. Thermal history during the final stage of exhumation of the NEHR is constrained by discordant hornblende cooling ages of 36-29 Ma from deep structural levels and biotite, muscovite, and potassium feldspar cooling ages of 27-21 Ma from a range of structural levels. Comparison of muscovite, biotite, and potassium feldspar cooling ages with previously published fission-track cooling ages implies very rapid cooling rates at temperatures below the closure temperature for muscovite (270??-350??C), but time gaps of > 7 m.y. between hornblende and mica cooling ages suggest that cooling at higher temperatures was more gradual. In addition, comparison of 40Ar 39Ar mica cooling ages with previously published fission-track apatite cooling ages suggests pronounced thermal gradients between the NEHR and adjacent areas during latest Oligocene to earliest Miocene time. Such thermal gradients could be readily explained if the RM-EHR detachment fault dipped > 30?? between the 300??C and 100??C isotherms. Finally, 40Ar 39Ar biotite cooling ages increase southward through the East Humboldt Range, compatible with northward extrapolation of a previously recognized pattern of WNW-younging biotite cooling ages from the Ruby Mountains. A simple model involving the propagation of footwall uplift in the direction of tectonic transport beneath an initially listric normal fault can explain the principle features of the Oligoce??ne to Miocene thermochronologic data set for the RM-EHR. ?? 1994.

Structural Prediction and In Silico Physicochemical Characterization for Mouse Caltrin I and Bovine Caltrin Proteins

PubMed Central

Grasso, Ernesto J.; Sottile, Adolfo E.; Coronel, Carlos E.

2016-01-01

It is known that caltrin (calcium transport inhibitor) protein binds to sperm cells during ejaculation and inhibits extracellular Ca2+ uptake. Although the sequence and some biological features of mouse caltrin I and bovine caltrin are known, their physicochemical properties and tertiary structure are mainly unknown. We predicted the 3D structures of mouse caltrin I and bovine caltrin by molecular homology modeling and threading. Surface electrostatic potentials and electric fields were calculated using the Poisson–Boltzmann equation. Several different bioinformatics tools and available web servers were used to thoroughly analyze the physicochemical characteristics of both proteins, such as their Kyte and Doolittle hydropathy scores and helical wheel projections. The results presented in this work significantly aid further understanding of the molecular mechanisms of caltrin proteins modulating physiological processes associated with fertilization. PMID:27812283

Pedagogical Practices of Reflection in Tertiary Dance Education

ERIC Educational Resources Information Center

Leijen, Ali; Lam, Ineke; Simons, P. Robert-Jan; Wildschut, Liesbeth

2008-01-01

The three different perspectives on reflection in education are embedded in the philosophical traditions of pragmatism, critical social theory and Kant. We aimed to describe the pedagogical practices of reflection, and to develop a descriptive model of the practices of reflection in tertiary dance education which can be used by dance educators to…

DEVELOPMENT OF PHYSIOLOGICAL-BASED PHARMACOKINETIC MODEL FOR DERMAL ABSORPTION NAD PENETRATION OF METHYL TERTIARY BUTYL ETHER IN HUMANS

EPA Science Inventory

Background: Methyl tertiary butyl ether (MTBE) is a volatile organic chemical that is added to gasoline as an octane booster and to reduce vehicular emissions of carbon monoxide. MTBE is introduced into the environment through fuel spills, leakage of storage tanks, and evaporat...

First Inversion: A Rationale for Implementing the "Flipped Approach" in Tertiary Music Courses

ERIC Educational Resources Information Center

Grant, Catherine

2013-01-01

For several reasons, current models of tertiary education seem unviable. A shifting educational landscape with rising student numbers, an increasingly diverse student cohort, and high levels of student disengagement have led to concerns about the continued relevance of "traditional" teaching and learning methods. At the same time, the…

Structural reinterpretation of the Ajo mining district, Pima County, Arizona, based on paleomagnetic and geochronologic studies.

USGS Publications Warehouse

Hagstrum, J.T.; Cox, D.P.; Miller, R.J.

1987-01-01

The Ajo mining district of southern Arizona is divided into two main structural blocks by the Gibson Arroyo fault. The eastern Camelback Mountain block contains the Late Cretaceous-early Tertiary porphyry copper deposit which has been previously thought to be associated with the displaced apex of a large intrusion exposed by deeper erosion in the western Cardigan Peak block. However, unpublished U-Pb data support a mid-Tertiary age for the western intrusion. The following sequence of mid-Tertiary events in the district are indicated: 1) emplacement of the western intrusion, 2) movement along the Gibson Arroyo fault, 3) unroofing and perhaps tilting of the pluton approx 70o to the south along with the Camelback Mountain block, 4) syntectonic depositions of the Locomotive Fanglomerate and the Ajo Volcanics, 5) continued uplift and tilting to the south totaling 40o to 60o, 6) intrusion of the youngest dikes with attendant alteration and remagnetization of the host rocks, and 7) minor (?) oblique movement along the Gibson Arroyo fault.-from Authors

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

PubMed

Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J; Chiu, Francis C K; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L; Urwyler, Heinrich; Charman, William N; Matile, Hugues; Wittlin, Sergio; Charman, Susan A; Vennerstrom, Jonathan L

2017-04-13

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK a and lower log D 7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D 7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

Thermodynamic Origins of Monovalent Facilitated RNA Folding

PubMed Central

Holmstrom, Erik D.; Fiore, Julie L.; Nesbitt, David J.

2012-01-01

Cations have long been associated with formation of native RNA structure and are commonly thought to stabilize the formation of tertiary contacts by favorably interacting with the electrostatic potential of the RNA, giving rise to an “ion atmosphere”. A significant amount of information regarding the thermodynamics of structural transitions in the presence of an ion atmosphere has accumulated and suggests stabilization is dominated by entropic terms. This work provides an analysis of how RNA–cation interactions affect the entropy and enthalpy associated with an RNA tertiary transition. Specifically, temperature-dependent single-molecule fluorescence resonance energy transfer studies have been exploited to determine the free energy (ΔG°), enthalpy (ΔH°), and entropy (ΔS°) of folding for an isolated tetraloop–receptor tertiary interaction as a function of Na+ concentration. Somewhat unexpectedly, increasing the Na+ concentration changes the folding enthalpy from a strongly exothermic process [e.g., ΔH° = −26(2) kcal/mol at 180 mM] to a weakly exothermic process [e.g., ΔH° = −4(1) kcal/mol at 630 mM]. As a direct corollary, it is the strong increase in folding entropy [Δ(ΔS°) > 0] that compensates for this loss of exothermicity for the achievement of more favorable folding [Δ(ΔG°) < 0] at higher Na+ concentrations. In conjunction with corresponding measurements of the thermodynamics of the transition state barrier, these data provide a detailed description of the folding pathway associated with the GAAA tetraloop–receptor interaction as a function of Na+ concentration. The results support a potentially universal mechanism for monovalent facilitated RNA folding, whereby an increasing monovalent concentration stabilizes tertiary structure by reducing the entropic penalty for folding. PMID:22448852

Distinct reaction pathway promoted by non-divalent-metal cations in a tertiary stabilized hammerhead ribozyme

PubMed Central

Roychowdhury-Saha, Manami; Burke, Donald H.

2007-01-01

Divalent ion sensitivity of hammerhead ribozymes is significantly reduced when the RNA structure includes appropriate tertiary stabilization. Therefore, we investigated the activity of the tertiary stabilized “RzB” hammerhead ribozyme in several nondivalent ions. Ribozyme RzB is active in spermidine and Na+ alone, although the cleavage rates are reduced by more than 1,000-fold relative to the rates observed in Mg2+ and in transition metal ions. The trivalent cobalt hexammine (CoHex) ion is often used as an exchange-inert analog of hydrated magnesium ion. Trans-cleavage rates exceeded 8 min−1 in 20 mM CoHex, which promoted cleavage through outersphere interactions. The stimulation of catalysis afforded by the tertiary structural interactions within RzB does not require Mg2+, unlike other extended hammerhead ribozymes. Site-specific interaction with at least one Mg2+ ion is suggested by CoHex competition experiments. In the presence of a constant, low concentration of Mg2+, low concentrations of CoHex decreased the rate by two to three orders of magnitude relative to the rate in Mg2+ alone. Cleavage rates increased as CoHex concentrations were raised further, but the final fraction cleaved was lower than what was observed in CoHex or Mg2+ alone. These observations suggest that Mg2+ and CoHex compete for binding and that they cause misfolded structures when they are together. The results of this study support the existence of an alternate catalytic mechanism used by nondivalent ions (especially CoHex) that is distinct from the one promoted by divalent metal ions, and they imply that divalent metals influence catalysis through a specific nonstructural role. PMID:17456566

A 'periodic table' for protein structures.

PubMed

Taylor, William R

2002-04-11

Current structural genomics programs aim systematically to determine the structures of all proteins coded in both human and other genomes, providing a complete picture of the number and variety of protein structures that exist. In the past, estimates have been made on the basis of the incomplete sample of structures currently known. These estimates have varied greatly (between 1,000 and 10,000; see for example refs 1 and 2), partly because of limited sample size but also owing to the difficulties of distinguishing one structure from another. This distinction is usually topological, based on the fold of the protein; however, in strict topological terms (neglecting to consider intra-chain cross-links), protein chains are open strings and hence are all identical. To avoid this trivial result, topologies are determined by considering secondary links in the form of intra-chain hydrogen bonds (secondary structure) and tertiary links formed by the packing of secondary structures. However, small additions to or loss of structure can make large changes to these perceived topologies and such subjective solutions are neither robust nor amenable to automation. Here I formalize both secondary and tertiary links to allow the rigorous and automatic definition of protein topology.

An analytic model for limiting high density LH transition by the onset of the tertiary instability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Raghvendra, E-mail: rsingh129@gmail.com; Jhang, Hogun; Kaang, Helen H.

2016-07-15

We perform an analytic study of the tertiary instability driven by a strong excitation of zonal flows during high density low to high (LH) mode transition. The drift resistive ballooning mode is assumed to be a dominant edge turbulence driver. The analysis reproduces main qualitative features of early computational results [Rogers and Drake, Phys. Rev. Lett. 81, 4396 (1998); Guzdar et al., Phys. Plasmas 14, 020701 (2007)], as well as new characteristics of the maximum edge density due to the onset of the tertiary instability. An analytical scaling indicates that the density scaling of LH transition power may be determinedmore » by the onset condition of the tertiary instability when the operating density approaches to the Greenwald density.« less

Elder abuse and socioeconomic inequalities: a multilevel study in 7 European countries.

PubMed

Fraga, Sílvia; Lindert, Jutta; Barros, Henrique; Torres-González, Francisco; Ioannidi-Kapolou, Elisabeth; Melchiorre, Maria Gabriella; Stankunas, Mindaugas; Soares, Joaquim F

2014-04-01

To compare the prevalence of elder abuse using a multilevel approach that takes into account the characteristics of participants as well as socioeconomic indicators at city and country level. In 2009, the project on abuse of elderly in Europe (ABUEL) was conducted in seven cities (Stuttgart, Germany; Ancona, Italy; Kaunas, Lithuania, Stockholm, Sweden; Porto, Portugal; Granada, Spain; Athens, Greece) comprising 4467 individuals aged 60-84 years. We used a 3-level hierarchical structure of data: 1) characteristics of participants; 2) mean of tertiary education of each city; and 3) country inequality indicator (Gini coefficient). Multilevel logistic regression was used and proportional changes in Intraclass Correlation Coefficient (ICC) were inspected to assert explained variance between models. The prevalence of elder abuse showed large variations across sites. Adding tertiary education to the regression model reduced the country level variance for psychological abuse (ICC=3.4%), with no significant decrease in the explained variance for the other types of abuse. When the Gini coefficient was considered, the highest drop in ICC was observed for financial abuse (from 9.5% to 4.3%). There is a societal and community level dimension that adds information to individual variability in explaining country differences in elder abuse, highlighting underlying socioeconomic inequalities leading to such behavior. Copyright © 2014 Elsevier Inc. All rights reserved.

Physician job satisfaction in Saudi Arabia: insights from a tertiary hospital survey.

PubMed

Aldrees, Turki; Al-Eissa, Sami; Badri, Motasim; Aljuhayman, Ahmed; Zamakhshary, Mohammed

2015-01-01

Job satisfaction refers to the extent to which people like or dislike their job. Job satisfaction varies across professions. Few studies have explored this issue among physicians in Saudi Arabia. The objective of this study is to determine the level and factors associated with job satisfaction among Saudi and non-Saudi physicians. In this cross-sectional study conducted in a major tertiary hospital in Riyadh, a 5-point Likert scale structured questionnaire was used to collect data on a wide range of socio-demographic, practice environment characteristics and level and consequences of job satisfaction from practicing physicians (consultants or residents) across different medical specialties. Logistic regression models were fitted to determine factors associated with job satisfaction. Of 344 participants, 300 (87.2%) were Saudis, 252 (73%) males, 255 (74%) married, 188 (54.7%) consultants and age [median (IQR)] was 32 (27-42.7) years. Overall, 104 (30%) respondents were dissatisfied with their jobs. Intensive care physicians were the most dissatisfied physicians (50%). In a multiple logistic regression model, income satisfaction (odds ratio [OR]=0.448 95% CI 0.278-0.723, P < .001) was the only factor independently associated with dissatisfaction. Factors adversely associated with physicians job satisfaction identified in this study should be addressed in governmental strategic planning aimed at improving the healthcare system and patient care.

Evaluation of Electronic Prescribing Decision Support System at a Tertiary Care Pediatric Hospital: The User Acceptance Perspective.

PubMed

Omar, Abdurahman; Ellenius, Johan; Lindemalm, Synnöve

2017-01-01

This study aims to evaluate pediatrician's acceptance, perception and use of Electronic Prescribing Decision Support Systems (EPDSS) at a tertiary care using Extended Technology Acceptance Model (TAM2). Qualitative research methodology was applied. Semi-structured questions were developed according to TAM2 model. Pediatricians perceived that the EPDSS is useful and they showed a favorable attitude. However, perceived ease of use and output quality appeared to affect use of EPDSS. Concerns were expressed about complicated screens, difficulty to read and view medication overview of the patient, the navigation requires many clicks and medication system don't meet their need. End users have difficulty of ordering drugs for ploy-clinical patients and they were unable to cancel or stop medications. Junior pediatricians were influenced by senior colleague since they can get better advice about medication order than the system. Applying TAM2 framework has revealed that pediatrician's attitude and acceptance of electronic prescribing system. This study has identified factors that are important for end user acceptance as well as suggestions for system improvement. Although pediatricians are positive to the usefulness of EPDSS, it appears there are some acceptance problems due to ease of use concern and usability issues of the system.

Turning limited experimental information into 3D models of RNA.

PubMed

Flores, Samuel Coulbourn; Altman, Russ B

2010-09-01

Our understanding of RNA functions in the cell is evolving rapidly. As for proteins, the detailed three-dimensional (3D) structure of RNA is often key to understanding its function. Although crystallography and nuclear magnetic resonance (NMR) can determine the atomic coordinates of some RNA structures, many 3D structures present technical challenges that make these methods difficult to apply. The great flexibility of RNA, its charged backbone, dearth of specific surface features, and propensity for kinetic traps all conspire with its long folding time, to challenge in silico methods for physics-based folding. On the other hand, base-pairing interactions (either in runs to form helices or isolated tertiary contacts) and motifs are often available from relatively low-cost experiments or informatics analyses. We present RNABuilder, a novel code that uses internal coordinate mechanics to satisfy user-specified base pairing and steric forces under chemical constraints. The code recapitulates the topology and characteristic L-shape of tRNA and obtains an accurate noncrystallographic structure of the Tetrahymena ribozyme P4/P6 domain. The algorithm scales nearly linearly with molecule size, opening the door to the modeling of significantly larger structures.

Validated near-atomic resolution structure of bacteriophage epsilon15 derived from cryo-EM and modeling

PubMed Central

Baker, Matthew L.; Hryc, Corey F.; Zhang, Qinfen; Wu, Weimin; Jakana, Joanita; Haase-Pettingell, Cameron; Afonine, Pavel V.; Adams, Paul D.; King, Jonathan A.; Jiang, Wen; Chiu, Wah

2013-01-01

High-resolution structures of viruses have made important contributions to modern structural biology. Bacteriophages, the most diverse and abundant organisms on earth, replicate and infect all bacteria and archaea, making them excellent potential alternatives to antibiotics and therapies for multidrug-resistant bacteria. Here, we improved upon our previous electron cryomicroscopy structure of Salmonella bacteriophage epsilon15, achieving a resolution sufficient to determine the tertiary structures of both gp7 and gp10 protein subunits that form the T = 7 icosahedral lattice. This study utilizes recently established best practice for near-atomic to high-resolution (3–5 Å) electron cryomicroscopy data evaluation. The resolution and reliability of the density map were cross-validated by multiple reconstructions from truly independent data sets, whereas the models of the individual protein subunits were validated adopting the best practices from X-ray crystallography. Some sidechain densities are clearly resolved and show the subunit–subunit interactions within and across the capsomeres that are required to stabilize the virus. The presence of the canonical phage and jellyroll viral protein folds, gp7 and gp10, respectively, in the same virus suggests that epsilon15 may have emerged more recently relative to other bacteriophages. PMID:23840063

Structural computational modeling of RNA aptamers.

PubMed

Xu, Xiaojun; Dickey, David D; Chen, Shi-Jie; Giangrande, Paloma H

2016-07-01

RNA aptamers represent an emerging class of biologics that can be easily adapted for personalized and precision medicine. Several therapeutic aptamers with desirable binding and functional properties have been developed and evaluated in preclinical studies over the past 25years. However, for the majority of these aptamers, their clinical potential has yet to be realized. A significant hurdle to the clinical adoption of this novel class of biologicals is the limited information on their secondary and tertiary structure. Knowledge of the RNA's structure would greatly facilitate and expedite the post-selection optimization steps required for translation, including truncation (to reduce costs of manufacturing), chemical modification (to enhance stability and improve safety) and chemical conjugation (to improve drug properties for combinatorial therapy). Here we describe a structural computational modeling methodology that when coupled to a standard functional assay, can be used to determine key sequence and structural motifs of an RNA aptamer. We applied this methodology to enable the truncation of an aptamer to prostate specific membrane antigen (PSMA) with great potential for targeted therapy that had failed previous truncation attempts. This methodology can be easily applied to optimize other aptamers with therapeutic potential. Copyright © 2016. Published by Elsevier Inc.

Structural Biology for A-Level Students

ERIC Educational Resources Information Center

Philip, Judith

2013-01-01

The relationship between the structure and function of proteins is an important area in biochemistry. Pupils studying A-level Biology are introduced to the four levels of protein structure (primary, secondary, tertiary and quaternary) and how these can be used to describe the progressive folding of a chain of amino acid residues to a final,…

Structure of an E. coli integral membrane sulfurtransferase and its structural transition upon SCN− binding defined by EPR-based hybrid method

PubMed Central

Ling, Shenglong; Wang, Wei; Yu, Lu; Peng, Junhui; Cai, Xiaoying; Xiong, Ying; Hayati, Zahra; Zhang, Longhua; Zhang, Zhiyong; Song, Likai; Tian, Changlin

2016-01-01

Electron paramagnetic resonance (EPR)-based hybrid experimental and computational approaches were applied to determine the structure of a full-length E. coli integral membrane sulfurtransferase, dimeric YgaP, and its structural and dynamic changes upon ligand binding. The solution NMR structures of the YgaP transmembrane domain (TMD) and cytosolic catalytic rhodanese domain were reported recently, but the tertiary fold of full-length YgaP was not yet available. Here, systematic site-specific EPR analysis defined a helix-loop-helix secondary structure of the YagP-TMD monomers using mobility, accessibility and membrane immersion measurements. The tertiary folds of dimeric YgaP-TMD and full-length YgaP in detergent micelles were determined through inter- and intra-monomer distance mapping and rigid-body computation. Further EPR analysis demonstrated the tight packing of the two YgaP second transmembrane helices upon binding of the catalytic product SCN−, which provides insight into the thiocyanate exportation mechanism of YgaP in the E. coli membrane. PMID:26817826

Delipidation of Cytochrome c Oxidase from Rhodobacter sphaeroides Destabilizes its Quaternary Structure

PubMed Central

Musatov, Andrej; Varhač, Rastislav; Hosler, Jonathan P.; Sedlák, Erik

2016-01-01

Delipidation of detergent-solubilized cytochrome c oxidase isolated from Rhodobacter sphaeroides (Rbs-CcO) has no apparent structural and/or functional effect on the protein, however affects its resistance against thermal or chemical denaturation. Phospholipase A2 (PLA2) hydrolysis of phospholipids that are co-purified with the enzyme removes all but two tightly bound phosphatidylethanolamines. Replacement of the removed phospholipids with nonionic detergent decreases both thermal stability of the enzyme and its resilience against the effect of chemical denaturants such as urea. In contrast to nondelipidated Rbs-CcO, the enzymatic activity of PLA2-treated Rbs-CcO is substantially diminished after exposure to high (>4M) urea concentration at room temperature without an alteration of its secondary structure. Absorbance spectroscopy and sedimentation velocity experiments revealed a strong correlation between intact tertiary structure of heme regions and quaternary structure, respectively, and the enzymatic activity of the protein. We concluded that phospholipid environment of Rbs-CcO has the protective role for stability of its tertiary and quaternary structures. PMID:26923069

A study of the thermal denaturation of the S-layer protein from Lactobacillus salivarius

NASA Astrophysics Data System (ADS)

Lighezan, Liliana; Georgieva, Ralitsa; Neagu, Adrian

2012-09-01

Surface layer (S-layer) proteins display an intrinsic self-assembly property, forming monomolecular crystalline arrays, identified in outermost structures of the cell envelope in many organisms, such as bacteria and archaea. Isolated S-layer proteins also possess the ability to recrystallize into regular lattices, being used in biotechnological applications, such as controlling the architecture of biomimetic surfaces. To this end, the stability of the S-layer proteins under high-temperature conditions is very important. In this study, the S-layer protein has been isolated from Lactobacillus salivarius 16 strain of human origin, and purified by cation-exchange chromatography. Using circular dichroism (CD) spectroscopy, we have investigated the thermal denaturation of the S-layer protein. The far- and near-UV CD spectra have been collected, and the temperature dependence of the CD signal in these spectral domains has been analyzed. The variable temperature results show that the secondary and tertiary structures of the S-layer protein change irreversibly due to the heating of the sample. After the cooling of the heated protein, the secondary and tertiary structures are partially recovered. The denaturation curves show that the protein unfolding depends on the sample concentration and on the heating rate. The secondary and tertiary structures of the protein suffer changes in the same temperature range. We have also detected an intermediate state in the protein denaturation pathway. Our results on the thermal behavior of the S-layer protein may be important for the use of S-layer proteins in biotechnological applications, as well as for a better understanding of the structure and function of S-layer proteins.

Probing the mechanism of insulin fibril formation with insulin mutants.

PubMed

Nielsen, L; Frokjaer, S; Brange, J; Uversky, V N; Fink, A L

2001-07-27

The molecular basis of insulin fibril formation was investigated by studying the structural properties and kinetics of fibril formation of 20 different human insulin mutants at both low pH (conditions favoring monomer/dimer) and at pH 7.4 (conditions favoring tetramer/hexamer). Small-angle X-ray scattering showed insulin to be monomeric in 20% acetic acid, 0.1 M NaCl, pH 2. The secondary structure of the mutants was assessed using far-UV circular dichroism, and the tertiary structure was determined using near-UV circular dichroism, quenching of intrinsic fluorescence by acrylamide and interactions with the hydrophobic probe 1-anilino-8-naphthalene-sulfonic acid (ANS). The kinetics of fibril formation were monitored with the fluorescent dye, Thioflavin T. The results indicate that the monomer is the state from which fibrils arise, thus under some conditions dissociation of hexamers may be rate limiting or partially rate limiting. The insulin mutants were found to retain substantial nativelike secondary and tertiary structure under all conditions studied. The results suggest that fibril formation of the insulin mutants is controlled by specific molecular interactions that are sensitive to variations in the primary structure. The observed effects of several mutations on the rate of fibril formation are inconsistent with a previously suggested model for fibrillation [Brange, J., Whittingham, J., Edwards, D., Youshang, Z., Wollmer, A., Brandenburg, D., Dodson, G., and Finch, J. (1997) Curr. Sci. 72, 470-476]. Two surfaces on the insulin monomer are identified as potential interacting sites in insulin fibrils, one consisting of the residues B10, B16, and B17 and the other consisting of at least the residues A8 and B25. The marked increase in the lag time for fibril formation with mutations to more polar residues, as well as mutations to charged residues, demonstrates the importance of both hydrophobic and electrostatic interactions in the initial stages of fibrillation. A model for insulin fibril formation is proposed in which the formation of a partially folded intermediate is the precursor for associated species on the pathway to fibril formation.

The pH-dependent tertiary structure of a designed helix-loop-helix dimer.

PubMed

Dolphin, G T; Baltzer, L

1997-01-01

De novo designed helix-loop-helix motifs can fold into well-defined tertiary structures if residues or groups of residues are incorporated at the helix-helix boundary to form helix-recognition sites that restrict the conformational degrees of freedom of the helical segments. Understanding the relationship between structure and function of conformational constraints therefore forms the basis for the engineering of non-natural proteins. This paper describes the design of an interhelical HisH+-Asp- hydrogen-bonded ion pair and the conformational stability of the folded helix-loop-helix motif. GTD-C, a polypeptide with 43 amino acid residues, has been designed to fold into a hairpin helix-loop-helix motif that can dimerise to form a four-helix bundle. The folded motif is in slow conformational exchange on the NMR timescale and has a well-dispersed 1H NMR spectrum, a narrow temperature interval for thermal denaturation and a near-UV CD spectrum with some fine structure. The conformational stability is pH dependent with an optimum that corresponds to the pH for maximum formation of a hydrogen-bonded ion pair between HisH17+ in helix I and Asp27- in helix II. The formation of an interhelical salt bridge is strongly suggested by the pH dependence of a number of spectroscopic probes to generate a well-defined tertiary structure in a designed helix-loop-helix motif. The thermodynamic stability of the folded motif is not increased by the formation of the salt bridge, but neighbouring conformations are destabilised. The use of this novel design principle in combination with hydrophobic interactions that provide sufficient binding energy in the folded structure should be of general use in de novo design of native-like proteins.

Fast protein tertiary structure retrieval based on global surface shape similarity.

PubMed

Sael, Lee; Li, Bin; La, David; Fang, Yi; Ramani, Karthik; Rustamov, Raif; Kihara, Daisuke

2008-09-01

Characterization and identification of similar tertiary structure of proteins provides rich information for investigating function and evolution. The importance of structure similarity searches is increasing as structure databases continue to expand, partly due to the structural genomics projects. A crucial drawback of conventional protein structure comparison methods, which compare structures by their main-chain orientation or the spatial arrangement of secondary structure, is that a database search is too slow to be done in real-time. Here we introduce a global surface shape representation by three-dimensional (3D) Zernike descriptors, which represent a protein structure compactly as a series expansion of 3D functions. With this simplified representation, the search speed against a few thousand structures takes less than a minute. To investigate the agreement between surface representation defined by 3D Zernike descriptor and conventional main-chain based representation, a benchmark was performed against a protein classification generated by the combinatorial extension algorithm. Despite the different representation, 3D Zernike descriptor retrieved proteins of the same conformation defined by combinatorial extension in 89.6% of the cases within the top five closest structures. The real-time protein structure search by 3D Zernike descriptor will open up new possibility of large-scale global and local protein surface shape comparison. 2008 Wiley-Liss, Inc.

Discrete Haar transform and protein structure.

PubMed

Morosetti, S

1997-12-01

The discrete Haar transform of the sequence of the backbone dihedral angles (phi and psi) was performed over a set of X-ray protein structures of high resolution from the Brookhaven Protein Data Bank. Afterwards, the new dihedral angles were calculated by the inverse transform, using a growing number of Haar functions, from the lower to the higher degree. New structures were obtained using these dihedral angles, with standard values for bond lengths and angles, and with omega = 0 degree. The reconstructed structures were compared with the experimental ones, and analyzed by visual inspection and statistical analysis. When half of the Haar coefficients were used, all the reconstructed structures were not yet collapsed to a tertiary folding, but they showed yet realized most of the secondary motifs. These results indicate a substantial separation of structural information in the space of Haar transform, with the secondary structural information mainly present in the Haar coefficients of lower degrees, and the tertiary one present in the higher degree coefficients. Because of this separation, the representation of the folded structures in the space of Haar transform seems a promising candidate to encompass the problem of premature convergence in genetic algorithms.

Structural perturbation of proteins in low denaturant concentrations.

PubMed

Basak, S; Debnath, D; Haque, E; Ray, S; Chakrabarti, A

2001-01-01

The presence of very low concentrations of the widely used chemical denaturants, guanidinium chloride and urea, induce changes in the tertiary structure of proteins. We have presented results on such changes in four structurally unrelated proteins to show that such structural perturbations are common irrespective of their origin. Data representative of such structural changes are shown for the monomeric globular proteins such as horseradish peroxidase (HRP) from a plant, human serum albumin (HSA) and prothrombin from ovine blood serum, and for the membrane-associated, worm-like elongated protein, spectrin, from ovine erythrocytes. Structural alterations in these proteins were reflected in quenching studies of tryptophan fluorescence using the widely used quencher acrylamide. Stern-Volmer quenching constants measured in presence of the denaturants, even at concentrations below 100 mM, were higher than those measured in absence of the denaturants. Both steady-state and time-resolved fluorescence emission properties of tryptophan and of the extrinsic probe PRODAN were used for monitoring conformational changes in the proteins in presence of different low concentrations of the denaturants. These results are consistent with earlier studies from our laboratory indicating structural perturbations in proteins at the tertiary level, keeping their native-like secondary structure and their biological activity more or less intact.

Photocatalytic oxidation mechanism of alkanes in contact with titanium dioxide

NASA Technical Reports Server (NTRS)

Formenti, M.; Juillet, F.; Teichner, S. J.

1977-01-01

Isobutane was photooxidized on titanium dioxide between -16 and +180 C in tertiary butanol and acetone. The formation of tertiary butanol preceded the formation of acetone. Above 20 C the latter compound became clearly predominant. The reaction kinetics obeyed a steady state model of oxygen chemisorption with the involvement of isobutane in the physisorbed phase.

A Model to Predict Educators' Attitudes towards Technology and Thus Technology Adoption

ERIC Educational Resources Information Center

Govender, D. W.

2012-01-01

"Technology," the buzz word for the last ten to fifteen years in South Africa. Technology availability is quite often mistaken for technology adoption and use. Technology has been made available to almost all tertiary institutions and at least some public schools. However, in most tertiary institutions many professors still refuse to use…

Industrial shifts, female employment, and occupational differentiation: a dynamic model for American cities, 1960-1970.

PubMed

Semyonov, M; Scott, R I

1983-05-01

Sex-linked occupational differentiation has been seen as influenced by both the industrial structure of the economy and the sex composition of the labor force. Here, with a sample of 70 SMSAs, it was found (a) that the odds of men relative to women of joining professional and managerial occupations increased between 1960 and 1970, and (b) that this increase was dependent on the growth of tertiary industries and the greater number of women joining the cash economy. The observed effect of industrial shifts on sex-occupational differentiation, however, is argued to be a spurious consequence of the gender-composition of the work force. Specifically, the development of tertiary industries generates greater demand for female labor. Intensive recruitment of women to the labor force in turn increases occupational differentiation because females, in sex-typed labor markets, are likely to be channeled in disproportionate numbers away from upper-status occupations. The findings demonstrate that traditional modernization theory is unable to account for this. However, the results lend support to expectations derived from a labor market sex-segmentation approach.

Ab initio/GIAO-CCSD(T) (13)C NMR study of the rearrangement and dynamic aspects of rapidly equilibrating tertiary carbocations, C6H13(+) and C7H15(+).

PubMed

Olah, George A; Prakash, G K Surya; Rasul, Golam

2016-01-05

The rearrangement pathways of the equilibrating tertiary carbocations, 2,3-dimethyl-2-butyl cation (C6H13(+), 1), 2,3,3-trimethyl-2-butyl cation (C7H15(+), 5) and 2,3-dimethyl-2-pentyl cation (C7H15(+), 8 and 9) were investigated using the ab initio/GIAO-CCSD(T) (13)C NMR method. Comparing the calculated and experimental (13)C NMR chemical shifts of a series of carbocations indicates that excellent prediction of δ(13)C could be achieved through scaling. In the case of symmetrical equilibrating cations (1 and 5) the Wagner-Meerwein 1,2-hydride and 1,2-methide shifts, respectively, produce the same structure. This indicates that the overall (13)C NMR chemical shifts are conserved and independent of temperature. However, in the case of unsymmetrical equilibrating cations (8 and 9) the Wagner-Meerwein shift produces different tertiary structures, which have slightly different thermodynamic stabilities and, thus, different spectra. At the MP4(SDTQ)/cc-pVTZ//MP2/cc-pVTZ + ZPE level structure 8 is only 90 calories/mol more stable than structure 9. Based on computed (13)C NMR chemical shift calculations, mole fractions of these isomers were determined by assuming the observed chemical shifts are due to the weighted average of the chemical shifts of the static ions. © 2015 Wiley Periodicals, Inc.

Metamorphic core complexes: Expression of crustal extension by ductile-brittle shearing of the geologic column

NASA Technical Reports Server (NTRS)

Davis, G. H.

1985-01-01

Metamorphic core complexes and detachment fault terranes in the American Southwest are products of stretching of continental crust in the Tertiary. The physical and geometric properties of the structures, fault rocks, and contact relationships that developed as a consequence of the extension are especially well displayed in southeastern Arizona. The structures and fault rocks, as a system, reflect a ductile-through-brittle continuum of deformation, with individual structures and faults rocks showing remarkably coordinated strain and displacement patterns. Careful mapping and analysis of the structural system has led to the realization that strain and displacement were partitioned across a host of structures, through a spectrum of scales, in rocks of progressively changing rheology. By integrating observations made in different parts of the extensional system, especially at different inferred depth levels, it has been possible to construct a descriptive/kinematic model of the progressive deformation that achieved continental crustal extension in general, and the development of metamorphic core complexes in particular.

Solution structure of a GAAA tetraloop receptor RNA.

PubMed Central

Butcher, S E; Dieckmann, T; Feigon, J

1997-01-01

The GAAA tetraloop receptor is an 11-nucleotide RNA sequence that participates in the tertiary folding of a variety of large catalytic RNAs by providing a specific binding site for GAAA tetraloops. Here we report the solution structure of the isolated tetraloop receptor as solved by multidimensional, heteronuclear magnetic resonance spectroscopy. The internal loop of the tetraloop receptor has three adenosines stacked in a cross-strand or zipper-like fashion. This arrangement produces a high degree of base stacking within the asymmetric internal loop without extrahelical bases or kinking the helix. Additional interactions within the internal loop include a U. U mismatch pair and a G.U wobble pair. A comparison with the crystal structure of the receptor RNA bound to its tetraloop shows that a conformational change has to occur upon tetraloop binding, which is in good agreement with previous biochemical data. A model for an alternative binding site within the receptor is proposed based on the NMR structure, phylogenetic data and previous crystallographic structures of tetraloop interactions. PMID:9405377

Shaping up the protein folding funnel by local interaction: lesson from a structure prediction study.

PubMed

Chikenji, George; Fujitsuka, Yoshimi; Takada, Shoji

2006-02-28

Predicting protein tertiary structure by folding-like simulations is one of the most stringent tests of how much we understand the principle of protein folding. Currently, the most successful method for folding-based structure prediction is the fragment assembly (FA) method. Here, we address why the FA method is so successful and its lesson for the folding problem. To do so, using the FA method, we designed a structure prediction test of "chimera proteins." In the chimera proteins, local structural preference is specific to the target sequences, whereas nonlocal interactions are only sequence-independent compaction forces. We find that these chimera proteins can find the native folds of the intact sequences with high probability indicating dominant roles of the local interactions. We further explore roles of local structural preference by exact calculation of the HP lattice model of proteins. From these results, we suggest principles of protein folding: For small proteins, compact structures that are fully compatible with local structural preference are few, one of which is the native fold. These local biases shape up the funnel-like energy landscape.

Shaping up the protein folding funnel by local interaction: Lesson from a structure prediction study

PubMed Central

Chikenji, George; Fujitsuka, Yoshimi; Takada, Shoji

2006-01-01

Predicting protein tertiary structure by folding-like simulations is one of the most stringent tests of how much we understand the principle of protein folding. Currently, the most successful method for folding-based structure prediction is the fragment assembly (FA) method. Here, we address why the FA method is so successful and its lesson for the folding problem. To do so, using the FA method, we designed a structure prediction test of “chimera proteins.” In the chimera proteins, local structural preference is specific to the target sequences, whereas nonlocal interactions are only sequence-independent compaction forces. We find that these chimera proteins can find the native folds of the intact sequences with high probability indicating dominant roles of the local interactions. We further explore roles of local structural preference by exact calculation of the HP lattice model of proteins. From these results, we suggest principles of protein folding: For small proteins, compact structures that are fully compatible with local structural preference are few, one of which is the native fold. These local biases shape up the funnel-like energy landscape. PMID:16488978

Analysis of RNA structure using small-angle X-ray scattering

PubMed Central

Cantara, William A.; Olson, Erik D.; Musier-Forsyth, Karin

2016-01-01

In addition to their role in correctly attaching specific amino acids to cognate tRNAs, aminoacyl-tRNA synthetases (aaRS) have been found to possess many alternative functions and often bind to and act on other nucleic acids. In contrast to the well-defined 3D structure of tRNA, the structures of many of the other RNAs recognized by aaRSs have not been solved. Despite advances in the use of X-ray crystallography (XRC), nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (cryo-EM) for structural characterization of biomolecules, significant challenges to solving RNA structures still exist. Recently, small-angle X-ray scattering (SAXS) has been increasingly employed to characterize the 3D structures of RNAs and RNA-protein complexes. SAXS is capable of providing low-resolution tertiary structure information under physiological conditions and with less intensive sample preparation and data analysis requirements than XRC, NMR and cryo-EM. In this article, we describe best practices involved in the process of RNA and RNA-protein sample preparation, SAXS data collection, data analysis, and structural model building. PMID:27777026

Differences in the quality of diabetes care caused by social inequalities disappear after treatment and education in a tertiary care centre.

PubMed

Bäz, L; Müller, N; Beluchin, E; Kloos, C; Lehmann, T; Wolf, G; Müller, U A

2012-05-01

To assess the relationship between social status and quality of diabetes care in a tertiary care centre in Germany. Social status was assessed in 940 consecutive patients in a university outpatient department by a questionnaire. The assessment comprised three components: education, highest professional position and household net income (total score 3-21). Quality of diabetes care was measured by HbA(1c) , blood pressure and BMI. The influence of social status on quality measures was analysed at entry and last visit by fitting linear mixed models. At the entry visit, patients with lower social status had a higher HbA(1c) compared with patients with higher status (0.06% per each point of social score difference). After a mean follow- up of 6.0 years (Type 2 diabetes) and 9.4 years (Type 1 diabetes) no significant differences in HbA(1c) could be found. However, difference in BMI (-0.41 kg/m² per each point of social score) persisted at last observation. Blood pressure was only negligibly affected by the care programme. Low social status is associated with worse quality of diabetes care at entry in a tertiary care centre. The differences in HbA(1c) disappeared after treatment and structured education, whereas the difference in BMI persisted. There was no significant influence of social status or treatment on blood pressure. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Distinct Stabilities of the Structurally Homologous Heptameric Co-Chaperonins GroES and gp31

NASA Astrophysics Data System (ADS)

Dyachenko, Andrey; Tamara, Sem; Heck, Albert J. R.

2018-05-01

The GroES heptamer is the molecular co-chaperonin that partners with the tetradecamer chaperonin GroEL, which assists in the folding of various nonnative polypeptide chains in Escherichia coli. Gp31 is a structural and functional analogue of GroES encoded by the bacteriophage T4, becoming highly expressed in T4-infected E. coli, taking over the role of GroES, favoring the folding of bacteriophage proteins. Despite being slightly larger, gp31 is quite homologous to GroES in terms of its tertiary and quaternary structure, as well as in its function and mode of interaction with the chaperonin GroEL. Here, we performed a side-by-side comparison of GroES and gp31 heptamer complexes by (ion mobility) tandem mass spectrometry. Surprisingly, we observed quite distinct fragmentation mechanisms for the GroES and gp31 heptamers, whereby GroES displays a unique and unusual bimodal charge distribution in its released monomers. Not only the gas-phase dissociation but also the gas-phase unfolding of GroES and gp31 were found to be very distinct. We rationalize these observations with the similar discrepancies we observed in the thermal unfolding characteristics and surface contacts within GroES and gp31 in the solution. From our data, we propose a model that explains the observed simultaneous dissociation pathways of GroES and the differences between GroES and gp31 gas-phase dissociation and unfolding. We conclude that, although GroES and gp31 exhibit high homology in tertiary and quaternary structure, they are quite distinct in their solution and gas-phase (un)folding characteristics and stability. [Figure not available: see fulltext.

Protein Tertiary Structure Prediction Based on Main Chain Angle Using a Hybrid Bees Colony Optimization Algorithm

NASA Astrophysics Data System (ADS)

Mahmood, Zakaria N.; Mahmuddin, Massudi; Mahmood, Mohammed Nooraldeen

Encoding proteins of amino acid sequence to predict classified into their respective families and subfamilies is important research area. However for a given protein, knowing the exact action whether hormonal, enzymatic, transmembranal or nuclear receptors does not depend solely on amino acid sequence but on the way the amino acid thread folds as well. This study provides a prototype system that able to predict a protein tertiary structure. Several methods are used to develop and evaluate the system to produce better accuracy in protein 3D structure prediction. The Bees Optimization algorithm which inspired from the honey bees food foraging method, is used in the searching phase. In this study, the experiment is conducted on short sequence proteins that have been used by the previous researches using well-known tools. The proposed approach shows a promising result.

Rigid-Docking Approaches to Explore Protein-Protein Interaction Space.

PubMed

Matsuzaki, Yuri; Uchikoga, Nobuyuki; Ohue, Masahito; Akiyama, Yutaka

Protein-protein interactions play core roles in living cells, especially in the regulatory systems. As information on proteins has rapidly accumulated on publicly available databases, much effort has been made to obtain a better picture of protein-protein interaction networks using protein tertiary structure data. Predicting relevant interacting partners from their tertiary structure is a challenging task and computer science methods have the potential to assist with this. Protein-protein rigid docking has been utilized by several projects, docking-based approaches having the advantages that they can suggest binding poses of predicted binding partners which would help in understanding the interaction mechanisms and that comparing docking results of both non-binders and binders can lead to understanding the specificity of protein-protein interactions from structural viewpoints. In this review we focus on explaining current computational prediction methods to predict pairwise direct protein-protein interactions that form protein complexes.

Designing cooperatively folded abiotic uni- and multimolecular helix bundles

NASA Astrophysics Data System (ADS)

de, Soumen; Chi, Bo; Granier, Thierry; Qi, Ting; Maurizot, Victor; Huc, Ivan

2018-01-01

Abiotic foldamers, that is foldamers that have backbones chemically remote from peptidic and nucleotidic skeletons, may give access to shapes and functions different to those of peptides and nucleotides. However, design methodologies towards abiotic tertiary and quaternary structures are yet to be developed. Here we report rationally designed interactional patterns to guide the folding and assembly of abiotic helix bundles. Computational design facilitated the introduction of hydrogen-bonding functionalities at defined locations on the aromatic amide backbones that promote cooperative folding into helix-turn-helix motifs in organic solvents. The hydrogen-bond-directed aggregation of helices not linked by a turn unit produced several thermodynamically and kinetically stable homochiral dimeric and trimeric bundles with structures that are distinct from the designed helix-turn-helix. Relative helix orientation within the bundles may be changed from parallel to tilted on subtle solvent variations. Altogether, these results prefigure the richness and uniqueness of abiotic tertiary structure behaviour.

Effect of structured physical activity on respiratory outcomes in sedentary elderly adults with mobility limitations

USDA-ARS?s Scientific Manuscript database

OBJECTIVES: To evaluate the effect of structured physical activity on respiratory outcomes in community dwelling elderly adults with mobility limitations. DESIGN: Multicenter, randomized trial of physical activity vs health education, with respiratory variables prespecified as tertiary outcomes over...

Importance of Diffuse Metal Ion Binding to RNA

PubMed Central

Tan, Zhi-Jie; Chen, Shi-Jie

2016-01-01

RNAs are highly charged polyanionic molecules. RNA structure and function are strongly correlated with the ionic condition of the solution. The primary focus of this article is on the role of diffusive ions in RNA folding. Due to the long-range nature of electrostatic interactions, the diffuse ions can contribute significantly to RNA structural stability and folding kinetics. We present an overview of the experimental findings as well as the theoretical developments on the diffuse ion effects in RNA folding. This review places heavy emphasis on the effect of magnesium ions. Magnesium ions play a highly efficient role in stabilizing RNA tertiary structures and promoting tertiary structural folding. The highly efficient role goes beyond the mean-field effect such as the ionic strength. In addition to the effects of specific ion binding and ion dehydration, ion-ion correlation for the diffuse ions can contribute to the efficient role of the multivalent ions such as the magnesium ions in RNA folding. PMID:22010269

Importance of diffuse metal ion binding to RNA.

PubMed

Tan, Zhi-Jie; Chen, Shi-Jie

2011-01-01

RNAs are highly charged polyanionic molecules. RNA structure and function are strongly correlated with the ionic condition of the solution. The primary focus of this article is on the role of diffusive ions in RNA folding. Due to the long-range nature of electrostatic interactions, the diffuse ions can contribute significantly to RNA structural stability and folding kinetics. We present an overview of the experimental findings as well as the theoretical developments on the diffuse ion effects in RNA folding. This review places heavy emphasis on the effect of magnesium ions. Magnesium ions play a highly efficient role in stabilizing RNA tertiary structures and promoting tertiary structural folding. The highly efficient role goes beyond the mean-field effect such as the ionic strength. In addition to the effects of specific ion binding and ion dehydration, ion-ion correlation for the diffuse ions can contribute to the efficient role of the multivalent ions such as the magnesium ions in RNA folding.

A novel assay to measure tertiary and quaternary amines in wastewater: An indicator for NDMA wastewater precursors.

PubMed

Woods-Chabane, Gwen C; Glover, Caitlin M; Marti, Erica J; Dickenson, Eric R V

2017-07-01

This study examined the potential of using a novel bulk amine assay as an approximation for the tertiary and quaternary amine load in wastewaters and surface water samples, and this approximation was compared to N-nitrosodimethylamine (NDMA) formation potential using chloramines. An existing colorimetric method was examined and optimized for the detection of amines in environmental water samples. The method consists of liquid-liquid extraction followed by a catalyzed reaction to form a yet-undefined product that is known to be both a strong chromophore and fluorophore. Previous work verified that this reaction was effectively catalyzed by a number of compounds containing tertiary and quaternary amine moieties. Many tertiary and quaternary compounds are also efficient producers of NDMA under chloramination conditions, and a linear correlation was consequently derived from the bulk amine signals vs. NDMA formation potential in various wastewater samples (R 2  = 0.74; n = 24; p-value < 0.05). The results provide evidence that approximately 2% of the tertiary and quaternary amines measured can form NDMA and an estimated 0.01-1.3% of nitrogen in dissolved organic nitrogen originates from these bulk amines. The normalization of NDMA concentration by the amine measurement revealed that ozone effectively destroyed those tertiary and quaternary amine structures more likely to form NDMA in treated wastewater samples. This bulk amine assay illustrates that proxy measurements of tertiary and quaternary amines can be linked to the NDMA formation potential of a given sample, and this approach may prove useful as a characterizing tool for NDMA precursors in wastewater. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Structure of human resources in a public hospital in Chile: an experience in introducing changes].

PubMed

Artaza Barrios, O; Montt Vidal, J; Vásquez Leichtle, C

1997-11-01

This article discusses the structural and operational reform process that took place beginning in 1994 in Luis Calvo Mackenna Hospital, a tertiary pediatric care facility run by Oriente Metropolitan Health Center in Santiago, Chile. The formation of the Chilean health care system is briefly outlined, along with the changes brought about by the military government in 1979 and other transformations introduced by the first democratic government in 1990 and by the second one, in 1994. In spite of Chile's favorable health indicators and of the current government's desire to establish equitable services and to launch a decentralized system, the health care system that was fundamentally modeled in the fifties and sixties has failed to respond successfully to the demographic transition and to the population's new epidemiologic profile. One of the main problems is that services at the secondary and tertiary levels lack what is necessary to respond to the demand. Under a new leadership with an interest in modern administrative methods, clinical services at Luis Calvo Mackenna Hospital were restructured with new departments and units, a study of the organizational climate was carried out, the entire staff was intensively trained so as to generate a spirit of involvement and a new vision of the hospital's mission and teamwork, and a strategic plan was drawn up that is still being implemented.

Ligand-mediated and tertiary interactions cooperatively stabilize the P1 region in the guanine-sensing riboswitch

PubMed Central

Hanke, Christian A.

2017-01-01

Riboswitches are genetic regulatory elements that control gene expression depending on ligand binding. The guanine-sensing riboswitch (Gsw) binds ligands at a three-way junction formed by paired regions P1, P2, and P3. Loops L2 and L3 cap the P2 and P3 helices and form tertiary interactions. Part of P1 belongs to the switching sequence dictating the fate of the mRNA. Previous studies revealed an intricate relationship between ligand binding and presence of the tertiary interactions, and between ligand binding and influence on the P1 region. However, no information is available on the interplay among these three main regions in Gsw. Here we show that stabilization of the L2-L3 region by tertiary interactions, and the ligand binding site by ligand binding, cooperatively influences the structural stability of terminal base pairs in the P1 region in the presence of Mg2+ ions. The results are based on molecular dynamics simulations with an aggregate simulation time of ~10 μs across multiple systems of the unbound state of the Gsw aptamer and a G37A/C61U mutant, and rigidity analyses. The results could explain why the three-way junction is a central structural element also in other riboswitches and how the cooperative effect could become contextual with respect to intracellular Mg2+ concentration. The results suggest that the transmission of allosteric information to P1 can be entropy-dominated. PMID:28640851

Physicochemical properties of the modeled structure of astacin metalloprotease moulting enzyme NAS-36 and mapping the druggable allosteric space of Heamonchus contortus, Brugia malayi and Ceanorhabditis elegans via molecular dynamics simulation.

PubMed

Sharma, Om Prakash; Agrawal, Sonali; Kumar, M Suresh

2013-12-01

Nematodes represent the second largest phylum in the animal kingdom. It is the most abundant species (500,000) in the planet. It causes chronic, debilitating infections worldwide such as ascariasis, trichuriasis, hookworm, enterobiasis, strongyloidiasis, filariasis and trichinosis, among others. Molecular modeling tools can play an important role in the identification and structural investigation of molecular targets that can act as a vital candidate against filariasis. In this study, sequence analysis of NAS-36 from H. contortus (Heamonchus contortus), B. malayi (Brugia malayi) and C. elegans (Ceanorhabditis elegans) has been performed, in order to identify the conserved residues. Tertiary structure was developed for an insight into the molecular structure of the enzyme. Molecular Dynamics Simulation (MDS) studies have been carried out to analyze the stability and the physical properties of the proposed enzyme models in the H. contortus, B. malayi and C. elegans. Moreover, the drug binding sites have been mapped for inhibiting the function of NAS-36 enzyme. The molecular identity of this protease could eventually demonstrate how ex-sheathment is regulated, as well as provide a potential target of anthelmintics for the prevention of nematode infections.

Structure of the Red Dog District, western Brooks Range, Alaska

USGS Publications Warehouse

de Vera, Jean-Pierre P.; McClay, K. R.

2004-01-01

The Red Dog district of the western Brooks Range of northern Alaska, which includes the sediment-hosted Zn-Pb-Ag ± Ba deposits at Red Dog, Su-Lik, and Anarraaq, contains one of the world's largest reserves of zinc. This paper presents a new model for the structural development of the area and shows that understanding the structure is crucial for future exploration efforts and new mineral discoveries in the district. In the Red Dog district, a telescoped Late Devonian through Jurassic continental passive margin is exposed in a series of subhorizontally stacked, internally imbricated, and regionally folded thrust sheets. These sheets were emplaced during the Middle Jurassic to Late Cretaceous Brookian orogeny and subsequently were uplifted by late tectonic activity in the Tertiary. The thrust sheet stack comprises seven tectonostratigraphically distinct allochthonous sheets, three of which have been subject to regional and detailed structural analysis. The lowermost of these is the Endicott Mountains allochthon, which is overlain by the structurally higher Picnic Creek and Kelly River allochthons. Each individual allochthon is itself internally imbricated into a series of tectonostratigraphically coherent and distinct thrust plates and subplates. This structural style gives rise to duplex development and imbrication at a range of scales, from a few meters to tens of kilometers. The variable mechanical properties of the lithologic units of the ancient passive margin resulted in changes in structural styles and scales of structures across allochthon boundaries. Structural mapping and analysis of the district indicate a dominant northwest to west-northwest direction of regional tectonic transport. Local north to north-northeast transport of thrust sheets is interpreted to reflect the influence of underlying lateral and/or oblique ramps, which may have been controlled by inherited basin margin structures. Some thrust-sheet stacking patterns suggest out-of-sequence thrusting. The west-northwest-east-southeast-trending Wrench Creek and Sivukat Mountain faults were previously interpreted to be strike-slip faults, but this study shows that they are Tertiary (Eocene?) late extensional faults with little or no lateral displacement.

Automated 3D structure composition for large RNAs

PubMed Central

Popenda, Mariusz; Szachniuk, Marta; Antczak, Maciej; Purzycka, Katarzyna J.; Lukasiak, Piotr; Bartol, Natalia; Blazewicz, Jacek; Adamiak, Ryszard W.

2012-01-01

Understanding the numerous functions that RNAs play in living cells depends critically on knowledge of their three-dimensional structure. Due to the difficulties in experimentally assessing structures of large RNAs, there is currently great demand for new high-resolution structure prediction methods. We present the novel method for the fully automated prediction of RNA 3D structures from a user-defined secondary structure. The concept is founded on the machine translation system. The translation engine operates on the RNA FRABASE database tailored to the dictionary relating the RNA secondary structure and tertiary structure elements. The translation algorithm is very fast. Initial 3D structure is composed in a range of seconds on a single processor. The method assures the prediction of large RNA 3D structures of high quality. Our approach needs neither structural templates nor RNA sequence alignment, required for comparative methods. This enables the building of unresolved yet native and artificial RNA structures. The method is implemented in a publicly available, user-friendly server RNAComposer. It works in an interactive mode and a batch mode. The batch mode is designed for large-scale modelling and accepts atomic distance restraints. Presently, the server is set to build RNA structures of up to 500 residues. PMID:22539264

Universal partitioning of the hierarchical fold network of 50-residue segments in proteins

PubMed Central

Ito, Jun-ichi; Sonobe, Yuki; Ikeda, Kazuyoshi; Tomii, Kentaro; Higo, Junichi

2009-01-01

Background Several studies have demonstrated that protein fold space is structured hierarchically and that power-law statistics are satisfied in relation between the numbers of protein families and protein folds (or superfamilies). We examined the internal structure and statistics in the fold space of 50 amino-acid residue segments taken from various protein folds. We used inter-residue contact patterns to measure the tertiary structural similarity among segments. Using this similarity measure, the segments were classified into a number (Kc) of clusters. We examined various Kc values for the clustering. The special resolution to differentiate the segment tertiary structures increases with increasing Kc. Furthermore, we constructed networks by linking structurally similar clusters. Results The network was partitioned persistently into four regions for Kc ≥ 1000. This main partitioning is consistent with results of earlier studies, where similar partitioning was reported in classifying protein domain structures. Furthermore, the network was partitioned naturally into several dozens of sub-networks (i.e., communities). Therefore, intra-sub-network clusters were mutually connected with numerous links, although inter-sub-network ones were rarely done with few links. For Kc ≥ 1000, the major sub-networks were about 40; the contents of the major sub-networks were conserved. This sub-partitioning is a novel finding, suggesting that the network is structured hierarchically: Segments construct a cluster, clusters form a sub-network, and sub-networks constitute a region. Additionally, the network was characterized by non-power-law statistics, which is also a novel finding. Conclusion Main findings are: (1) The universe of 50 residue segments found here was characterized by non-power-law statistics. Therefore, the universe differs from those ever reported for the protein domains. (2) The 50-residue segments were partitioned persistently and universally into some dozens (ca. 40) of major sub-networks, irrespective of the number of clusters. (3) These major sub-networks encompassed 90% of all segments. Consequently, the protein tertiary structure is constructed using the dozens of elements (sub-networks). PMID:19454039

Stability of Secondary and Tertiary Structures of Virus-Like Particles Representing Noroviruses: Effects of pH, Ionic Strength, and Temperature and Implications for Adhesion to Surfaces.

PubMed

Samandoulgou, Idrissa; Hammami, Riadh; Morales Rayas, Rocio; Fliss, Ismail; Jean, Julie

2015-11-01

Loss of ordered molecular structure in proteins is known to increase their adhesion to surfaces. The aim of this work was to study the stability of norovirus secondary and tertiary structures and its implications for viral adhesion to fresh foods and agrifood surfaces. The pH, ionic strength, and temperature conditions studied correspond to those prevalent in the principal vehicles of viral transmission (vomit and feces) and in the food processing and handling environment (pasteurization and refrigeration). The structures of virus-like particles representing GI.1, GII.4, and feline calicivirus (FCV) were studied using circular dichroism and intrinsic UV fluorescence. The particles were remarkably stable under most of the conditions. However, heating to 65°C caused losses of β-strand structure, notably in GI.1 and FCV, while at 75°C the α-helix content of GII.4 and FCV decreased and tertiary structures unfolded in all three cases. Combining temperature with pH or ionic strength caused variable losses of structure depending on the particle type. Regardless of pH, heating to pasteurization temperatures or higher would be required to increase GII.4 and FCV adhesion, while either low or high temperatures would favor GI.1 adhesion. Regardless of temperature, increased ionic strength would increase GII.4 adhesion but would decrease GI.1 adhesion. FCV adsorption would be greater at refrigeration, pasteurization, or high temperature combined with a low salt concentration or at a higher NaCl concentration regardless of temperature. Norovirus adhesion mediated by hydrophobic interaction may depend on hydrophobic residues normally exposed on the capsid surface at pH 3, pH 8, physiological ionic strength, and low temperature, while at pasteurization temperatures it may rely more on buried hydrophobic residues exposed upon structural rearrangement. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Epilepsy diagnostic and treatment needs identified with a collaborative database involving tertiary centers in France.

PubMed

Chipaux, Mathilde; Szurhaj, William; Vercueil, Laurent; Milh, Mathieu; Villeneuve, Nathalie; Cances, Claude; Auvin, Stéphane; Chassagnon, Serge; Napuri, Sylvia; Allaire, Catherine; Derambure, Philippe; Marchal, Cécile; Caubel, Isabelle; Ricard-Mousnier, Brigitte; N'Guyen The Tich, Sylvie; Pinard, Jean-Marc; Bahi-Buisson, Nadia; de Baracé, Claire; Kahane, Philippe; Gautier, Agnès; Hamelin, Sophie; Coste-Zeitoun, Delphine; Rosenberg, Sarah-Dominique; Clerson, Pierre; Nabbout, Rima; Kuchenbuch, Mathieu; Picot, Marie-Christine; Kaminska, Anna

2016-05-01

To obtain perspective on epilepsy in patients referred to tertiary centers in France, and describe etiology, epilepsy syndromes, and identify factors of drug resistance and comorbidities. We performed a cross-sectional analysis of the characteristics of 5,794 pediatric and adult patients with epilepsy included in a collaborative database in France between 2007 and 2013. Comparisons between groups used Student's t-test or Fisher's exact test for binary or categorical variables. Factors associated with drug resistance and intellectual disability were evaluated in multi-adjusted logistic regression models. Mean age at inclusion was 17.9 years; children accounted for 67%. Epilepsy was unclassified in 20% of patients, and etiology was unknown in 65%, including those with idiopathic epilepsies. Etiologies differed significantly in adult- when compared to pediatric-onset epilepsy; however, among focal structural epilepsies, mesial temporal lobe epilepsy with hippocampal sclerosis began as often in the pediatric as in adult age range. Drug resistance concerned 53% of 4,210 patients evaluable for seizure control and was highest in progressive myoclonic epilepsy (89%), metabolic diseases (84%), focal cortical dysplasia (70%), other cortical malformations (69%), and mesial temporal lobe epilepsy with hippocampal sclerosis (67%). Fifty-nine percent of patients with focal structural epilepsy and 69% with epileptic encephalopathies were drug resistant; however, 40-50% of patients with West syndrome and epileptic encephalopathy with continuous spike-and-waves during sleep were seizure-free. Ages at onset in infancy and in young adults shared the highest risk of drug resistance. Epilepsy onset in infancy comprised the highest risk of intellectual disability, whereas specific cognitive impairment affected 36% of children with idiopathic focal epilepsy. Our study provides a snapshot on epilepsy in patients referred to tertiary centers and discloses needs for diagnosis and treatment. Large databases help identify patients with rare conditions that could benefit from specific prospective studies. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Contribution of Long-Range Interactions to the Secondary Structure of an Unfolded Globin

PubMed Central

Fedyukina, Daria V.; Rajagopalan, Senapathy; Sekhar, Ashok; Fulmer, Eric C.; Eun, Ye-Jin; Cavagnero, Silvia

2010-01-01

This work explores the effect of long-range tertiary contacts on the distribution of residual secondary structure in the unfolded state of an α-helical protein. N-terminal fragments of increasing length, in conjunction with multidimensional nuclear magnetic resonance, were employed. A protein representative of the ubiquitous globin fold was chosen as the model system. We found that, while most of the detectable α-helical population in the unfolded ensemble does not depend on the presence of the C-terminal region (corresponding to the native G and H helices), specific N-to-C long-range contacts between the H and A-B-C regions enhance the helical secondary structure content of the N terminus (A-B-C regions). The simple approach introduced here, based on the evaluation of N-terminal polypeptide fragments of increasing length, is of general applicability to identify the influence of long-range interactions in unfolded proteins. PMID:20816043

In silico structural analysis of group 3, 6 and 9 allergens from Dermatophagoides farinae.

PubMed

Teng, Feixiang; Yu, Lili; Bian, Yonghua; Sun, Jinxia; Wu, Juansong; Ling, Cunbao; Yang, Li; Wang, Yungang; Cui, Yubao

2015-05-01

Dermatophagoides farinae (Hughes; Acari: Pyroglyphidae) are the predominant source of dust mite allergens, which provoke allergic diseases, such as rhinitis, asthma and eczema. Of the 30 allergen groups produced by D. farinae, the Der f 3, Der f 6 and Der f 9 allergens are all trypsin‑associated proteins, however little else is currently known about them. The present study used in silico tools to compare the amino acid sequences, and predict the secondary and tertiary structures of Der f 3, Der f 6 and Der f 9 allergens. Protein sequence alignment detected ~46% identity between Der f 3, Der f 6 and Der f 9. Furthermore, each protein was shown to contain three active sites and two highly conserved trypsin functional domains. Predictions of the secondary and tertiary structure identified α‑helices, β‑sheets and random coils. The active sites of the three proteins appeared to fold onto each other in a three‑dimensional model, constituting the active site of the enzyme. Epitope analysis demonstrated that Der f 3, Der f 6 and Der f 9 have 4‑5 potential epitopes located in random coils, and the epitope sequences of Der f 3, Der f 6 and Der f 9 were shown to overlap in two domains (at amino acids 83‑87 and 179‑180); however the residues in these two domains were not identical. The present study aimed to conduct a biochemical and genetic analysis of these three allergens, and to potentially contribute to the development of vaccines for allergen‑specific immunotherapy.

Effects of high pressure processing on activity and structure of soluble acid invertase in mango pulp, crude extract, purified form and model systems.

PubMed

Li, Renjie; Wang, Yongtao; Ling, Jiangang; Liao, Xiaojun

2017-09-15

The effects of high pressure processing (HPP) on the activity of soluble acid invertase (SAI) in mango pulp, crude extract, purified SAI and purified SAI in model systems (pectin, bovine serum albumin (BSA), sugars and pH 3-7) were investigated. The activity of SAI in mango pulp was increased after HPP, and that in crude extract stayed unchanged. The activity of purified SAI was decreased after HPP at 45 and 50°C. Pectin exhibited a concentration-dependent protection for purified SAI against HPP at 50°C/600MPa for 30min. Pectin that had an esterification degree (DE) of 85% exhibited a greater protection than pectin that had a DE of 20-34%. BSA, acidic pH (3-6) and sucrose also exhibited protection for purified SAI against HPP. HPP at 50°C/600MPa for 30min disrupted the secondary structure and tertiary structure of purified SAI, but no aggregation of purified SAI was observed after HPP. Copyright © 2017 Elsevier Ltd. All rights reserved.

Direct Observation of Insulin Association Dynamics with Time-Resolved X-ray Scattering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rimmerman, Dolev; Leshchev, Denis; Hsu, Darren J.

Biological functions frequently require protein-protein interactions that involve secondary and tertiary structural perturbation. Here we study protein-protein dissociation and reassociation dynamics in insulin, a model system for protein oligomerization. Insulin dimer dissociation into monomers was induced by a nanosecond temperature-jump (T-jump) of ~8 °C in aqueous solution, and the resulting protein and solvent dynamics were tracked by time-resolved X-ray solution scattering (TRXSS) on time scales of 10 ns to 100 ms. The protein scattering signals revealed the formation of five distinguishable transient species during the association process that deviate from simple two state kinetics. Our results show that the combinationmore » of T-jump pump coupled to TRXSS probe allows for direct tracking of structural dynamics in nonphotoactive proteins.« less

Solid, Cystic, and Tubular: Novice Ultrasound Skills Training Using a Versatile, Affordable Practice Model.

PubMed

Sevak, Shruti; Lurvey, Benjamin; Woodfin, Ashley A; Hothem, Zachary; Callahan, Rose E; Robbins, James; Ziegler, Kathryn

2018-04-09

In spite of the recognized benefits of ultrasound, many physicians have little experience with using ultrasound to perform procedures. Many medical schools and residency programs lack a formal ultrasound training curriculum. We describe an affordable ultrasound training curriculum and versatile, inexpensive practice model. Participants underwent a didactic session to teach the theory required to perform ultrasound-guided procedures. Motor skills were taught using a practice model incorporating analogs of common anatomic and pathologic structures into an opacified gelatin substrate. The Marcia and Eugene Applebaum Simulation Learning Institute, Beaumont Hospital, Royal Oak, MI; a private nonprofit tertiary care hospital associated with the OUWB School of Medicine, Rochester, MI. The model was tested in a cohort of 50 medical students and general surgery residents. The gelatin model can be constructed for $1.03 per learner. The solid, cystic, and vascular structural analogs were readily identifiable on ultrasound and easily differentiated based on their echotextures. Eighty-four percent of participants successfully aspirated the cystic structure, 88% successfully biopsied a portion of the solid structure, and 76% successfully cannulated the tubular structure. Overall, 82% of participants achieved a passing score for the exercise based on a validated Objective Structured Assessment of Technical Skill instrument. There were no significant differences between the medical students and residents. This model can be used to teach basic ultrasound skills such as aspiration, biopsy, and vessel cannulation, providing a foundation for the use of ultrasound in a broad range of clinical procedures, as well as providing practice opportunities for medical students and residents to gain increased ultrasound competency and confidence. Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Publications - RI 2000-1A | Alaska Division of Geological & Geophysical

Science.gov Websites

; Folding; Formations; Fossils; Generalized; Geologic; Geologic Map; Geology; Geomorphology; Glacial ; Silt; Structure; Surficial; Surficial Geology; Tectonics; Tertiary; Thaw Lakes; Trace Fossils

Insights upon upper crustal arhitecture of a subduction zone and its surroundings - Vrancea Zone and Focsani Basin - substantiated by geophysical studies

NASA Astrophysics Data System (ADS)

Bocin, A.; Stephenson, R.; Mocanu, V.

2007-12-01

The DACIA PLAN (Danube and Carpathian Integrated Action on Processes in the Lithosphere and Neotectonics) deep seismic reflection survey was performed in August-September 2001, with the proposed objective of obtaining new information on the deep structure of the external Carpathians nappes and the architecture of Tertiary/Quaternary basin developed within and adjacent to the Vrancea zone, including the rapidly subsiding Focsani Basin. The DACIA-PLAN profile is about 140 km long, having a roughly NW-SE direction, from near the southeast Transylvanian Basin, across the mountainous southeastern Carpathians and their foreland to near the Danube River. A high resolution 2.5D velocity model of the upper crust along the seismic profile has been determined from a tomographic inversion and a 2D ray tracing forward modelling of the DACIA PLAN first arrival data. Peculiar shallow high velocities indicate that pre-Tertiary basement in the Vrancea Zone (characterised by velocities greater than 5.6 km/s) is involved in Carpathian thrusting while rapid alternance, vertically or horizontally, of velocity together with narrowingly contemporary crustal events suggests uplifting. Further to the east, at the foreland basin-thrust belt transition zone (well defined within velocity values), the velocity model suggests a nose of the Miocene Subcarpathians nappe being underlain by Focsani Basin units. A Miocene and younger Focsani Basin sedimentary succession of ~10 km thickness is ascertained by a gradual increase of velocities and strongly defined velocity boundaries.

Phylogeography and genetic structure of a Tertiary relict tree species, Tapiscia sinensis (Tapisciaceae): implications for conservation

PubMed Central

Zhang, Jinju; Li, Zuozhou; Fritsch, Peter W.; Tian, Hua; Yang, Aihong; Yao, Xiaohong

2015-01-01

Background and Aims The phylogeography of plant species in sub-tropical China remains largely unclear. This study used Tapiscia sinensis, an endemic and endangered tree species widely but disjunctly distributed in sub-tropical China, as a model to reveal the patterns of genetic diversity and phylogeographical history of Tertiary relict plant species in this region. The implications of the results are discussed in relation to its conservation management. Methods Samples were taken from 24 populations covering the natural geographical distribution of T. sinensis. Genetic structure was investigated by analysis of molecular variance (AMOVA) and spatial analysis of molecular variance (SAMOVA). Phylogenetic relationships among haplotypes were constructed with maximum parsimony and haplotype network methods. Historical population expansion events were tested with pairwise mismatch distribution analysis and neutrality tests. Species potential range was deduced by ecological niche modelling (ENM). Key Results A low level of genetic diversity was detected at the population level. A high level of genetic differentiation and a significant phylogeographical structure were revealed. The mean divergence time of the haplotypes was approx. 1·33 million years ago. Recent range expansion in this species is suggested by a star-like haplotype network and by the results from the mismatch distribution analysis and neutrality tests. Conclusions Climatic oscillations during the Pleistocene have had pronounced effects on the extant distribution of Tapiscia relative to the Last Glacial Maximum (LGM). Spatial patterns of molecular variation and ENM suggest that T. sinensis may have retreated in south-western and central China and colonized eastern China prior to the LGM. Multiple montane refugia for T. sinense existing during the LGM are inferred in central and western China. The populations adjacent to or within these refugia of T. sinense should be given high priority in the development of conservation policies and management strategies for this endangered species. PMID:26187222

Phylogeography and genetic structure of a Tertiary relict tree species, Tapiscia sinensis (Tapisciaceae): implications for conservation.

PubMed

Zhang, Jinju; Li, Zuozhou; Fritsch, Peter W; Tian, Hua; Yang, Aihong; Yao, Xiaohong

2015-10-01

The phylogeography of plant species in sub-tropical China remains largely unclear. This study used Tapiscia sinensis, an endemic and endangered tree species widely but disjunctly distributed in sub-tropical China, as a model to reveal the patterns of genetic diversity and phylogeographical history of Tertiary relict plant species in this region. The implications of the results are discussed in relation to its conservation management. Samples were taken from 24 populations covering the natural geographical distribution of T. sinensis. Genetic structure was investigated by analysis of molecular variance (AMOVA) and spatial analysis of molecular variance (SAMOVA). Phylogenetic relationships among haplotypes were constructed with maximum parsimony and haplotype network methods. Historical population expansion events were tested with pairwise mismatch distribution analysis and neutrality tests. Species potential range was deduced by ecological niche modelling (ENM). A low level of genetic diversity was detected at the population level. A high level of genetic differentiation and a significant phylogeographical structure were revealed. The mean divergence time of the haplotypes was approx. 1·33 million years ago. Recent range expansion in this species is suggested by a star-like haplotype network and by the results from the mismatch distribution analysis and neutrality tests. Climatic oscillations during the Pleistocene have had pronounced effects on the extant distribution of Tapiscia relative to the Last Glacial Maximum (LGM). Spatial patterns of molecular variation and ENM suggest that T. sinensis may have retreated in south-western and central China and colonized eastern China prior to the LGM. Multiple montane refugia for T. sinense existing during the LGM are inferred in central and western China. The populations adjacent to or within these refugia of T. sinense should be given high priority in the development of conservation policies and management strategies for this endangered species. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Macrodamage Accumulation Model for a Human Femur

PubMed Central

2017-01-01

The objective of this study was to more fully understand the mechanical behavior of bone tissue that is important to find an alternative material to be used as an implant and to develop an accurate model to predict the fracture of the bone. Predicting and preventing bone failure is an important area in orthopaedics. In this paper, the macrodamage accumulation models in the bone tissue have been investigated. Phenomenological models for bone damage have been discussed in detail. In addition, 3D finite element model of the femur prepared from imaging data with both cortical and trabecular structures is delineated using MIMICS and ANSYS® and simulated as a composite structure. The damage accumulation occurring during cyclic loading was analyzed for fatigue scenario. We found that the damage accumulates sooner in the multiaxial than in the uniaxial loading condition for the same number of cycles, and the failure starts in the cortical bone. The damage accumulation behavior seems to follow a three-stage growth: a primary phase, a secondary phase of damage growth marked by linear damage growth, and a tertiary phase that leads to failure. Finally, the stiffness of the composite bone comprising the cortical and trabecular bone was significantly different as expected. PMID:28951659

Parameterization of an empirical model for the prediction of n-octanol, alkane and cyclohexane/water as well as brain/blood partition coefficients.

PubMed

Zerara, Mohamed; Brickmann, Jürgen; Kretschmer, Robert; Exner, Thomas E

2009-02-01

Quantitative information of solvation and transfer free energies is often needed for the understanding of many physicochemical processes, e.g the molecular recognition phenomena, the transport and diffusion processes through biological membranes and the tertiary structure of proteins. Recently, a concept for the localization and quantification of hydrophobicity has been introduced (Jäger et al. J Chem Inf Comput Sci 43:237-247, 2003). This model is based on the assumptions that the overall hydrophobicity can be obtained as a superposition of fragment contributions. To date, all predictive models for the logP have been parameterized for n-octanol/water (logP(oct)) solvent while very few models with poor predictive abilities are available for other solvents. In this work, we propose a parameterization of an empirical model for n-octanol/water, alkane/water (logP(alk)) and cyclohexane/water (logP(cyc)) systems. Comparison of both logP(alk) and logP(cyc) with the logarithms of brain/blood ratios (logBB) for a set of structurally diverse compounds revealed a high correlation showing their superiority over the logP(oct) measure in this context.

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA

PubMed Central

2016-01-01

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results. PMID:27983843

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA.

PubMed

Hayatshahi, Hamed S; Roe, Daniel R; Galindo-Murillo, Rodrigo; Hall, Kathleen B; Cheatham, Thomas E

2017-01-26

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results.

Variation in Inflammatory/Regulatory Cytokines in Secondary, Tertiary, and Quaternary Challenges with Dengue Virus

PubMed Central

Sierra, Beatriz; Pérez, Ana B.; Alvarez, Mayling; García, Gissel; Vogt, Katrin; Aguirre, Eglys; Schmolke, Kathrin; Volk, Hans-Dieter; Guzmán, María G.

2012-01-01

Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-β after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections. PMID:22802438

Chemoselective SN2' Allylations of Detrifluoroacetylatively In Situ Generated 3-Fluoroindolin-2-one-Derived Tertiary Enolates with Morita-Baylis-Hillman Carbonates.

PubMed

Zhu, Yi; Mei, Haibo; Han, Jianlin; Soloshonok, Vadim A; Zhou, Jie; Pan, Yi

2017-12-15

The first example of the S N 2' reaction type of the detrifluoroacetylatively in situ generated tertiary fluoro-enolates in the uncatalyzed reactions with Morita-Baylis-Hillman derivatives has been described. The S N 2' substitution takes place in a highly chemoselective manner as no corresponding S N 2 products were observed in the reaction mixtures. Due to the excellent stereochemical outcome, the reactions seem to have an apparent synthetic value for the preparation of structurally new fluorinated oxindoles.

Geophysical interpretations west of and within the northwestern part of the Nevada Test Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grauch, V.J.; Sawyer, D.A.; Fridrich, C.J.

1997-12-31

This report focuses on interpretation of gravity and new magnetic data west of the Nevada Test Site (NTS) and within the northwestern part of NTS. The interpretations integrate the gravity and magnetic data with other geophysical, geological, and rock property data to put constraints on tectonic and magmatic features not exposed at the surface. West of NTS, where drill hole information is absent, these geophysical data provide the best available information on the subsurface. Interpreted subsurface features include calderas, intrusions, basalt flows and volcanoes, Tertiary basins, structurally high pre-Tertiary rocks, and fault zones. New features revealed by this study includemore » (1) a north-south buried tectonic fault east of Oasis Mountain, which the authors call the Hogback fault; (2) an east striking fault or accommodation zone along the south side of Oasis Valley basin, which they call the Hot Springs fault; (3) a NNE striking structural zone coinciding with the western margins of the caldera complexes; (4) regional magnetic highs that probably represent a thick sequence of Tertiary volcanic rocks; and (5) two probable buried calderas that may be related to the tuffs of Tolicha Peak and of Sleeping Butte, respectively.« less

Group 6 metal pentacarbonyl complexes of air-stable primary, secondary, and tertiary ferrocenylethylphosphines.

PubMed

Rabiee Kenaree, Amir; Sauvé, Ethan R; Ragogna, Paul J; Gilroy, Joe B

2016-02-21

The synthesis and characterization of a series of Group 6 metal pentacarbonyl complexes of air stable primary, secondary, and tertiary phosphines containing ferrocenylethyl substituents are reported [M(CO)5L: M = Cr, Mo, W; L = PH2(CH2CH2Fc), PH(CH2CH2Fc)2, P(CH2CH2Fc)3]. The structure and composition of the complexes were confirmed by multinuclear NMR spectroscopy, IR and UV-Vis absorption spectroscopy, mass spectrometry, X-ray crystallography, and elemental analysis. The solid-state structural data reported revealed trends in M-C and M-P bond lengths that mirrored those of the atomic radii of the Group 6 metals involved. UV-Vis absorption spectroscopy and cyclic voltammetry highlighted characteristics consistent with electronically isolated ferrocene units including wavelengths of maximum absorption between 435 and 441 nm and reversible one-electron (per ferrocene unit) oxidation waves between 10 and -5 mV relative to the ferrocene/ferrocenium redox couple. IR spectroscopy confirmed that the σ donating ability of the phosphines increased as ferrocenylethyl substituents were introduced and that the tertiary phosphine ligand described is a stronger σ donor than PPh3 and a weaker σ donor than PEt3, respectively.

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

PubMed Central

Hill, David G.; Yu, Liang; Gao, Hugh; Balic, Jesse J.; West, Alison; Oshima, Hiroko; McLeod, Louise; Oshima, Masanobu; Gallimore, Awen; D'Costa, Kimberley; Bhathal, Prithi S.; Sievert, William; Ferrero, Richard L.

2018-01-01

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130 F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130 F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis. PMID:29417587

Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation.

PubMed

Wang, Pei; He, Yi-Liang; Huang, Ching-Hua

2010-12-01

Fluoroquinolones (FQs) are a group of widely prescribed antibiotics and have been frequently detected in the aquatic environment. The reaction kinetics and transformation of seven FQs (ciprofloxacin (CIP), enrofloxacin (ENR), norfloxacin (NOR), ofloxacin (OFL), lomefloxacin (LOM), pipemidic acid (PIP) and flumequine (FLU)) and three structurally related amines (1-phenylpiperazine (PP), N-phenylmorpholine (PM) and 4-phenylpiperidine (PD)) toward chlorine dioxide (ClO(2)) were investigated to elucidate the behavior of FQs during ClO(2) disinfection processes. The reaction kinetics are highly pH-dependent, can be well described by a second-order kinetic model incorporating speciation of FQs, and follow the trend of OFL > ENR > CIP ∼ NOR ∼ LOM > > PIP in reactivity. Comparison among FQs and related amines and product characterization indicate that FQs' piperazine ring is the primary reactive center toward ClO(2). ClO(2) likely attacks FQ's piperazinyl N4 atom followed by concerted fragmentation involving piperazinyl N1 atom, leading to dealkylation, hydroxylation and intramolecular ring closure at the piperazine moiety. While FQs with tertiary N4 react faster with ClO(2) than FQs with secondary N4, the overall reactivity of the piperazine moiety also depends strongly on the quinolone ring through electronic effects. The reaction rate constants obtained in clean water matrix can be used to model the decay of CIP by ClO(2) in surface water samples, but overestimate the decay in wastewater samples. Overall, transformation of FQs, particularly for those with tertiary N4 amines, could be expected under typical ClO(2) disinfection conditions. However, the transformation may not eliminate antibacterial activity because of little destruction at the quinolone ring. Copyright © 2010 Elsevier Ltd. All rights reserved.

Modeling Long-term Creep Performance for Welded Nickel-base Superalloy Structures for Power Generation Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Chen

2015-01-01

We report here a constitutive model for predicting long-term creep strain evolution in’ strengthened Ni-base superalloys. Dislocation climb-bypassing’, typical in intermediate’ volume fraction (~20%) alloys, is considered as the primary deformation mechanism. Dislocation shearing’ to anti-phase boundary (APB) faults and diffusional creep are also considered for high-stress and high-temperature low-stress conditions, respectively. Additional damage mechanism is taken into account for rapid increase in tertiary creep strain. The model has been applied to Alloy 282, and calibrated in a temperature range of 1375-1450°F, and stress range of 15-45ksi. The model parameters and a MATLAB code are provided. This report is preparedmore » by Monica Soare and Chen Shen at GE Global Research. Technical discussions with Dr. Vito Cedro are greatly appreciated. This work was supported by DOE program DE-FE0005859« less

Crustal structure of Wrangellia and adjacent terranes inferred from geophysical studies along a transect through the northern Talkeetna Mountains

USGS Publications Warehouse

Glen, J.M.G.; Schmidt, J.; Pellerin, L.; McPhee, D.K.; O'Neill, J. M.

2007-01-01

Recent investigations of the Talkeetna Mountains in south-central Alaska were undertaken to study the region's framework geophysics and to reinterpret structures and crustal composition. Potential field (gravity and magnetic) and magnetotelluric (MT) data were collected along northwest-trending profiles as part of the U.S. Geological Survey's Talkeetna Mountains transect project. The Talkeetna Mountains transect area comprises eight 1:63,360 quadrangles (???9500 km2) in the Healy and Talkeetna Mountains 1?? ?? 3?? sheets that span four major lithostratigraphic terranes (Glen et al., this volume) including the Wrangellia and Peninsular terranes and two Mesozoic overlap assemblages inboard (northwest) of Wrangellia. These data were used here to develop 21/2-dimensional models for the three profiles. Modeling results reveal prominent gravity, magnetic, and MT gradients (???3.25 mGal/ km, ???100nT/km, ???300 ohm-m/km) corresponding to the Talkeetna Suture Zone-a first-order crustal discontinuity in the deep crust that juxtaposes rocks with strongly contrasting rock properties. This discontinuity corresponds with the suture between relatively dense magnetic crust of Wrangellia (likely of oceanic composition) and relatively less dense transitional crust underlying Jurassic to Cretaceous flysch basins developed between Wrangellia and North America. Some area of the oceanic crust beneath Wrangellia may also have been underplated by mafic material during early to mid-Tertiary volcanism. The prominent crustal break underlies the Fog Lakes basin approximately where theTalkeetna thrust faultwaspreviouslymappedas a surface feature. Potential fieldand MT models, however, indicate that the Talkeetna Suture Zone crustal break along the transect is a deep (2-8 km), steeply west-dipping structure-not a shallow east-dipping Alpine nappe-like thrust. Indeed, most of the crustal breaks in the area appear to be steep in the geophysical data, which is consistent with regional geologic mapping that indicates that most of the faults are steep normal, reverse, strike-slip, or oblique-slip faults. Mapping further indicates that many of these features, which likely formed during Jurassic and Cretaceous time, such as the Talkeetna Suture Zone have reactivated inTertiary time (O'Neill et al., 2005). Copyright ?? 2007 The Geological Society of America.

Chloramination of nitrogenous contaminants (pharmaceuticals and pesticides): NDMA and halogenated DBPs formation.

PubMed

Le Roux, Julien; Gallard, Hervé; Croué, Jean-Philippe

2011-05-01

Disinfection with chloramines is often used to reduce the production of regulated disinfection by-products (DBPs) such as trihalomethanes (THMs) and haloacetic acids (HAAs). However, chloramination can lead to the formation of N-nitrosamines, including N-nitrosodimethylamine (NDMA), a probable human carcinogen. Previous research used dimethylamine (DMA) as a model precursor of NDMA, but certain widely used tertiary dimethylamines (e.g. the pharmaceutical ranitidine) show much higher conversion rates to NDMA than DMA. This study investigates the NDMA formation potential of several tertiary amines including pharmaceuticals and herbicides. The reactivity of these molecules with monochloramine (NH(2)Cl) is studied through the formation of NDMA, and other halogenated DBPs such as haloacetonitriles (HANs) and AOX (Adsorbable Organic Halides). Several compounds investigated formed NDMA in greater amounts than DMA, revealing the importance of structural characteristics of tertiary amines for NDMA formation. Among these compounds, the pharmaceutical ranitidine showed the highest molar conversion to NDMA. The pH and dissolved oxygen content of the solution were found to play a major role for the formation of NDMA from ranitidine. NDMA was formed in higher amounts at pH around pH 8 and a lower concentration of dissolved oxygen dramatically decreased NDMA yields. These findings seem to indicate that dichloramine (NHCl(2)) is not the major oxidant involved in the formation of NDMA from ranitidine, results in contradiction with the reaction mechanisms proposed in the literature. Dissolved oxygen was also found to influence the formation of other oxygen-containing DBPs (i.e. trichloronitromethane and haloketones). The results of this study identify several anthropogenic precursors of NDMA, indicating that chloramination of waters impacted by these tertiary amines could lead to the formation of significant amounts of NDMA and other non-regulated DBPs of potential health concern (e.g. dichloroacetonitrile or trichloronitromethane). This could be of particular importance for the chloramination of wastewater effluents, especially during water reuse processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Peptide-surfactant interactions: A combined spectroscopic and molecular dynamics simulation approach

NASA Astrophysics Data System (ADS)

Roussel, Guillaume; Caudano, Yves; Matagne, André; Sansom, Mark S.; Perpète, Eric A.; Michaux, Catherine

2018-02-01

In the present contribution, we report a combined spectroscopic and computational approach aiming to unravel at atomic resolution the effect of the anionic SDS detergent on the structure of two model peptides, the α-helix TrpCage and the β-stranded TrpZip. A detailed characterization of the specific amino acids involved is performed. Monomeric (single molecules) and micellar SDS species differently interact with the α-helix and β-stranded peptides, emphasizing the different mechanisms occurring below and above the critical aggregation concentration (CAC). Below the CAC, the α-helix peptide is fully unfolded, losing its hydrophobic core and its Asp-Arg salt bridge, while the β-stranded peptide keeps its native structure with its four Trp well oriented. Above the CAC, the SDS micelles have the same effect on both peptides, that is, destabilizing the tertiary structure while keeping their secondary structure. Our studies will be helpful to deepen our understanding of the action of the denaturant SDS on peptides and proteins.

Activity, Stability, and Structure of Native and Modified by Woodward Reagent K Mushroom Tyrosinase

NASA Astrophysics Data System (ADS)

Emami, S.; Piri, H.; Gheibi, N.

2018-01-01

Mushroom tyrosinase (MT) was considered a good model for studying the inhibition, activation, and mutation of tyrosinase as the key enzyme of melanogenesis. In the present study, the activity, structure, reduction, and stability of native and modified enzymes were investigated after the modification of MT carboxylic residues by the Woodward reagent K (WRK). The relative activity of the sole enzyme was reduced from 100 to 77.9, 53.8, 39.4, and 26.4% after its modification by 2.5, 5, 25, and 50 ratios of [WRK]/[MT], respectively. The Tm values were calculated from thermal denaturation curves at 61.2, 60.1, 58.3, 53.9, and 45.5oC for the sole and modified enzymes. The reduction of the Δ {G}_{{H}_2O} values for the modified enzyme in chemical denaturation indicated instability. A structural study by CD and intrinsic fluorescence technique revealed the fluctuation of the secondary and tertiary structures of MT.

Structural insights into a key carotenogenesis related enzyme phytoene synthase of P. falciparum: a novel drug target for malaria.

PubMed

Agarwal, Shalini; Sharma, Vijeta; Phulera, Swastik; Abdin, M Z; Ayana, R; Singh, Shailja

2015-12-01

Carotenoids represent a diverse group of pigments derived from the common isoprenoid precursors and fulfill a variety of critical functions in plants and animals. Phytoene synthase (PSY), a transferase enzyme that catalyzes the first specific step in carotenoid biosynthesis plays a central role in the regulation of a number of essential functions mediated via carotenoids. PSYs have been deeply investigated in plants, bacteria and algae however in apicomplexans it is poorly studied. In an effort to characterize PSY in apicomplexans especially the malaria parasite Plasmodium falciparum (P. falciparum), a detailed bioinformatics analysis is undertaken. We have analysed the Phylogenetic relationship of PSY also referred to as octaprenyl pyrophosphate synthase (OPPS) in P. falciparum with other taxonomic groups. Further, we in silico characterized the secondary and tertiary structures of P. falciparum PSY/OPPS and compared the tertiary structures with crystal structure of Thermotoga maritima (T. maritima) OPPS. Our results evidenced the resemblance of P. falciparum PSY with the active site of T. maritima OPPS. Interestingly, the comparative structural analysis revealed an unconserved unique loop in P. falciparum OPPS/PSY. Such structural insights might contribute novel accessory functions to the protein thus, offering potential drug targets.

Contributions of historical and contemporary geographic and environmental factors to phylogeographic structure in a Tertiary relict species, Emmenopterys henryi (Rubiaceae)

PubMed Central

Zhang, Yong-Hua; Wang, Ian J.; Comes, Hans Peter; Peng, Hua; Qiu, Ying-Xiong

2016-01-01

Examining how historical and contemporary geographic and environmental factors contribute to genetic divergence at different evolutionary scales is a central yet largely unexplored question in ecology and evolution. Here, we examine this key question by investigating how environmental and geographic factors across different epochs have driven genetic divergence at deeper (phylogeographic) and shallower (landscape genetic) evolutionary scales in the Chinese Tertiary relict tree Emmenopterys henryi. We found that geography played a predominant role at all levels – phylogeographic clades are broadly geographically structured, the deepest levels of divergence are associated with major geological or pre-Quaternary climatic events, and isolation by distance (IBD) primarily explained population genetic structure. However, environmental factors are clearly also important – climatic fluctuations since the Last Interglacial (LIG) have likely contributed to phylogeographic structure, and the population genetic structure (in our AFLP dataset) was partly explained by isolation by environment (IBE), which may have resulted from natural selection in environments with divergent climates. Thus, historical and contemporary geography and historical and contemporary environments have all shaped patterns of genetic structure in E. henryi, and, in fact, changes in the landscape through time have also been critical factors. PMID:27137438

Structure of coastal community occupational in responsible environmental quality at Tanjung Burung village, Tangerang regency

NASA Astrophysics Data System (ADS)

Syahdanul, Darul; Sumabrata, Jachrizal; Darmajanti, Linda

2018-03-01

Tanjung Burung Village is an area located on the river mouth. The position makes the occupational structure of the community has a relationship with the environmental conditions of the river mouth. The occupational structure of the estuary community tends to be in the primary sector. However, at present, the environmental condition of the Cisadane River estuary has a quality degradation in terms of the intensity of river water pollution, the frequency of flooding, and the intensity of groundwater contamination. This study aims to analyze the relationship between environmental degradation and changes in occupational structure, and analysis on the quality of life of the community. In collecting and processing data, this research uses sequential exploratory strategy. This process refers to the geographical map of Tanjung Burung Village in 1996, 2006, 2016; Population data of 1995, 2000, 2005, 2011, 2016; as well as environmental quality data from 1995 to 2017. The results of this study show that within 20 years the community has strengthened occupational structure in the tertiary sector. Furthermore, the strengthening of occupational structure in the tertiary sector has not been able to improve the quality of life of Tanjung Burung villagers.

Contributions of historical and contemporary geographic and environmental factors to phylogeographic structure in a Tertiary relict species, Emmenopterys henryi (Rubiaceae).

PubMed

Zhang, Yong-Hua; Wang, Ian J; Comes, Hans Peter; Peng, Hua; Qiu, Ying-Xiong

2016-05-03

Examining how historical and contemporary geographic and environmental factors contribute to genetic divergence at different evolutionary scales is a central yet largely unexplored question in ecology and evolution. Here, we examine this key question by investigating how environmental and geographic factors across different epochs have driven genetic divergence at deeper (phylogeographic) and shallower (landscape genetic) evolutionary scales in the Chinese Tertiary relict tree Emmenopterys henryi. We found that geography played a predominant role at all levels - phylogeographic clades are broadly geographically structured, the deepest levels of divergence are associated with major geological or pre-Quaternary climatic events, and isolation by distance (IBD) primarily explained population genetic structure. However, environmental factors are clearly also important - climatic fluctuations since the Last Interglacial (LIG) have likely contributed to phylogeographic structure, and the population genetic structure (in our AFLP dataset) was partly explained by isolation by environment (IBE), which may have resulted from natural selection in environments with divergent climates. Thus, historical and contemporary geography and historical and contemporary environments have all shaped patterns of genetic structure in E. henryi, and, in fact, changes in the landscape through time have also been critical factors.

A hybrid MD-kMC algorithm for folding proteins in explicit solvent.

PubMed

Peter, Emanuel Karl; Shea, Joan-Emma

2014-04-14

We present a novel hybrid MD-kMC algorithm that is capable of efficiently folding proteins in explicit solvent. We apply this algorithm to the folding of a small protein, Trp-Cage. Different kMC move sets that capture different possible rate limiting steps are implemented. The first uses secondary structure formation as a relevant rate event (a combination of dihedral rotations and hydrogen-bonding formation and breakage). The second uses tertiary structure formation events through formation of contacts via translational moves. Both methods fold the protein, but via different mechanisms and with different folding kinetics. The first method leads to folding via a structured helical state, with kinetics fit by a single exponential. The second method leads to folding via a collapsed loop, with kinetics poorly fit by single or double exponentials. In both cases, folding times are faster than experimentally reported values, The secondary and tertiary move sets are integrated in a third MD-kMC implementation, which now leads to folding of the protein via both pathways, with single and double-exponential fits to the rates, and to folding rates in good agreement with experimental values. The competition between secondary and tertiary structure leads to a longer search for the helix-rich intermediate in the case of the first pathway, and to the emergence of a kinetically trapped long-lived molten-globule collapsed state in the case of the second pathway. The algorithm presented not only captures experimentally observed folding intermediates and kinetics, but yields insights into the relative roles of local and global interactions in determining folding mechanisms and rates.

Academic Communication across Disciplines and Cultures. Selected Proceedings of the National Conference on Tertiary Literacy: Research and Practice, Volume 2 (1st, Melbourne, Australia, March 14-16, 1996).

ERIC Educational Resources Information Center

Golebiowski, Zofia, Ed.; Borland, Helen, Ed.

These selected papers from the First Conference on Tertiary Literacy focus on communication across differences of culture and discipline in Australian universities. Many of the papers have resulted from cooperation between applied linguists and specialist lecturers and describe cooperative models of literacy education based on interdisciplinary…

Structural framework and Mesozoic Cenozoic evolution of Ponta Grossa Arch, Paraná Basin, southern Brazil

NASA Astrophysics Data System (ADS)

Strugale, Michael; Rostirolla, Sidnei Pires; Mancini, Fernando; Portela Filho, Carlos Vieira; Ferreira, Francisco José Fonseca; de Freitas, Rafael Corrêa

2007-09-01

The integration of structural analyses of outcrops, aerial photographs, satellite images, aeromagnetometric data, and digital terrain models can establish the structural framework and paleostress trends related to the evolution of Ponta Grossa Arch, one of the most important structures of the Paraná Basin in southern Brazil. In the study area, the central-northern region of Paraná State, Brazil, the arch crosses outcropping areas of the Pirambóia, Botucatu, and Serra Geral Formations (São Bento Group, Mesozoic). The Pirambóia and Botucatu Formations are composed of quartz sandstones and subordinated siltstones. The Serra Geral Formation comprises tholeiitic basalt lava flows and associated intrusive rocks. Descriptive and kinematic structural analyses reveal the imprint of two brittle deformation phases: D1, controlled by the activation of an extensional system of regional faults that represent a progressive deformation that generated discontinuous brittle structures and dike swarm emplacement along a NW-SE trend, and D2, which was controlled by a strike-slip (transtensional) deformation system, probably of Late Cretaceous-Tertiary age, responsible for important fault reactivation along dykes and deformation bands in sandstones.

RNA FRABASE 2.0: an advanced web-accessible database with the capacity to search the three-dimensional fragments within RNA structures

PubMed Central

2010-01-01

Background Recent discoveries concerning novel functions of RNA, such as RNA interference, have contributed towards the growing importance of the field. In this respect, a deeper knowledge of complex three-dimensional RNA structures is essential to understand their new biological functions. A number of bioinformatic tools have been proposed to explore two major structural databases (PDB, NDB) in order to analyze various aspects of RNA tertiary structures. One of these tools is RNA FRABASE 1.0, the first web-accessible database with an engine for automatic search of 3D fragments within PDB-derived RNA structures. This search is based upon the user-defined RNA secondary structure pattern. In this paper, we present and discuss RNA FRABASE 2.0. This second version of the system represents a major extension of this tool in terms of providing new data and a wide spectrum of novel functionalities. An intuitionally operated web server platform enables very fast user-tailored search of three-dimensional RNA fragments, their multi-parameter conformational analysis and visualization. Description RNA FRABASE 2.0 has stored information on 1565 PDB-deposited RNA structures, including all NMR models. The RNA FRABASE 2.0 search engine algorithms operate on the database of the RNA sequences and the new library of RNA secondary structures, coded in the dot-bracket format extended to hold multi-stranded structures and to cover residues whose coordinates are missing in the PDB files. The library of RNA secondary structures (and their graphics) is made available. A high level of efficiency of the 3D search has been achieved by introducing novel tools to formulate advanced searching patterns and to screen highly populated tertiary structure elements. RNA FRABASE 2.0 also stores data and conformational parameters in order to provide "on the spot" structural filters to explore the three-dimensional RNA structures. An instant visualization of the 3D RNA structures is provided. RNA FRABASE 2.0 is freely available at http://rnafrabase.cs.put.poznan.pl. Conclusions RNA FRABASE 2.0 provides a novel database and powerful search engine which is equipped with new data and functionalities that are unavailable elsewhere. Our intention is that this advanced version of the RNA FRABASE will be of interest to all researchers working in the RNA field. PMID:20459631

RNA FRABASE 2.0: an advanced web-accessible database with the capacity to search the three-dimensional fragments within RNA structures.

PubMed

Popenda, Mariusz; Szachniuk, Marta; Blazewicz, Marek; Wasik, Szymon; Burke, Edmund K; Blazewicz, Jacek; Adamiak, Ryszard W

2010-05-06

Recent discoveries concerning novel functions of RNA, such as RNA interference, have contributed towards the growing importance of the field. In this respect, a deeper knowledge of complex three-dimensional RNA structures is essential to understand their new biological functions. A number of bioinformatic tools have been proposed to explore two major structural databases (PDB, NDB) in order to analyze various aspects of RNA tertiary structures. One of these tools is RNA FRABASE 1.0, the first web-accessible database with an engine for automatic search of 3D fragments within PDB-derived RNA structures. This search is based upon the user-defined RNA secondary structure pattern. In this paper, we present and discuss RNA FRABASE 2.0. This second version of the system represents a major extension of this tool in terms of providing new data and a wide spectrum of novel functionalities. An intuitionally operated web server platform enables very fast user-tailored search of three-dimensional RNA fragments, their multi-parameter conformational analysis and visualization. RNA FRABASE 2.0 has stored information on 1565 PDB-deposited RNA structures, including all NMR models. The RNA FRABASE 2.0 search engine algorithms operate on the database of the RNA sequences and the new library of RNA secondary structures, coded in the dot-bracket format extended to hold multi-stranded structures and to cover residues whose coordinates are missing in the PDB files. The library of RNA secondary structures (and their graphics) is made available. A high level of efficiency of the 3D search has been achieved by introducing novel tools to formulate advanced searching patterns and to screen highly populated tertiary structure elements. RNA FRABASE 2.0 also stores data and conformational parameters in order to provide "on the spot" structural filters to explore the three-dimensional RNA structures. An instant visualization of the 3D RNA structures is provided. RNA FRABASE 2.0 is freely available at http://rnafrabase.cs.put.poznan.pl. RNA FRABASE 2.0 provides a novel database and powerful search engine which is equipped with new data and functionalities that are unavailable elsewhere. Our intention is that this advanced version of the RNA FRABASE will be of interest to all researchers working in the RNA field.

IPMP Global Fit - A one-step direct data analysis tool for predictive microbiology.

PubMed

Huang, Lihan

2017-12-04

The objective of this work is to develop and validate a unified optimization algorithm for performing one-step global regression analysis of isothermal growth and survival curves for determination of kinetic parameters in predictive microbiology. The algorithm is incorporated with user-friendly graphical interfaces (GUIs) to develop a data analysis tool, the USDA IPMP-Global Fit. The GUIs are designed to guide the users to easily navigate through the data analysis process and properly select the initial parameters for different combinations of mathematical models. The software is developed for one-step kinetic analysis to directly construct tertiary models by minimizing the global error between the experimental observations and mathematical models. The current version of the software is specifically designed for constructing tertiary models with time and temperature as the independent model parameters in the package. The software is tested with a total of 9 different combinations of primary and secondary models for growth and survival of various microorganisms. The results of data analysis show that this software provides accurate estimates of kinetic parameters. In addition, it can be used to improve the experimental design and data collection for more accurate estimation of kinetic parameters. IPMP-Global Fit can be used in combination with the regular USDA-IPMP for solving the inverse problems and developing tertiary models in predictive microbiology. Published by Elsevier B.V.

Comprehensive comparison of two protein family of P-ATPases (13A1 and 13A3) in insects.

PubMed

Seddigh, Samin

2017-06-01

The P-type ATPases (P-ATPases) are present in all living cells where they mediate ion transport across membranes on the expense of ATP hydrolysis. Different ions which are transported by these pumps are protons like calcium, sodium, potassium, and heavy metals such as manganese, iron, copper, and zinc. Maintenance of the proper gradients for essential ions across cellular membranes makes P-ATPases crucial for cell survival. In this study, characterization of two families of P-ATPases including P-ATPase 13A1 and P-ATPase 13A3 protein was compared in two different insect species from different orders. According to the conserved motifs found with MEME, nine motifs were shared by insects of 13A1 family but eight in 13A3 family. Seven different insect species from 13A1 and five samples from 13A3 family were selected as the representative samples for functional and structural analyses. The structural and functional analyses were performed with ProtParam, SOPMA, SignalP 4.1, TMHMM 2.0, ProtScale and ProDom tools in the ExPASy database. The tertiary structure of Bombus terrestris as a sample of each family of insects were predicted by the Phyre2 and TM-score servers and their similarities were verified by SuperPose server. The tertiary structures were predicted via the "c3b9bA" model (PDB Accession Code: 3B9B) in P-ATPase 13A1 family and "c2zxeA" model (PDB Accession Code: 2ZXE) in P-ATPase 13A3 family. A phylogenetic tree was constructed with MEGA 6.06 software using the Neighbor-joining method. According to the results, there was a high identity of P-ATPase families so that they should be derived from a common ancestor however they belonged to separate groups. In protein-protein interaction analysis by STRING 10.0, six common enriched pathways of KEGG were identified in B. terrestris in both families. The obtained data provide a background for bioinformatic studies of the function and evolution of other insects and organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

First Indications of Intraplate Deformations in Central Germany from Reprocessed GNSS Time Series and Geological Data

NASA Astrophysics Data System (ADS)

Becker, Matthias; Leinen, Stefan; Läufer, Gwendolyn; Lehné, Rouwen

2013-04-01

Six years of GPS data have been reprocessed in ITRF2008 for a regional SAPOS CORS network in the federal state of Hesse with 25 stations and some anchor sites of IGS and EPN to derive accurate and consistent coordinate time series. Based on daily network solutions coordinate time series parameters like velocities, offsets in case of antenna changes and annual periodic variation have been estimated. The estimation process includes the fitting of a sophisticated stochastic model for the time series which accounts for inherent time correlation. The results are blended with geological data to verify information from geology on potential recent deformations by the geodetic analyses. Besides of some information on the reprocessing of the GNSS the results the stochastics of the derived velocity field will be discussed in detail. Special emphasis will be on the intra-plate deformation: for the horizontal component the residual velocity field after removal of a plate rotation model is presented, while for the vertical velocities the datum-induced systematic effect is removed in order to analyze the remaining vertical motion. The residual velocity field is then matched with the geology for Hesse. Correlation of both vertical and horizontal movements with major geological structures reveals good accordance. SAPOS stations with documented significant subsidence are mainly located in tertiary Graben structures such as the Lower Hessian Basin (station Kassel), the Wetterau (station Kloppenheim) or the Upper Rhine Graben (Station Darmstadt). From the geological point of view these structures are supposed to be subsiding ones. Other major geological features, i.e. the Rhenish Shield as well as the East Hessian Bunter massif are supposed to be affected by recent uplift. SAPOS stations located in these regions match the assumed movement (e.g. Weilburg, Wiesbaden, Bingen, Fulda). Furthermore SAPOS-derived horizontal movements seem to trace tectonic movements in the region, i.e. extension along the tertiary Graben structures, including a sinistral strike slip component. However, a more detailed analysis is needed to confirm the link between detected movement and geodynamic processes.

Use of Toll-Like Receptor Agonists to Induce Ectopic Lymphoid Structures in Myasthenia Gravis Mouse Models

PubMed Central

Robinet, Marieke; Villeret, Bérengère; Maillard, Solène; Cron, Mélanie A.; Berrih-Aknin, Sonia; Le Panse, Rozen

2017-01-01

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. MG symptoms are characterized by muscle weaknesses. The thymus of MG patients is very often abnormal and possesses all the characteristics of tertiary lymphoid organs such as neoangiogenesis processes, overexpression of inflammatory cytokines and chemokines, and infiltration of B lymphocytes leading to ectopic germinal center (GC) development. We previously demonstrated that injections of mice with polyinosinic–polycytidylic acid [Poly(I:C)], a synthetic double-stranded RNA mimicking viral infection, induce thymic changes and trigger MG symptoms. Upon Poly(I:C) injections, we observed increased thymic expressions of α-AChR, interferon-β and chemokines such as CXCL13 and CCL21 leading to B-cell recruitment. However, these changes were only transient. In order to develop an experimental MG model associated with thymic GCs, we used Poly(I:C) in the classical experimental autoimmune MG model induced by immunizations with purified AChR emulsified in complete Freund’s adjuvant. We observed that Poly(I:C) strongly favored the development of MG as almost all mice displayed MG symptoms. Nevertheless, we did not observe any ectopic GC development. We next challenged mice with Poly(I:C) together with other toll-like receptor (TLR) agonists known to be involved in GC development and that are overexpressed in MG thymuses. Imiquimod and CpG oligodeoxynucleotides that activate TLR7 and TLR9, respectively, did not induce thymic changes. In contrast, lipopolysaccharide that activates TLR4 potentiated Poly(I:C) effects and induced a significant expression of CXCL13 mRNA in the thymus associated with a higher recruitment of B cells that induced over time thymic B-lymphoid structures. Altogether, these data suggest that tertiary lymphoid genesis in MG thymus could result from a combined activation of TLR signaling pathways. PMID:28970832

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors

PubMed Central

Thompson, A J; Lochner, M; Lummis, S C R

2007-01-01

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5-HT3 responses were blocked with IC 50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA 2 values of 4.92 (K B=12.0 μM) and 4.97 (K B=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with K i values of 15.0, 24.2 and 35.7 μ M. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. Conclusions and Implications: This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists. PMID:17502851

BASIN ANALYSIS AND PETROLEUM SYSTEM CHARACTERIZATION AND MODELING, INTERIOR SALT BASINS, CENTRAL AND EASTERN GULF OF MEXICO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ernest A. Mancini; Donald A. Goddard; Ronald K. Zimmerman

2005-05-10

The principal research effort for Year 2 of the project has been data compilation and the determination of the burial and thermal maturation histories of the North Louisiana Salt Basin and basin modeling and petroleum system identification. In the first nine (9) months of Year 2, the research focus was on the determination of the burial and thermal maturation histories, and during the remainder of the year the emphasis has basin modeling and petroleum system identification. Existing information on the North Louisiana Salt Basin has been evaluated, an electronic database has been developed, regional cross sections have been prepared, structuremore » and isopach maps have been constructed, and burial history, thermal maturation history and hydrocarbon expulsion profiles have been prepared. Seismic data, cross sections, subsurface maps and related profiles have been used in evaluating the tectonic, depositional, burial and thermal maturation histories of the basin. Oil and gas reservoirs have been found to be associated with salt-supported anticlinal and domal features (salt pillows, turtle structures and piercement domes); with normal faulting associated with the northern basin margin and listric down-to-the-basin faults (state-line fault complex) and faulted salt features; and with combination structural and stratigraphic features (Sabine and Monroe Uplifts) and monoclinal features with lithologic variations. Petroleum reservoirs are mainly Upper Jurassic and Lower Cretaceous fluvial-deltaic sandstone facies and Lower Cretaceous and Upper Cretaceous shoreline, marine bar and shallow shelf sandstone facies. Cretaceous unconformities significantly contribute to the hydrocarbon trapping mechanism capacity in the North Louisiana Salt Basin. The chief petroleum source rock in this basin is Upper Jurassic Smackover lime mudstone beds. The generation of hydrocarbons from Smackover lime mudstone was initiated during the Early Cretaceous and continued into the Tertiary. Hydrocarbon expulsion commenced during the Early Cretaceous and continued into the Tertiary with peak expulsion occurring mainly during the Late Cretaceous.« less

A multi-state coarse grained modeling approach for an intrinsically disordered peptide

NASA Astrophysics Data System (ADS)

Ramezanghorbani, Farhad; Dalgicdir, Cahit; Sayar, Mehmet

2017-09-01

Many proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LKα 14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters. LKα 14 is disordered in dilute solutions; however, it strictly adopts the α -helix conformation upon aggregation or when in contact with a hydrophobic/hydrophilic interface. Our bottom-up approach combines a generic base model, that is unbiased for any particular secondary structure, with nonbonded interactions which represent hydrogen bonds, electrostatics, and hydrophobic forces. We demonstrate that by using carefully designed all atom potential of mean force calculations from all three states of interest, one can get a balanced representation of the nonbonded interactions. Our CG model behaves intrinsically disordered in bulk water, folds into an α -helix in the presence of an interface or a neighboring peptide, and is stable as a tetrameric unit, successfully reproducing the all atom molecular dynamics simulations and experimental results.

A multi-state coarse grained modeling approach for an intrinsically disordered peptide.

PubMed

Ramezanghorbani, Farhad; Dalgicdir, Cahit; Sayar, Mehmet

2017-09-07

Many proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LKα14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters. LKα14 is disordered in dilute solutions; however, it strictly adopts the α-helix conformation upon aggregation or when in contact with a hydrophobic/hydrophilic interface. Our bottom-up approach combines a generic base model, that is unbiased for any particular secondary structure, with nonbonded interactions which represent hydrogen bonds, electrostatics, and hydrophobic forces. We demonstrate that by using carefully designed all atom potential of mean force calculations from all three states of interest, one can get a balanced representation of the nonbonded interactions. Our CG model behaves intrinsically disordered in bulk water, folds into an α-helix in the presence of an interface or a neighboring peptide, and is stable as a tetrameric unit, successfully reproducing the all atom molecular dynamics simulations and experimental results.

Geochemical processes controlling water salinization in an irrigated basin in Spain: identification of natural and anthropogenic influence.

PubMed

Merchán, D; Auqué, L F; Acero, P; Gimeno, M J; Causapé, J

2015-01-01

Salinization of water bodies represents a significant risk in water systems. The salinization of waters in a small irrigated hydrological basin is studied herein through an integrated hydrogeochemical study including multivariate statistical analyses and geochemical modeling. The study zone has two well differentiated geologic materials: (i) Quaternary sediments of low salinity and high permeability and (ii) Tertiary sediments of high salinity and very low permeability. In this work, soil samples were collected and leaching experiments conducted on them in the laboratory. In addition, water samples were collected from precipitation, irrigation, groundwater, spring and surface waters. The waters show an increase in salinity from precipitation and irrigation water to ground- and, finally, surface water. The enrichment in salinity is related to the dissolution of soluble mineral present mainly in the Tertiary materials. Cation exchange, precipitation of calcite and, probably, incongruent dissolution of dolomite, have been inferred from the hydrochemical data set. Multivariate statistical analysis provided information about the structure of the data, differentiating the group of surface waters from the groundwaters and the salinization from the nitrate pollution processes. The available information was included in geochemical models in which hypothesis of consistency and thermodynamic feasibility were checked. The assessment of the collected information pointed to a natural control on salinization processes in the Lerma Basin with minimal influence of anthropogenic factors. Copyright © 2014 Elsevier B.V. All rights reserved.

Structural characterization of the α-mating factor prepro-peptide for secretion of recombinant proteins in Pichia pastoris.

PubMed

Chahal, Sabreen; Wei, Peter; Moua, Pachai; Park, Sung Pil James; Kwon, Janet; Patel, Arth; Vu, Anthony T; Catolico, Jason A; Tsai, Yu Fang Tina; Shaheen, Nadia; Chu, Tiffany T; Tam, Vivian; Khan, Zill-E-Huma; Joo, Hyun Henry; Xue, Liang; Lin-Cereghino, Joan; Tsai, Jerry W; Lin-Cereghino, Geoff P

2017-01-20

The methylotrophic yeast Pichia pastoris has been used extensively for expressing recombinant proteins because it combines the ease of genetic manipulation, the ability to provide complex posttranslational modifications and the capacity for efficient protein secretion. The most successful and commonly used secretion signal leader in Pichia pastoris has been the alpha mating factor (MATα) prepro secretion signal. However, limitations exist as some proteins cannot be secreted efficiently, leading to strategies to enhance secretion efficiency by modifying the secretion signal leader. Based on a Jpred secondary structure prediction and knob-socket modeling of tertiary structure, numerous deletions and duplications of the MATα prepro leader were engineered to evaluate the correlation between predicted secondary structure and the secretion level of the reporters horseradish peroxidase (HRP) and Candida antarctica lipase B. In addition, circular dichroism analyses were completed for the wild type and several mutant pro-peptides to evaluate actual differences in secondary structure. The results lead to a new model of MATα pro-peptide signal leader, which suggests that the N and C-termini of MATα pro-peptide need to be presented in a specific orientation for proper interaction with the cellular secretion machinery and for efficient protein secretion. Copyright © 2016 Elsevier B.V. All rights reserved.

Electromagnetically Inferred Structure of the Caja del Rio Plateau, New Mexico

NASA Astrophysics Data System (ADS)

Layton, M. E.; Speed, C.; Shukla, M.; Vila, A.; Chon, E.; Kitamikado, C.; Feucht, D. W.; Bedrosian, P.; Pellerin, L.

2016-12-01

Magnetotelluric (MT) and transient electromagnetic (TEM) data were acquired by students from the Summer of Applied Geophysical Experience (SAGE) to construct structural models in and around the Caja del Rio Plateau, New Mexico. The Caja del Rio is located on the La Bajada-Jemez constriction that separates the Española and Santa Domingo basins in the Rio Grande Rift. The Rio Grande Rift, the result of tectonic extensional forces, extends approximately north-south across northern New Mexico. MT data collected in 2016 were merged with that from previous years to make up an 11 km north line and a 16 km south line extending from the west side of the Caja Del Rio to the east off the plateau in the Old Buckman Road area. The resistivity distributions revealed in one-dimensional (1-D) and two-dimensional (2-D) inverse models show some robust features. Models of the north are interpreted as a top resistive layer (<500m) of Tertiary volcanoclastic rock, to a central conductive layer (600-200m) of Mesozoic and Paleozoic sediments of the Santa Fe group to crystalline basement rock. Models for the south line show low resistivity for the first 3 to 5 km and then transitions into higher resistivity values consistent with the models for the north line. At a period of 100 seconds induction arrows (Parkinson's convention) point in the northwest direction towards the conductive Valles Caldera. The MT models are consistent with geologic interpretations of the stratigraphic units. In addition, models disclose an additional conductive layer below the basement that we interpret as the mid-crustal conductor. Transient electromagnetic (TEM) data were collected in seven locations atop the Caja del Rio plateau in an attempt to identify the basal contact of the Cerros del Rio volcanic field, which, in turn, allow for the thickness of these basaltic and andesitic deposits to be mapped across the plateau. One-dimensional inverse models produced from the TEM data were aligned and interpreted geologically. A resistive ( 1000 ohm-m) unit, interpreted to represent the Cerros del Rio volcanics, thickens from 70m to 175m from southeast to northwest. The volcanics are overlain by a thin conductor, interpreted as weathered material. The resistive body is underlain by a thicker conductor, interpreted as sedimentary rocks of the Tertiary-aged Santa Fe Group.

A novel endogenous inhibitor of phenoloxidase from Musca domestica has a cystine motif commonly found in snail and spider toxins.

PubMed

Daquinag, A C; Sato, T; Koda, H; Takao, T; Fukuda, M; Shimonishi, Y; Tsukamoto, T

1999-02-16

Phenoloxidase inhibitor (POI), found in the hemolymph of housefly pupae, is a novel dopa-containing and cystine-rich peptide that competitively inhibits phenoloxidase with a Ki in the nanomolar range. [Tyr32]POI is a potential precursor molecule also found in the hemolymph that may be posttranslationally oxidized to the dopa-containing peptide after creation of a rigid structure. By employing both a solid-phase peptide synthesis system based on a 9-fluorenylmethoxycarbonyl strategy and a specific air oxidation technique to ensure correct folding, we have been able to synthesize [Tyr32]POI. The synthetic [Tyr32]POI was confirmed to be identical to the native [Tyr32]POI by coelution high-performance liquid chromatography analysis and by enzymatic analysis using the phenoloxidase inhibition assay. To determine the disulfide pairings within the peptides, a series of enzyme hydrolyses and partial reduction/alkylation steps were performed. Three cystine pairs (Cys11-Cys25, Cys18-Cys29, and Cys24-Cys36) were determined by identification of the resulting peptides. The disulfide pairings of the two adjacent Cys residues (Cys11-Cys25 and Cys24-Cys36) were unambiguously assigned by comparing the derived fragments with the two possible isomers synthesized through a novel disulfide-linking technique. The arrangement of the disulfide bridges in POI was found to be topologically identical to those found for several peptides within the inhibitor cystine knot structural family. Although these peptides share a low primary sequence homology and display a diversity of biological functions, they nonetheless share similarities in their cystine motifs and tertiary structure. The tertiary structure model of POI, which was derived through molecular dynamics and energy minimization studies using restraints with determined disulfide connectivities, suggests that POI is a new class member of the inhibitor cystine-knot structural family.

Cooperative catalysis by tertiary amino-thioureas: mechanism and basis for enantioselectivity of ketone cyanosilylation.

PubMed

Zuend, Stephan J; Jacobsen, Eric N

2007-12-26

The mechanism of the enantioselective cyanosilylation of ketones catalyzed by tertiary amino-thiourea derivatives was investigated using a combination of experimental and theoretical methods. The kinetic analysis is consistent with a cooperative mechanism in which both the thiourea and the tertiary amine of the catalyst are involved productively in the rate-limiting cyanide addition step. Density functional theory calculations were used to distinguish between mechanisms involving thiourea activation of ketone or of cyanide in the enantioselectivity-determining step. The strong correlation obtained between experimental and calculated ee's for a range of substrates and catalysts provides support for the most favorable calculated transition structures involving amine-bound HCN adding to thiourea-bound ketone. The calculations suggest that enantioselectivity arises from direct interactions between the ketone substrate and the amino-acid derived portion of the catalyst. On the basis of this insight, more enantioselective catalysts with broader substrate scope were prepared and evaluated experimentally.

New Mapping in the Sand Springs Range of Western Nevada Clarifies and Constrains Regional Deformation Sequences of the Luning-Fencemaker Thrust Belt

NASA Astrophysics Data System (ADS)

Czarnecki, S.; Jarvis, J.; Satterfield, J. I.

2016-12-01

The Sand Springs Range in western Nevada exposes Mesozoic through Cenozoic structures of the eastern Sierra Nevada, Luning-Fencemaker Thrust Belt (LFTB), Basin and Range province, and Walker Lane. A recent undergraduate geologic mapping project in the northern Sand Springs Range (nSSR) set out to map igneous intrusions in detail, specifically smaller intrusions which had not been a focus in previous work. This was accomplished using different techniques including mapping at a smaller scale (1:8000 vs. 1:24000), locating contacts and faults using handheld GPS, and focusing on relationships between metamorphic tectonites and igneous units. This revealed key cross-cutting relations between structures and diverse Triassic through Tertiary igneous rocks as well as distinctions between the nSSR and the surrounding LFTB assemblages. During our mapping we identified four metamorphic tectonite map units, Cretaceous granitoid and diorite plutons and sills, Tertiary rhyolite sills and dikes, and interbedded Tertiary basalt and ash flow tuff. The cross-cutting relations of these units overturn previously published sequences of events and constrain the timing of a deformation sequence which differs from the surrounding LFTB assemblages. We found that the nSSR contains three phases of deformation: a pre-LFTB syn-metamorphic event which achieved amphibolite facies that is not described elsewhere in the LFTB (D1), followed by two non-metamorphic folding and thrusting phases characteristic of the LFTB (D2 and D3). Our mapping provided four key timing constraints. First, D1 axial-planar cleavage (S1) deformed Triassic intrusions. Second, Cretaceous granitoid and diorite units cross-cut S1 foliation, D1 folds, and low-angle faults. Third, Cretaceous and Tertiary sills that locally terminate at a low-angle fault actually post-dated faulting. Fourth, cross-cutting relations showed a basaltic lava previously mapped as Jurassic is actually Tertiary. The large Sand Springs Pluton was the only intrusion mapped in detail during previous studies; but our mapping has demonstrated the importance of both small and large intrusions in understanding the overall structural history of a complex area. This project was supported by research grants from Angelo State University and the Southwest Section AAPG.

Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching Using Morpheeins

ERIC Educational Resources Information Center

Lawrence, Sarah H.; Jaffe, Eileen K.

2008-01-01

A morpheein is a homo-oligomeric protein that can exist as an ensemble of physiologically significant and functionally distinct alternate quaternary assemblies. Morpheeins exist in nature and use conformational equilibria between different tertiary structures to form distinct oligomers as a means of regulating their function. Notably, alternate…

Basics of Sterile Compounding: Manipulating Peptides and Proteins.

PubMed

Akers, Michael J

2017-01-01

Biopharmaceuticals contain primary and secondary structure, which offer few problems. It is the tertiary structure that causes problems, resulting in both physical and chemical stability issues. The thrust of this article is to share briefly what can be done to minimize these problems. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Molecular crowding overcomes the destabilizing effects of mutations in a bacterial ribozyme

DOE PAGES

Lee, Hui-Ting; Kilburn, D.; Behrouzi, R.; ...

2014-12-05

The native structure of the Azoarcus group I ribozyme is stabilized by the cooperative formation of tertiary interactions between double helical domains. Thus, even single mutations that break this network of tertiary interactions reduce ribozyme activity in physiological Mg2+ concentrations. Here, we report that molecular crowding comparable to that in the cell compensates for destabilizing mutations in the Azoarcus ribozyme. Small angle X-ray scattering, native polyacrylamide gel electrophoresis and activity assays were used to compare folding free energies in dilute and crowded solutions containing 18% PEG1000. Crowder molecules allowed the wild-type and mutant ribozymes to fold at similarly low Mg2+more » concentrations and stabilized the active structure of the mutant ribozymes under physiological conditions. This compensation helps explains why ribozyme mutations are often less deleterious in the cell than in the test tube. Nevertheless, crowding did not rescue the high fraction of folded but less active structures formed by double and triple mutants. We conclude that crowding broadens the fitness landscape by stabilizing compact RNA structures without improving the specificity of self-assembly.« less

Molecular crowding overcomes the destabilizing effects of mutations in a bacterial ribozyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Hui-Ting; Kilburn, D.; Behrouzi, R.

The native structure of the Azoarcus group I ribozyme is stabilized by the cooperative formation of tertiary interactions between double helical domains. Thus, even single mutations that break this network of tertiary interactions reduce ribozyme activity in physiological Mg2+ concentrations. Here, we report that molecular crowding comparable to that in the cell compensates for destabilizing mutations in the Azoarcus ribozyme. Small angle X-ray scattering, native polyacrylamide gel electrophoresis and activity assays were used to compare folding free energies in dilute and crowded solutions containing 18% PEG1000. Crowder molecules allowed the wild-type and mutant ribozymes to fold at similarly low Mg2+more » concentrations and stabilized the active structure of the mutant ribozymes under physiological conditions. This compensation helps explains why ribozyme mutations are often less deleterious in the cell than in the test tube. Nevertheless, crowding did not rescue the high fraction of folded but less active structures formed by double and triple mutants. We conclude that crowding broadens the fitness landscape by stabilizing compact RNA structures without improving the specificity of self-assembly.« less

Modeling a terminology-based electronic nursing record system: an object-oriented approach.

PubMed

Park, Hyeoun-Ae; Cho, InSook; Byeun, NamSoo

2007-10-01

The aim of this study was to present our perspectives on healthcare information analysis at a conceptual level and the lessons learned from our experience with the development of a terminology-based enterprise electronic nursing record system - which was one of components in an EMR system at a tertiary teaching hospital in Korea - using an object-oriented system analysis and design concept. To ensure a systematic approach and effective collaboration, the department of nursing constituted a system modeling team comprising a project manager, systems analysts, user representatives, an object-oriented methodology expert, and healthcare informaticists (including the authors). A rational unified process (RUP) and the Unified Modeling Language were used as a development process and for modeling notation, respectively. From the scenario and RUP approach, user requirements were formulated into use case sets and the sequence of activities in the scenario was depicted in an activity diagram. The structure of the system was presented in a class diagram. This approach allowed us to identify clearly the structural and behavioral states and important factors of a terminology-based ENR system (e.g., business concerns and system design concerns) according to the viewpoints of both domain and technical experts.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miles, Andrew J.; Fedosova, Natalya U.; Hoffmann, Søren V.

Highlights: •Ouabain binding to pig and shark Na,K-ATPase enhances thermal stability. •Ouabain stabilises both membrane-bound and solubilised Na,K-ATPase. •Synchrotron radiation circular dichroism is used for structure determination. •Secondary structure in general is not affected by ouabain binding. •Stabilisation is due to re-arrangement of tertiary structure. -- Abstract: Cardiotonic steroids such as ouabain bind with high affinity to the membrane-bound cation-transporting P-type Na,K-ATPase, leading to complete inhibition of the enzyme. Using synchrotron radiation circular dichroism spectroscopy we show that the enzyme-ouabain complex is less susceptible to thermal denaturation (unfolding) than the ouabain-free enzyme, and this protection is observed with Na,K-ATPase purifiedmore » from pig kidney as well as from shark rectal glands. It is also shown that detergent-solubilised preparations of Na,K-ATPase are stabilised by ouabain, which could account for the successful crystallisation of Na,K-ATPase in the ouabain-bound form. The secondary structure is not significantly affected by the binding of ouabain. Ouabain appears however, to induce a reorganization of the tertiary structure towards a more compact protein structure which is less prone to unfolding; recent crystal structures of the two enzymes are consistent with this interpretation. These circular dichroism spectroscopic studies in solution therefore provide complementary information to that provided by crystallography.« less

Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

PubMed

Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

2016-01-01

Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

The Colorado front range: anatomy of a Laramide uplift

USGS Publications Warehouse

Kellogg, Karl; Bryant, Bruce; Reed, John C.

2004-01-01

Along a transect across the Front Range from Denver to the Blue River valley near Dillon, the trip explores the geologic framework and Laramide (Late Cretaceous to early Eocene) uplift history of this basement-cored mountain range. Specific items for discussion at various stops are (1) the sedimentary and structural record along the upturned eastern margin of the range, which contains several discontinuous, east-directed reverse faults; (2) the western structural margin of the range, which contains a minimum of 9 km of thrust overhang and is significantly different in structural style from the eastern margin; (3) mid- to late-Tertiary modifications to the western margin of the range from extensional faulting along the northern Rio Grande rift trend; (4) the thermal and uplift history of the range as revealed by apatite fission track analysis; (5) the Proterozoic basement of the range, including the significance of northeast-trending shear zones; and (6) the geologic setting of the Colorado mineral belt, formed during Laramide and mid-Tertiary igneous activity.

An excited state underlies gene regulation of a transcriptional riboswitch

PubMed Central

Zhao, Bo; Guffy, Sharon L.; Williams, Benfeard; Zhang, Qi

2017-01-01

Riboswitches control gene expression through ligand-dependent structural rearrangements of the sensing aptamer domain. However, we found that the Bacillus cereus fluoride riboswitch aptamer adopts identical tertiary structures in solution with and without ligand. Using chemical exchange saturation transfer (CEST) NMR spectroscopy, we revealed that the structured ligand-free aptamer transiently accesses a low-populated (~1%) and short-lived (~3 ms) excited conformational state that unravels a conserved ‘linchpin’ base pair to signal transcription termination. Upon fluoride binding, this highly localized fleeting process is allosterically suppressed to activate transcription. We demonstrated that this mechanism confers effective fluoride-dependent gene activation over a wide range of transcription rates, which is essential for robust toxicity response across diverse cellular conditions. These results unveil a novel switching mechanism that employs ligand-dependent suppression of an aptamer excited state to coordinate regulatory conformational transitions rather than adopting distinct aptamer ground-state tertiary architectures, exemplifying a new mode of ligand-dependent RNA regulation. PMID:28719589

Striped tertiary storage arrays

NASA Technical Reports Server (NTRS)

Drapeau, Ann L.

1993-01-01

Data stripping is a technique for increasing the throughput and reducing the response time of large access to a storage system. In striped magnetic or optical disk arrays, a single file is striped or interleaved across several disks; in a striped tape system, files are interleaved across tape cartridges. Because a striped file can be accessed by several disk drives or tape recorders in parallel, the sustained bandwidth to the file is greater than in non-striped systems, where access to the file are restricted to a single device. It is argued that applying striping to tertiary storage systems will provide needed performance and reliability benefits. The performance benefits of striping for applications using large tertiary storage systems is discussed. It will introduce commonly available tape drives and libraries, and discuss their performance limitations, especially focusing on the long latency of tape accesses. This section will also describe an event-driven tertiary storage array simulator that is being used to understand the best ways of configuring these storage arrays. The reliability problems of magnetic tape devices are discussed, and plans for modeling the overall reliability of striped tertiary storage arrays to identify the amount of error correction required are described. Finally, work being done by other members of the Sequoia group to address latency of accesses, optimizing tertiary storage arrays that perform mostly writes, and compression is discussed.

Geologic assessment of undiscovered oil and gas resources: Oligocene Frio and Anahuac Formations, United States Gulf of Mexico coastal plain and State waters

USGS Publications Warehouse

Swanson, Sharon M.; Karlsen, Alexander W.; Valentine, Brett J.

2013-01-01

The Oligocene Frio and Anahuac Formations were assessed as part of the 2007 U.S. Geological Survey (USGS) assessment of Tertiary strata of the U.S. Gulf of Mexico Basin onshore and State waters. The Frio Formation, which consists of sand-rich fluvio-deltaic systems, has been one of the largest hydrocarbon producers from the Paleogene in the Gulf of Mexico. The Anahuac Formation, an extensive transgressive marine shale overlying the Frio Formation, contains deltaic and slope sandstones in Louisiana and Texas and carbonate rocks in the eastern Gulf of Mexico. In downdip areas of the Frio and Anahuac Formations, traps associated with faulted, rollover anticlines are common. Structural traps commonly occur in combination with stratigraphic traps. Faulted salt domes in the Frio and Anahuac Formations are present in the Houston embayment of Texas and in south Louisiana. In the Frio Formation, stratigraphic traps are found in fluvial, deltaic, barrier-bar, shelf, and strandplain systems. The USGS Tertiary Assessment Team defined a single, Upper Jurassic-Cretaceous-Tertiary Composite Total Petroleum System (TPS) for the Gulf Coast basin, based on previous studies and geochemical analysis of oils in the Gulf Coast basin. The primary source rocks for oil and gas within Cenozoic petroleum systems, including Frio Formation reservoirs, in the northern, onshore Gulf Coastal region consist of coal and shale rich in organic matter within the Wilcox Group (Paleocene–Eocene), with some contributions from the Sparta Sand of the Claiborne Group (Eocene). The Jurassic Smackover Formation and Cretaceous Eagle Ford Formation also may have contributed substantial petroleum to Cenozoic reservoirs. Modeling studies of thermal maturity by the USGS Tertiary Assessment Team indicate that downdip portions of the basal Wilcox Group reached sufficient thermal maturity to generate hydrocarbons by early Eocene; this early maturation is the result of rapid sediment accumulation in the early Tertiary, combined with the reaction kinetic parameters used in the models. A number of studies indicate that the migration of oil and gas in the Cenozoic Gulf of Mexico basin is primarily vertical, occurring along abundant growth faults associated with sediment deposition or along faults associated with salt domes. The USGS Tertiary assessment team developed a geologic model based on recurring regional-scale structural and depositional features in Paleogene strata to define assessment units (AUs). Three general areas, as described in the model, are found in each of the Paleogene stratigraphic intervals assessed: “Stable Shelf,” “Expanded Fault,” and “Slope and Basin Floor” zones. On the basis of this model, three AUs for the Frio Formation were defined: (1) the Frio Stable Shelf Oil and Gas AU, containing reservoirs with a mean depth of about 4,800 feet in normally pressured intervals; (2) the Frio Expanded Fault Zone Oil and Gas AU, containing reservoirs with a mean depth of about 9,000 feet in primarily overpressured intervals; and (3) the Frio Slope and Basin Floor Gas AU, which currently has no production but has potential for deep gas resources (>15,000 feet). AUs also were defined for the Hackberry trend, which consists of a slope facies stratigraphically in the middle part of the Frio Formation, and the Anahuac Formation. The Frio Basin Margin AU, an assessment unit extending to the outcrop of the Frio (or basal Miocene), was not quantitatively assessed because of its low potential for production. Two proprietary, commercially available databases containing field and well production information were used in the assessment. Estimates of undiscovered resources for the five AUs were based on a total of 1,734 reservoirs and 586,500 wells producing from the Frio and Anahuac Formations. Estimated total mean values of technically recoverable, undiscovered resources are 172 million barrels of oil (MMBO), 9.4 trillion cubic feet of natural gas (TCFG), and 542 million barrels of natural gas liquids for all of the Frio and Anahuac AUs. Of the five units assessed, the Frio Slope and Basin Floor Gas AU has the greatest potential for undiscovered gas resources, having an estimated mean of 5.6 TCFG. The Hackberry Oil and Gas AU shows the second highest potential for gas of the five units assessed, having an estimated mean of 1.8 TCFG. The largest undiscovered, conventional crude oil resource was estimated for the Frio Slope and Basin Floor Gas AU; the estimated mean for oil in this AU is 110 MMBO.

Structural geologic analysis of Nevada using ERTS-1 images: A preliminary report

NASA Technical Reports Server (NTRS)

Rowan, L. C.; Wetlaufer, P. H.

1973-01-01

Structural analysis of Nevada using ERTS-1 images showns several previously unrecognized lineaments which may be the surface manifestations of major fault or fracture zones. Principle trends are NE, NW, NNE-NNW, and ENE. Two lineament zones, the Walker Lane and Midas Trench lineament system, transect the predominantly NNE-NNW trending mountain ranges for more than 500 km. 50 circular features have been delineated. Comparison with known Tertiary volcanic centers and reference to geologic maps suggest 8 new centers. Preferred distribution of mines and Tertiary volcanic centers along some of the major lineament suggests a genetic relationship. The intersection of three previously unmapped lineaments in northwestern Nevada is the location of a highly productive metallogenic district. In the Walker Lane, ENE-trending lineament appear to be related to the occurrence of productive ore deposits.

Sequencing proteins with transverse ionic transport in nanochannels.

PubMed

Boynton, Paul; Di Ventra, Massimiliano

2016-05-03

De novo protein sequencing is essential for understanding cellular processes that govern the function of living organisms and all sequence modifications that occur after a protein has been constructed from its corresponding DNA code. By obtaining the order of the amino acids that compose a given protein one can then determine both its secondary and tertiary structures through structure prediction, which is used to create models for protein aggregation diseases such as Alzheimer's Disease. Here, we propose a new technique for de novo protein sequencing that involves translocating a polypeptide through a synthetic nanochannel and measuring the ionic current of each amino acid through an intersecting perpendicular nanochannel. We find that the distribution of ionic currents for each of the 20 proteinogenic amino acids encoded by eukaryotic genes is statistically distinct, showing this technique's potential for de novo protein sequencing.

Origin and late quaternary tectonism of a western Canadian continental shelf trough

NASA Astrophysics Data System (ADS)

Moslow, Thomas F.; Luternauer, John L.; Rohr, Kristin

1991-08-01

Analyses of high resolution and multi-channel seismic profiles from the central continental shelf of western Canada ascribe a late Quaternary glacial origin to large-scale troughs. Along the margins of Moresby Trough, one of three large-scale cross-shelf bathymetric depressions in Queen Charlotte Sound, seismic profiles within Quaternary sediments show a divergence of reflectors, thickening and folding of seismic units, and concavity of reflectors suggestive of drag. Compactional subsidence, growth faulting, and compaction faulting are also observed. Fault traces commonly terminate below the seabed. Deformation of Quaternary sediments due to faulting is plastic in nature and maximum offset of reflectors is 2.5 m. The observed Quaternary deformation appears to be a product of rapid deposition, loading and subsidence of late Quaternary sediment, which is unrelated to seismic activity. In addition, Quaternary faulting was probably activated by post-glacial loading and isostatic rebound of consolidated Tertiary strata along the margins of continental shelf troughs. The presence of mass movement (slump or debris flow) deposits overlying lithified Tertiary strata along the flanks of Moresby Trough provides the only evidence of seismic activity in the study area. The lack of a mud drape over these deposits implies a late Holocene age for the timing of their emplacement. The Quaternary troughs are incised into Tertiary-aged sedimentary fill of the Queen Charlotte basin. Previous workers had interpreted seafloor escarpments paralleling the trough margins to indicate that the location of Moresby Trough was controlled by renewed or continued activity on Tertiary-aged faults. A multi-channel seismic line across Moresby Trough shows that such an escarpment on the seafloor does not correlate to faults either in the Tertiary basin fill or the underlying basement. Tertiary reflectors are continuous underneath Moresby Trough; the seafloor escarpment is an erosional feature and was not created by reactivation of Tertiary structures. Trough erosion and subsequent fill (up to 175 m thick) are entirely of Quaternary age.

Quantitative evaluation of protein conformation in pharmaceuticals using cross-linking reactions coupled with LC-MS/MS analysis.

PubMed

Yamaguchi, Hideto; Hirakura, Yutaka; Shirai, Hiroki; Mimura, Hisashi; Toyo'oka, Toshimasa

2011-06-01

The need for a simple and high-throughput method for identifying the tertiary structure of protein pharmaceuticals has increased. In this study, a simple method for mapping the protein fold is proposed for use as a complementary quality test. This method is based on cross-linking a protein using a [bis(sulfosuccinimidyl)suberate (BS(3))], followed by peptide mapping by LC-MS. Consensus interferon (CIFN) was used as the model protein. The tryptic map obtained via liquid chromatography tandem mass spectroscopy (LC-MS/MS) and the mass mapping obtained via matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy were used to identify cross-linked peptides. While LC-MS/MS analyses found that BS(3) formed cross-links in the loop region of the protein, which was regarded as the biologically active site, sodium dodecyl-sulfate polyacrylamide gel electrophoresis demonstrated that cross-linking occurred within a protein molecule, but not between protein molecules. The occurrence of cross-links at the active site depends greatly on the conformation of the protein, which is determined by the denaturing conditions. Quantitative evaluation of the tertiary structure of CIFN was thus possible by monitoring the amounts of cross-linked peptides generated. Assuming that background information is available at the development stage, this method may be applicable to process development as a complementary test for quality control. Copyright © 2011 Elsevier B.V. All rights reserved.

Managing patient pathways to achieve lung cancer waiting time targets: mixed methods study

PubMed Central

Ip, Hugh; Amer, Tarik; Dangoor, Michael; Zamir, Affan; Gibbings-Isaac, Darryl; Kochhar, Ranjeev; Heymann, Timothy

2012-01-01

Objectives England's National Health Service (NHS) introduced a 62-day target, from referral to treatment, to make lung cancer patient pathways more efficient. This study aims to understand pathway delays that lead to breaches of the target when patients need care in both secondary and tertiary setting, so more than one institution is involved. Design Mixed methods cross case analysis. Setting Two tertiary referral hospitals in London. Participants Database records of 53 patients were analysed. Nineteen sets of patient notes were used for pathway mapping. Seventeen doctors, four nurses, eight managers and administrators were interviewed. Main outcome measures Qualitative methods include pathway mapping and semi-structured interviews. Quantitative analysis of patient pathway times from cancer services records. Results The majority of the patient pathway (68.4%) is spent in secondary centres. There is more variability in the processes of secondary centres but tertiary centres do not have perfect processes either. Three themes emerged from discussions: information flows, pathway performance and the role of the multidisciplinary approach. Conclusions The actions of secondary centres have a greater influence on whether a patient breaches the 62-day target, compared with tertiary centres. Nevertheless variability exists in both, with potential for improvement. PMID:23162682

Reconnaissance guidelines for gold exploration in Central Alaska

USGS Publications Warehouse

Light, T.D.; Moll, S.H.; Bie, S.W.; Lee, G.K.

1993-01-01

Distribution of more than 300 gold-bearing samples from the Livengood (Tolovana) and parts of the Fairbanks and Rampart mining districts in central Alaska, USA, indicate that the concentration of gold in placers is spatially related both to structural features and to Late Cretaceous and (or) Tertiary felsic plutons. The regional consistency of these spatial relationships is demonstrated by proximity analysis using a Geographic Information System (GIS), and suggests a genetic association between faults, felsic plutons, and gold occurrences. The local presence of gold within several of the plutons indicates that these are the source of some of the gold. In addition, some gold occurs proximal to faults where plutons are not present, suggesting that some of the gold was also derived from the country rock. We envision a model whereby weakly mineralized solutions, thermally driven by latent plutonic heat, were enriched by circulation through clastic units that may have had a naturally elevated gold background. The resultant enriched solutions were channeled and reconcentrated along or adjacent to large-scale fault systems. Future exploration to define individual target areas should be directed toward areas where Late Cretaceous and (or) Tertiary felsic plutons occur near major faults. ?? 1993.

Sequential events in the irreversible thermal denaturation of human brain-type creatine kinase by spectroscopic methods.

PubMed

Gao, Yan-Song; Su, Jing-Tan; Yan, Yong-Bin

2010-06-25

The non-cooperative or sequential events which occur during protein thermal denaturation are closely correlated with protein folding, stability, and physiological functions. In this research, the sequential events of human brain-type creatine kinase (hBBCK) thermal denaturation were studied by differential scanning calorimetry (DSC), CD, and intrinsic fluorescence spectroscopy. DSC experiments revealed that the thermal denaturation of hBBCK was calorimetrically irreversible. The existence of several endothermic peaks suggested that the denaturation involved stepwise conformational changes, which were further verified by the discrepancy in the transition curves obtained from various spectroscopic probes. During heating, the disruption of the active site structure occurred prior to the secondary and tertiary structural changes. The thermal unfolding and aggregation of hBBCK was found to occur through sequential events. This is quite different from that of muscle-type CK (MMCK). The results herein suggest that BBCK and MMCK undergo quite dissimilar thermal unfolding pathways, although they are highly conserved in the primary and tertiary structures. A minor difference in structure might endow the isoenzymes dissimilar local stabilities in structure, which further contribute to isoenzyme-specific thermal stabilities.

Definition and classification of evaluation units for tertiary structure prediction in CASP12 facilitated through semi-automated metrics.

PubMed

Abriata, Luciano A; Kinch, Lisa N; Tamò, Giorgio E; Monastyrskyy, Bohdan; Kryshtafovych, Andriy; Dal Peraro, Matteo

2018-03-01

For assessment purposes, CASP targets are split into evaluation units. We herein present the official definition of CASP12 evaluation units (EUs) and their classification into difficulty categories. Each target can be evaluated as one EU (the whole target) or/and several EUs (separate structural domains or groups of structural domains). The specific scenario for a target split is determined by the domain organization of available templates, the difference in server performance on separate domains versus combination of the domains, and visual inspection. In the end, 71 targets were split into 96 EUs. Classification of the EUs into difficulty categories was done semi-automatically with the assistance of metrics provided by the Prediction Center. These metrics account for sequence and structural similarities of the EUs to potential structural templates from the Protein Data Bank, and for the baseline performance of automated server predictions. The metrics readily separate the 96 EUs into 38 EUs that should be straightforward for template-based modeling (TBM) and 39 that are expected to be hard for homology modeling and are thus left for free modeling (FM). The remaining 19 borderline evaluation units were dubbed FM/TBM, and were inspected case by case. The article also overviews structural and evolutionary features of selected targets relevant to our accompanying article presenting the assessment of FM and FM/TBM predictions, and overviews structural features of the hardest evaluation units from the FM category. We finally suggest improvements for the EU definition and classification procedures. © 2017 Wiley Periodicals, Inc.

Do family and neighbourhood matter in secondary school completion? A multilevel study of determinants and their interactions in a life-course perspective.

PubMed

Myhr, Arnhild; Lillefjell, Monica; Espnes, Geir Arild; Halvorsen, Thomas

2017-01-01

Completion of secondary education is important for individuals' future health and health behaviour. The fundamental purpose of this study is to investigate the variation and clustering of school completion in families and neighbourhoods. Secondly, we aim to examine the impact of individuals' family structure and neighbourhood of residence and examine to what extent parental education level moderates these associations. Longitudinal register data for 30% of the entire Norwegian population aged 21-27 years in 2010 (N = 107,003) was extracted from Statistic Norway´s event database. Three-level logistic regression models, which incorporated individual, family, and neighbourhood contextual factors, were applied to estimate the family and neighbourhood general contextual effects and detect possible educational differences in the impact of family structure and urban place of residence in school completion. Completion rates were significantly higher within families with higher education level (79% in tertiary educated families vs. 61% and 48% in secondary and primary educated families respectively) and were strongly correlated within families (ICC = 39.6) and neighbourhoods (ICC = 5.7). Several structural factors at the family level negatively associated with school completion (e.g., family disruption, large family size, and young maternal age) were more prevalent and displayed more negative impact among primary educated individuals. Urban residence was associated with school completion, but only among the tertiary educated. Investment in the resources in the individuals' immediate surroundings, including family and neighbourhood, may address a substantial portion of the social inequalities in the completion of upper secondary education. The high intra-familial correlation in school completion suggests that public health policies and future research should acknowledge family environments in order to improve secondary education completion rates among young people within lower educated families.

Crustal implications of bedrock geology along the Trans-Alaska Crustal Transect (TACT) in the Brooks Range, northern Alaska

USGS Publications Warehouse

Moore, Thomas E.; Wallace, W.K.; Mull, C.G.; Adams, K.E.; Plafker, G.; Nokleberg, W.J.

1997-01-01

Geologic mapping of the Trans-Alaska Crustal Transect (TACT) project along the Dalton Highway in northern Alaska indicates that the Endicott Mountains allochthon and the Hammond terrane compose a combined allochthon that was thrust northward at least 90 km in the Early Cretaceous. The basal thrust of the combined allochthon climbs up section in the hanging wall from a ductile shear zone, in the south through lower Paleozoic rocks of the Hammond terrane and into Upper Devonian rocks of the Endicott Mountains allochthon at the Mount Doonerak antiform, culminating in Early Cretaceous shale in the northern foothills of the Brooks Range. Footwall rocks north of the Mount Doonerak antiform are everywhere parautochthonous Permian and Triassic shale of the North Slope terrane rather than Jurassic and Lower Cretaceous strata of the Colville Basin as shown in most other tectonic models of the central Brooks Range. Stratigraphic and structural relations suggest that this thrust was the basal detachment for Early Cretaceous deformation. Younger structures, such as the Tertiary Mount Doonerak antiform, deform the Early Cretaceous structures and are cored by thrusts that root at a depth of about 10 to 30 km along a deeper detachment than the Early Cretaceous detachment. The Brooks Range, therefore, exposes (1) an Early Cretaceous thin-skinned deformational belt developed during arc-continent collision and (2) a mainly Tertiary thick-skinned orogen that is probably the northward continuation of the Rocky Mountains erogenic belt. A down-to-the-south zone of both ductile and brittle normal faulting along the southern margin of the Brooks Range probably formed in the mid-Cretaceous by extensional exhumation of the Early Cretaceous contractional deformation. copyright. Published in 1997 by the American Geophysical Union.

The IntFOLD server: an integrated web resource for protein fold recognition, 3D model quality assessment, intrinsic disorder prediction, domain prediction and ligand binding site prediction.

PubMed

Roche, Daniel B; Buenavista, Maria T; Tetchner, Stuart J; McGuffin, Liam J

2011-07-01

The IntFOLD server is a novel independent server that integrates several cutting edge methods for the prediction of structure and function from sequence. Our guiding principles behind the server development were as follows: (i) to provide a simple unified resource that makes our prediction software accessible to all and (ii) to produce integrated output for predictions that can be easily interpreted. The output for predictions is presented as a simple table that summarizes all results graphically via plots and annotated 3D models. The raw machine readable data files for each set of predictions are also provided for developers, which comply with the Critical Assessment of Methods for Protein Structure Prediction (CASP) data standards. The server comprises an integrated suite of five novel methods: nFOLD4, for tertiary structure prediction; ModFOLD 3.0, for model quality assessment; DISOclust 2.0, for disorder prediction; DomFOLD 2.0 for domain prediction; and FunFOLD 1.0, for ligand binding site prediction. Predictions from the IntFOLD server were found to be competitive in several categories in the recent CASP9 experiment. The IntFOLD server is available at the following web site: http://www.reading.ac.uk/bioinf/IntFOLD/.

Gender norms in South Africa: implications for HIV and pregnancy prevention among African and Indian women students at a South African tertiary institution.

PubMed

Mantell, Joanne E; Needham, Sarah L; Smit, Jennifer Ann; Hoffman, Susie; Cebekhulu, Queen; Adams-Skinner, Jessica; Exner, Theresa M; Mabude, Zonke; Beksinska, Mags; Stein, Zena A; Milford, Cecilia

2009-02-01

In post-Apartheid South Africa, women are constitutionally guaranteed protections and freedoms that were previously unknown to them. These freedoms may have positive implications for women's ability to negotiate sexual protection with partners and hence prevent unintended pregnancy and decrease their risk of HIV. Among tertiary institution students, who are a relatively 'privileged' group, there is little information on gender norms that might shape responses to HIV-prevention programmes. To elicit gender norms regarding women's and men's roles, condom and contraceptive use, sexual communication and sexual pleasure, we conducted 10 semi-structured focus group discussions with African and Indian female tertiary institution students in order to understand how norms might be used to buttress HIV- and pregnancy-prevention. Participants reported dramatic changes in the structure of gender norms and relations with the formal recognition of women's rights in the post-Apartheid context. These generational shifts in norms are supported by other research in South Africa. At the same time, women recognized the co-existence of traditional constructions of gender that operate to constrain women's freedom. The perceived changes that have taken place provide an entry point for intervention, particularly for reinforcing emerging gender norms that promote women's protection against unintended pregnancy and HIV/STIs.

Evaluation of an experimental rat model for comparative studies of bleaching agents.

PubMed

Cintra, Luciano Tavares Angelo; Benetti, Francine; Ferreira, Luciana Louzada; Rahal, Vanessa; Ervolino, Edilson; Jacinto, Rogério de Castilho; Gomes Filho, João Eduardo; Briso, André Luiz Fraga

2016-04-01

Dental materials in general are tested in different animal models prior to the clinical use in humans, except for bleaching agents. Objectives To evaluate an experimental rat model for comparative studies of bleaching agents, by investigating the influence of different concentrations and application times of H2O2 gel in the pulp tissue during in-office bleaching of rats' vital teeth. Material and Methods The right and left maxillary molars of 50 Wistar rats were bleached with 20% and 35% H2O2 gels, respectively, for 5, 10, 15, 30, or 45 min (n=10 rats/group). Ten animals were untreated (control). The rats were killed after 2 or 30 days, and the maxillae were examined by light microscopy. Inflammation was evaluated through histomorphometric analysis with inflammatory cell count in the coronal and radicular thirds of the pulp. Fibroblasts were also counted. Scores were attributed to odontoblastic layer and vascular changes. Tertiary dentin area and pulp chamber central area were measured histomorphometrically. Data were compared by analysis of variance and Kruskal-Wallis test (p<0.05). Results After 2 days, the amount of inflammatory cells increased in the coronal pulp occlusal third up to the 15-min application groups of each bleaching gel. In the groups exposed to each concentration for 30 and 45 min, the number of inflammatory cells decreased along with the appearance of necrotic areas. After 30 days, reduction on the pulp chamber central area and enlargement of the tertiary dentin area were observed, without the detection of inflammation areas. Conclusion The rat model of extracoronal bleaching showed to be adequate for studies of bleaching protocols, as it was possible to observe alterations in the pulp tissues and tooth structure caused by different concentrations and application periods of bleaching agents.

Evaluation of an experimental rat model for comparative studies of bleaching agents

PubMed Central

CINTRA, Luciano Tavares Angelo; BENETTI, Francine; FERREIRA, Luciana Louzada; RAHAL, Vanessa; ERVOLINO, Edilson; JACINTO, Rogério de Castilho; GOMES, João Eduardo; BRISO, André Luiz Fraga

2016-01-01

ABSTRACT Dental materials in general are tested in different animal models prior to the clinical use in humans, except for bleaching agents. Objectives To evaluate an experimental rat model for comparative studies of bleaching agents, by investigating the influence of different concentrations and application times of H2O2 gel in the pulp tissue during in-office bleaching of rats’ vital teeth. Material and Methods The right and left maxillary molars of 50 Wistar rats were bleached with 20% and 35% H2O2 gels, respectively, for 5, 10, 15, 30, or 45 min (n=10 rats/group). Ten animals were untreated (control). The rats were killed after 2 or 30 days, and the maxillae were examined by light microscopy. Inflammation was evaluated through histomorphometric analysis with inflammatory cell count in the coronal and radicular thirds of the pulp. Fibroblasts were also counted. Scores were attributed to odontoblastic layer and vascular changes. Tertiary dentin area and pulp chamber central area were measured histomorphometrically. Data were compared by analysis of variance and Kruskal-Wallis test (p<0.05). Results After 2 days, the amount of inflammatory cells increased in the coronal pulp occlusal third up to the 15-min application groups of each bleaching gel. In the groups exposed to each concentration for 30 and 45 min, the number of inflammatory cells decreased along with the appearance of necrotic areas. After 30 days, reduction on the pulp chamber central area and enlargement of the tertiary dentin area were observed, without the detection of inflammation areas. Conclusion The rat model of extracoronal bleaching showed to be adequate for studies of bleaching protocols, as it was possible to observe alterations in the pulp tissues and tooth structure caused by different concentrations and application periods of bleaching agents. PMID:27119766

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trevena, A.S.; Varga, R.J.; Collins, I.D.

Salin basin of central Myanmar is a tertiary fore-arc basin that extends over 10,000 mi{sup 2} and contains 30,000+ ft of siliciclastic rocks. In the western Salin basin, Tertiary deltaic and fluvial formations contain thousands of feet of lithic sandstones that alternate with transgressive shallow marine shales. Facies and paleocurrent studies indicate deposition by north-to-south prograding tidal deltas and associated fluvial systems in a semi-restricted basin. Presence of serpentinite and volcanic clasts in Tertiary sandstones may imply that the basin was bounded to the east by the volcanic arc and to the west by a fore-arc accretionary ridge throughout muchmore » of the Cenozoic. Salin basin is currently defined by a regional north/south-trending syncline with uplifts along the eastern and western margins. Elongate folds along the eastern basin margin verge to the east and lie above the reverse faults that dip west; much of Myanmar's present hydrocarbon production is from these structures. Analogous structures occur along the western margin, but verge to the west and are associated with numerous hydrocarbon seeps and hand-dug wells. These basin-bounding structures are the result of fault-propagation folding. In the western Salin basin, major detachments occur within the shaly Tabyin and Laungshe formations. Fault ramps propagated through steep forelimbs on the western sides of the folds, resulting in highly asymmetric footwall synclines. Stratigraphic and apatite fission track data are consistent with dominantly Plio-Pleistocene uplift, with limited uplift beginning approximately 10 Ma. Paleostress analysis of fault/slickenside data indicates that fold and thrust structures formed during regional east/west compression and are not related in any simple way to regional transpression as suggested by plate kinematics.« less

Systematic detection of internal symmetry in proteins using CE-Symm.

PubMed

Myers-Turnbull, Douglas; Bliven, Spencer E; Rose, Peter W; Aziz, Zaid K; Youkharibache, Philippe; Bourne, Philip E; Prlić, Andreas

2014-05-29

Symmetry is an important feature of protein tertiary and quaternary structures that has been associated with protein folding, function, evolution, and stability. Its emergence and ensuing prevalence has been attributed to gene duplications, fusion events, and subsequent evolutionary drift in sequence. This process maintains structural similarity and is further supported by this study. To further investigate the question of how internal symmetry evolved, how symmetry and function are related, and the overall frequency of internal symmetry, we developed an algorithm, CE-Symm, to detect pseudo-symmetry within the tertiary structure of protein chains. Using a large manually curated benchmark of 1007 protein domains, we show that CE-Symm performs significantly better than previous approaches. We use CE-Symm to build a census of symmetry among domain superfamilies in SCOP and note that 18% of all superfamilies are pseudo-symmetric. Our results indicate that more domains are pseudo-symmetric than previously estimated. We establish a number of recurring types of symmetry-function relationships and describe several characteristic cases in detail. With the use of the Enzyme Commission classification, symmetry was found to be enriched in some enzyme classes but depleted in others. CE-Symm thus provides a methodology for a more complete and detailed study of the role of symmetry in tertiary protein structure [availability: CE-Symm can be run from the Web at http://source.rcsb.org/jfatcatserver/symmetry.jsp. Source code and software binaries are also available under the GNU Lesser General Public License (version 2.1) at https://github.com/rcsb/symmetry. An interactive census of domains identified as symmetric by CE-Symm is available from http://source.rcsb.org/jfatcatserver/scopResults.jsp]. Copyright © 2014. Published by Elsevier Ltd.

Tb3+-cleavage assays reveal specific Mg2+ binding sites necessary to pre-fold the btuB riboswitch for AdoCbl binding

NASA Astrophysics Data System (ADS)

Choudhary, Pallavi K.; Gallo, Sofia; Sigel, Roland K. O.

2017-03-01

Riboswitches are RNA elements that bind specific metabolites in order to regulate the gene expression involved in controlling the cellular concentration of the respective molecule or ion. Ligand recognition is mostly facilitated by Mg2+ mediated pre-organization of the riboswitch to an active tertiary fold. To predict these specific Mg2+ induced tertiary interactions of the btuB riboswitch from E. coli, we here report Mg2+ binding pockets in its aptameric part in both, the ligand-free and the ligand-bound form. An ensemble of weak and strong metal ion binding sites distributed over the entire aptamer was detected by terbium(III) cleavage assays, Tb3+ being an established Mg2+ mimic. Interestingly many of the Mn+ (n = 2 or 3) binding sites involve conserved bases within the class of coenzyme B12-binding riboswitches. Comparison with the published crystal structure of the coenzyme B12 riboswitch of S. thermophilum aided in identifying a common set of Mn+ binding sites that might be crucial for tertiary interactions involved in the organization of the aptamer. Our results suggest that Mn+ binding at strategic locations of the btuB riboswitch indeed facilitates the assembly of the binding pocket needed for ligand recognition. Binding of the specific ligand, coenzyme B12 (AdoCbl), to the btuB aptamer does however not lead to drastic alterations of these Mn+ binding cores, indicating the lack of a major rearrangement within the three-dimensional structure of the RNA. This finding is strengthened by Tb3+ mediated footprints of the riboswitch's structure in its ligand-free and ligand-bound state indicating that AdoCbl indeed induces local changes rather than a global structural rearrangement.

Atomistic details of the disordered states of KID and pKID. Implications in coupled binding and folding.

PubMed

Ganguly, Debabani; Chen, Jianhan

2009-04-15

Intrinsically disordered proteins (IDPs) are a newly recognized class of functional proteins for which a lack of stable tertiary fold is required for function. Because of the heterogeneous and dynamical nature, molecular modeling is necessary to provide the missing details of disordered states of IDP that are crucial for understanding their functions. In particular, generalized Born (GB) implicit solvent, combined with replica exchange (REX), might offer an optimal balance between accuracy and efficiency for modeling IDPs. We carried out extensive REX simulations in an optimized GB force field to characterize the disordered states of a regulatory IDP, KID domain of transcription factor CREB, and its phosphorylated form, pKID. The results revealed that both KID and pKID, though highly disordered on the tertiary level, are compact and mainly occupy a small number of helical substates. Interestingly, although phosphorylation of KID Ser133 leads only to marginal changes in average helicities on the ensemble level, underlying conformational substates differ significantly. In particular, pSer133 appears to restrict the accessible conformational space of the loop region and thus reduces the entropic cost of KID folding upon binding to the KIX domain of CREB-binding protein. Such an expanded role of phosphorylation in the KID:KIX recognition was not previously recognized because of a lack of substantial conformational changes on the ensemble level and inaccessibility of the structural details from experiments. The results also suggest that an implicit solvent-based modeling framework, despite various existing limitations, might be feasible for accurate atomistic simulation of small IDPs in general.

Updates to Blast Injury Criteria Models for Nuclear Casualty Estimation

DTIC Science & Technology

2015-12-01

the likelihood of blast-related injury use a two-step process. First, the maximum velocity obtained by the human body or secondary missile is determined...the human body . Secondary injuries are caused by missiles that are accelerated by the blast wave. Tertiary injuries are caused by the acceleration of...the human body and the ensuing deceleration. In this work, we focus on secondary and tertiary injuries. Because of the dramatic effects experienced

Formation of NDMA and halogenated DBPs by chloramination of tertiary amines: the influence of bromide ion.

PubMed

Le Roux, Julien; Gallard, Hervé; Croué, Jean-Philippe

2012-02-07

The formation of NDMA and other DBPs (including THMs, HANs, and HKs) has been investigated by chloramination of several tertiary amines in the absence and presence of bromide ion. NDMA formation from the most reactive tertiary amines (e.g., dimethylaminomethylfurfuryl alcohol or DMP30) was enhanced in the presence of bromide due to the formation of brominated oxidant species such as bromochloramine (NHBrCl) and the hypothetical UDMH-Br as an intermediate. The formation of NDMA by chloramination of less reactive model compounds was inhibited in the presence of bromide. This can be explained by competitive reactions leading to the production of brominated DBPs (i.e., THMs). In the presence of bromide, the formation of brominated THMs during chloramination can be attributed to the presence of small amounts of HOBr produced by the decomposition of chloramines and bromamines. The results are of particular interest to understand NDMA formation mechanisms, especially during chloramination of wastewaters impacted by anthropogenic tertiary amines and containing bromide ion.

Examination of factors predicting secondary students' interest in tertiary STEM education

NASA Astrophysics Data System (ADS)

Chachashvili-Bolotin, Svetlana; Milner-Bolotin, Marina; Lissitsa, Sabina

2016-02-01

Based on the Social Cognitive Career Theory (SCCT), the study aims to investigate factors that predict students' interest in pursuing science, technology, engineering, and mathematics (STEM) fields in tertiary education both in general and in relation to their gender and socio-economic background. The results of the analysis of survey responses of 2458 secondary public school students in the fifth-largest Israeli city indicate that STEM learning experience positively associates with students' interest in pursuing STEM fields in tertiary education as opposed to non-STEM fields. Moreover, studying advanced science courses at the secondary school level decreases (but does not eliminate) the gender gap and eliminates the effect of family background on students' interest in pursuing STEM fields in the future. Findings regarding outcome expectations and self-efficacy beliefs only partially support the SCCT model. Outcome expectations and self-efficacy beliefs positively correlate with students' entering tertiary education but did not differentiate between their interests in the fields of study.

Using RNA Sequence and Structure for the Prediction of Riboswitch Aptamer: A Comprehensive Review of Available Software and Tools

PubMed Central

Antunes, Deborah; Jorge, Natasha A. N.; Caffarena, Ernesto R.; Passetti, Fabio

2018-01-01

RNA molecules are essential players in many fundamental biological processes. Prokaryotes and eukaryotes have distinct RNA classes with specific structural features and functional roles. Computational prediction of protein structures is a research field in which high confidence three-dimensional protein models can be proposed based on the sequence alignment between target and templates. However, to date, only a few approaches have been developed for the computational prediction of RNA structures. Similar to proteins, RNA structures may be altered due to the interaction with various ligands, including proteins, other RNAs, and metabolites. A riboswitch is a molecular mechanism, found in the three kingdoms of life, in which the RNA structure is modified by the binding of a metabolite. It can regulate multiple gene expression mechanisms, such as transcription, translation initiation, and mRNA splicing and processing. Due to their nature, these entities also act on the regulation of gene expression and detection of small metabolites and have the potential to helping in the discovery of new classes of antimicrobial agents. In this review, we describe software and web servers currently available for riboswitch aptamer identification and secondary and tertiary structure prediction, including applications. PMID:29403526

Using a Strategy of "Structured Conversation" to Enhance the Quality of Tutorial Time

ERIC Educational Resources Information Center

Robinson, Stephanie

2008-01-01

This article considers the impact of a technique of structured conversation to enhance a student-centred approach to tutorial time. It is suggested that the development of such an approach can provide enhanced learning support in the current challenge of widening diversity in the learner population. Many students in modern tertiary education show…

Water-stable helical structure of tertiary amides of bicyclic β-amino acid bearing 7-azabicyclo[2.2.1]heptane. Full control of amide cis-trans equilibrium by bridgehead substitution.

PubMed

Hosoya, Masahiro; Otani, Yuko; Kawahata, Masatoshi; Yamaguchi, Kentaro; Ohwada, Tomohiko

2010-10-27

Helical structures of oligomers of non-natural β-amino acids are significantly stabilized by intramolecular hydrogen bonding between main-chain amide moieties in many cases, but the structures are generally susceptible to the environment; that is, helices may unfold in protic solvents such as water. For the generation of non-hydrogen-bonded ordered structures of amides (tertiary amides in most cases), control of cis-trans isomerization is crucial, even though there is only a small sterical difference with respect to cis and trans orientations. We have established methods for synthesis of conformationally constrained β-proline mimics, that is, bridgehead-substituted 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acids. Our crystallographic, 1D- and 2D-NMR, and CD spectroscopic studies in solution revealed that a bridgehead methoxymethyl substituent completely biased the cis-trans equilibrium to the cis-amide structure along the main chain, and helical structures based on the cis-amide linkage were generated independently of the number of residues, from the minimalist dimer through the tetramer, hexamer, and up to the octamer, and irrespective of the solvent (e.g., water, alcohol, halogenated solvents, and cyclohexane). Generality of the control of the amide equilibrium by bridgehead substitution was also examined.

Distributed cooperative control of AC microgrids

NASA Astrophysics Data System (ADS)

Bidram, Ali

In this dissertation, the comprehensive secondary control of electric power microgrids is of concern. Microgrid technical challenges are mainly realized through the hierarchical control structure, including primary, secondary, and tertiary control levels. Primary control level is locally implemented at each distributed generator (DG), while the secondary and tertiary control levels are conventionally implemented through a centralized control structure. The centralized structure requires a central controller which increases the reliability concerns by posing the single point of failure. In this dissertation, the distributed control structure using the distributed cooperative control of multi-agent systems is exploited to increase the secondary control reliability. The secondary control objectives are microgrid voltage and frequency, and distributed generators (DGs) active and reactive powers. Fully distributed control protocols are implemented through distributed communication networks. In the distributed control structure, each DG only requires its own information and the information of its neighbors on the communication network. The distributed structure obviates the requirements for a central controller and complex communication network which, in turn, improves the system reliability. Since the DG dynamics are nonlinear and non-identical, input-output feedback linearization is used to transform the nonlinear dynamics of DGs to linear dynamics. Proposed control frameworks cover the control of microgrids containing inverter-based DGs. Typical microgrid test systems are used to verify the effectiveness of the proposed control protocols.

All-atom four-body knowledge-based statistical potential to distinguish native tertiary RNA structures from nonnative folds.

PubMed

Masso, Majid

2018-09-14

Scientific breakthroughs in recent decades have uncovered the capability of RNA molecules to fulfill a wide array of structural, functional, and regulatory roles in living cells, leading to a concomitantly significant increase in both the number and diversity of experimentally determined RNA three-dimensional (3D) structures. Atomic coordinates from a representative training set of solved RNA structures, displaying low sequence and structure similarity, facilitate derivation of knowledge-based energy functions. Here we develop an all-atom four-body statistical potential and evaluate its capacity to distinguish native RNA 3D structures from nonnative folds based on calculated free energy scores. Atomic four-body nearest-neighbors are objectively identified by their occurrence as tetrahedral vertices in the Delaunay tessellations of RNA structures, and rates of atomic quadruplet interactions expected by chance are obtained from a multinomial reference distribution. Our four-body energy function, referred to as RAMP (ribonucleic acids multibody potential), is subsequently derived by applying the inverted Boltzmann principle to the frequency data, yielding an energy score for each type of atomic quadruplet interaction. Several well-known benchmark datasets reveal that RAMP is comparable with, and often outperforms, existing knowledge- and physics-based energy functions. To the best of our knowledge, this is the first study detailing an RNA tertiary structure-based multibody statistical potential and its comparative evaluation. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Preliminary Investigation of The Structure of Southern Yucca Flat, Massachusetts Mountain, and CP Basin, Nevada Test Site, Nevada, Based on Geophysical Modeling

USGS Publications Warehouse

Phelps, Geoffrey A.; Justet, Leigh; Moring, Barry C.; Roberts, Carter W.

2006-01-01

New gravity and magnetic data collected in the vicinity of Massachusetts Mountain and CP basin (Nevada Test Site, NV) provides a more complex view of the structural relationships present in the vicinity of CP basin than previous geologic models, helps define the position and extent of structures in southern Yucca Flat and CP basin, and better constrains the configuration of the basement structure separating CP basin and Frenchman Flat. The density and gravity modeling indicates that CP basin is a shallow, oval-shaped basin which trends north-northeast and contains ~800 m of basin-filling rocks and sediment at its deepest point in the northeast. CP basin is separated from the deeper Frenchman Flat basin by a subsurface ridge that may represent a Tertiary erosion surface at the top of the Paleozoic strata. The magnetic modeling indicates that the Cane Spring fault appears to merge with faults in northwest Massachusetts Mountain, rather than cut through to Yucca Flat basin and that the basin is downed-dropped relative to Massachusetts Mountain. The magnetic modeling indicates volcanic units within Yucca Flat basin are down-dropped on the west and supports the interpretations of Phelps and KcKee (1999). The magnetic data indicate that the only faults that appear to be through-going from Yucca Flat into either Frenchman Flat or CP basin are the faults that bound the CP hogback. In general, the north-trending faults present along the length of Yucca Flat bend, merge, and disappear before reaching CP hogback and Massachusetts Mountain or French Peak.

Determinants of career satisfaction among pediatric hospitalists: a qualitative exploration

PubMed Central

Leyenaar, JoAnna K.; Capra, Lisa A.; O'Brien, Emily R.; Leslie, Laurel K.; Mackie, Thomas I.

2014-01-01

Objectives To characterize determinants of career satisfaction among pediatric hospitalists working in diverse practice settings, and to develop a framework to conceptualize factors influencing career satisfaction. Methods Semi-structured interviews were conducted with community and tertiary care hospitalists, using purposeful sampling to attain maximum response diversity. We employed close- and open-ended questions to assess levels of career satisfaction and its determinants. Interviews were conducted by telephone, recorded, and transcribed verbatim. Emergent themes were identified and analyzed using an inductive approach to qualitative analysis. Results A total of 30 interviews were conducted with community and tertiary care hospitalists, representing 20 hospital medicine programs and 7 Northeastern states. Qualitative analysis yielded 657 excerpts which were coded and categorized into four domains and associated determinants of career satisfaction: (i) professional responsibilities; (ii) hospital medicine program administration; (iii) hospital and healthcare systems; and (iv) career development. While community and tertiary care hospitalists reported similar levels of career satisfaction, they expressed variation in perspectives across these four domains. While the role of hospital medicine program administration was consistently emphasized by all hospitalists, community hospitalists prioritized resource availability, work schedule and clinical responsibilities while tertiary care hospitalists prioritized diversity in non-clinical responsibilities and career development. Conclusions We illustrate how hospitalists in different organizational settings prioritize both consistent and unique determinants of career satisfaction. Given associations between physician satisfaction and healthcare quality, efforts to optimize modifiable factors within this framework, at both community and tertiary care hospitals, may have broad impacts. PMID:24976348

The tertiary structures of porcine AhR and ARNT proteins and molecular interactions within the TCDD/AhR/ARNT complex.

PubMed

Orlowska, Karina; Molcan, Tomasz; Swigonska, Sylwia; Sadowska, Agnieszka; Jablonska, Monika; Nynca, Anna; Jastrzebski, Jan P; Ciereszko, Renata E

2016-06-01

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse synthetic and natural chemicals, including toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the present study, homology models of the porcine AhR-ligand binding domain (LBD) and the porcine aryl hydrocarbon receptor nuclear translocator-ligand binding domain (ARNT-LBD) were created on the basis of structures of closely related respective proteins i.e., human Hif-2α and ARNT. Molecular docking of TCDD to the porcine AhR-LBD model revealed high binding affinity (-8.8kcal/mol) between TCDD and the receptor. Moreover, formation of the TCDD/AhR-LBD complex was confirmed experimentally with the use of electrophoretic mobility shift assay (EMSA). It was found that TCDD (10nM, 2h of incubation) not only bound to the AhR in the porcine granulosa cells but also activated the receptor. The current study provides a framework for examining the key events involved in the ligand-dependent activation of the AhR. Copyright © 2016 Elsevier Inc. All rights reserved.

Ab-initio conformational epitope structure prediction using genetic algorithm and SVM for vaccine design.

PubMed

Moghram, Basem Ameen; Nabil, Emad; Badr, Amr

2018-01-01

T-cell epitope structure identification is a significant challenging immunoinformatic problem within epitope-based vaccine design. Epitopes or antigenic peptides are a set of amino acids that bind with the Major Histocompatibility Complex (MHC) molecules. The aim of this process is presented by Antigen Presenting Cells to be inspected by T-cells. MHC-molecule-binding epitopes are responsible for triggering the immune response to antigens. The epitope's three-dimensional (3D) molecular structure (i.e., tertiary structure) reflects its proper function. Therefore, the identification of MHC class-II epitopes structure is a significant step towards epitope-based vaccine design and understanding of the immune system. In this paper, we propose a new technique using a Genetic Algorithm for Predicting the Epitope Structure (GAPES), to predict the structure of MHC class-II epitopes based on their sequence. The proposed Elitist-based genetic algorithm for predicting the epitope's tertiary structure is based on Ab-Initio Empirical Conformational Energy Program for Peptides (ECEPP) Force Field Model. The developed secondary structure prediction technique relies on Ramachandran Plot. We used two alignment algorithms: the ROSS alignment and TM-Score alignment. We applied four different alignment approaches to calculate the similarity scores of the dataset under test. We utilized the support vector machine (SVM) classifier as an evaluation of the prediction performance. The prediction accuracy and the Area Under Receiver Operating Characteristic (ROC) Curve (AUC) were calculated as measures of performance. The calculations are performed on twelve similarity-reduced datasets of the Immune Epitope Data Base (IEDB) and a large dataset of peptide-binding affinities to HLA-DRB1*0101. The results showed that GAPES was reliable and very accurate. We achieved an average prediction accuracy of 93.50% and an average AUC of 0.974 in the IEDB dataset. Also, we achieved an accuracy of 95.125% and an AUC of 0.987 on the HLA-DRB1*0101 allele of the Wang benchmark dataset. The results indicate that the proposed prediction technique "GAPES" is a promising technique that will help researchers and scientists to predict the protein structure and it will assist them in the intelligent design of new epitope-based vaccines. Copyright © 2017 Elsevier B.V. All rights reserved.

Biospheric effects of a large extraterrestrial impact: Case study of the Cretaceous/Tertiary boundary crater

NASA Technical Reports Server (NTRS)

Pope, Kevin O.

1994-01-01

The Chicxulub Crater in Yucatan, Mexico, is the primary candidate for the impact that caused mass extinctions at the Cretaceous/Tertiary boundary. The target rocks at Chicxulub contain 750 to 1500 m of anhydrite (CaSO4), which was vaporized upon impact, creating a large sulfuric acid aerosol cloud. In this study we apply a hydrocode model of asteroid impact to calculate the amount of sulfuric acid produced. We then apply a radiative transfer model to determine the atmospheric effects. Results include 6 to 9 month period of darkness followed by 12 to 26 years of cooling.

Medium-term electric power demand forecasting based on economic-electricity transmission model

NASA Astrophysics Data System (ADS)

Li, Wenfeng; Bao, Fangmin; Bai, Hongkun; Liu, Wei; Liu, Yongmin; Mao, Yubin; Wang, Jiangbo; Liu, Junhui

2018-06-01

Electric demand forecasting is a basic work to ensure the safe operation of power system. Based on the theories of experimental economics and econometrics, this paper introduces Prognoz Platform 7.2 intelligent adaptive modeling platform, and constructs the economic electricity transmission model that considers the economic development scenarios and the dynamic adjustment of industrial structure to predict the region's annual electricity demand, and the accurate prediction of the whole society's electricity consumption is realized. Firstly, based on the theories of experimental economics and econometrics, this dissertation attempts to find the economic indicator variables that drive the most economical growth of electricity consumption and availability, and build an annual regional macroeconomic forecast model that takes into account the dynamic adjustment of industrial structure. Secondly, it innovatively put forward the economic electricity directed conduction theory and constructed the economic power transfer function to realize the group forecast of the primary industry + rural residents living electricity consumption, urban residents living electricity, the second industry electricity consumption, the tertiary industry electricity consumption; By comparing with the actual value of economy and electricity in Henan province in 2016, the validity of EETM model is proved, and the electricity consumption of the whole province from 2017 to 2018 is predicted finally.

Evolutionary Strategies for Protein Folding

NASA Astrophysics Data System (ADS)

Murthy Gopal, Srinivasa; Wenzel, Wolfgang

2006-03-01

The free energy approach for predicting the protein tertiary structure describes the native state of a protein as the global minimum of an appropriate free-energy forcefield. The low-energy region of the free-energy landscape of a protein is extremely rugged. Efficient optimization methods must therefore speed up the search for the global optimum by avoiding high energy transition states, adapt large scale moves or accept unphysical intermediates. Here we investigate an evolutionary strategies(ES) for optimizing a protein conformation in our all-atom free-energy force field([1],[2]). A set of random conformations is evolved using an ES to get a diverse population containing low energy structure. The ES is shown to balance energy improvement and yet maintain diversity in structures. The ES is implemented as a master-client model for distributed computing. Starting from random structures and by using this optimization technique, we were able to fold a 20 amino-acid helical protein and 16 amino-acid beta hairpin[3]. We compare ES to basin hopping method. [1]T. Herges and W. Wenzel,Biophys.J. 87,3100(2004) [2] A. Verma and W. Wenzel Stabilization and folding of beta-sheet and alpha-helical proteins in an all-atom free energy model(submitted)(2005) [3] S. M. Gopal and W. Wenzel Evolutionary Strategies for Protein Folding (in preparation)

Rational truncation of an RNA aptamer to prostate-specific membrane antigen using computational structural modeling.

PubMed

Rockey, William M; Hernandez, Frank J; Huang, Sheng-You; Cao, Song; Howell, Craig A; Thomas, Gregory S; Liu, Xiu Ying; Lapteva, Natalia; Spencer, David M; McNamara, James O; Zou, Xiaoqin; Chen, Shi-Jie; Giangrande, Paloma H

2011-10-01

RNA aptamers represent an emerging class of pharmaceuticals with great potential for targeted cancer diagnostics and therapy. Several RNA aptamers that bind cancer cell-surface antigens with high affinity and specificity have been described. However, their clinical potential has yet to be realized. A significant obstacle to the clinical adoption of RNA aptamers is the high cost of manufacturing long RNA sequences through chemical synthesis. Therapeutic aptamers are often truncated postselection by using a trial-and-error process, which is time consuming and inefficient. Here, we used a "rational truncation" approach guided by RNA structural prediction and protein/RNA docking algorithms that enabled us to substantially truncateA9, an RNA aptamer to prostate-specific membrane antigen (PSMA),with great potential for targeted therapeutics. This truncated PSMA aptamer (A9L; 41mer) retains binding activity, functionality, and is amenable to large-scale chemical synthesis for future clinical applications. In addition, the modeled RNA tertiary structure and protein/RNA docking predictions revealed key nucleotides within the aptamer critical for binding to PSMA and inhibiting its enzymatic activity. Finally, this work highlights the utility of existing RNA structural prediction and protein docking techniques that may be generally applicable to developing RNA aptamers optimized for therapeutic use.

Assessment of physical stability of an antibody drug conjugate by higher order structure analysis: impact of thiol- maleimide chemistry.

PubMed

Guo, Jianxin; Kumar, Sandeep; Prashad, Amarnauth; Starkey, Jason; Singh, Satish K

2014-07-01

To provide a systematic biophysical approach towards a better understanding of impact of conjugation chemistry on higher order structure and physical stability of an antibody drug conjugate (ADC). ADC was prepared using thiol-maleimide chemistry. Physical stabilities of ADC and its parent IgG1 mAb were compared using calorimetric, spectroscopic and molecular modeling techniques. ADC and mAb respond differently to thermal stress. Both the melting temperatures and heat capacities are substantially lower for the ADC. Spectroscopic experiments show that ADC and mAb have similar secondary and tertiary structures, but these are more easily destabilized by thermal stress on the ADC indicating reduced conformational stability. Molecular modeling calculations suggest a substantial decrease in the conformational energy of the mAb upon conjugation. The local surface around the conjugation sites also becomes more hydrophobic in the ADC, explaining the lower colloidal stability and greater tendency of the ADC to aggregate. Computational and biophysical analyses of an ADC and its parent mAb have provided insights into impact of conjugation on physical stability and pinpointed reasons behind lower structural stability and increased aggregation propensity of the ADC. This knowledge can be used to design appropriate formulations to stabilize the ADC.

Course Cost Modelling in Australian Tertiary Education.

ERIC Educational Resources Information Center

Sharma, Raj

1986-01-01

A mathematical model for costing college courses, designed for purposes of accountability, subprogram cost analysis, marketing to foreign students (in Australia), and course cost analysis across institutions, is presented and discussed. (MSE)

An Amino Acid Packing Code for α-helical Structure and Protein Design

PubMed Central

Joo, Hyun; Chavan, Archana G.; Phan, Jamie; Day, Ryan; Tsai, Jerry

2012-01-01

This work demonstrates that all packing in α-helices can be simplified to repetitive patterns of a single motif: the knob-socket. Using the precision of Voronoi Polyhedra/Deluaney Tessellations to identify contacts, the knob-socket is a 4 residue tetrahedral motif: a knob residue on one α-helix packs into the 3 residue socket on another α-helix. The principle of the knob-socket model relates the packing between levels of protein structure: the intra-helical packing arrangements within secondary structure that permit inter-helix tertiary packing interactions. Within an α-helix, the 3 residue sockets arrange residues into a uniform packing lattice. Inter-helix packing results from a definable pattern of interdigitated knob-socket motifs between 2 α-helices. Furthermore, the knob-socket model classifies 3 types of sockets: 1) free: favoring only intra-helical packing, 2) filled: favoring inter-helical interactions and 3) non: disfavoring α-helical structure. The amino acid propensities in these 3 socket classes essentially represent an amino acid code for structure in α-helical packing. Using this code, a novel yet straightforward approach for the design of α-helical structure was used to validate the knob-socket model. Unique sequences for 3 peptides were created to produce a predicted amount of α-helical structure: mostly helical, some helical, and no-helix. These 3 peptides were synthesized and helical content assessed using CD spectroscopy. The measured α-helicity of each peptide was consistent with the expected predictions. These results and analysis demonstrate that the knob-socket motif functions as the basic unit of packing and presents an intuitive tool to decipher the rules governing packing in protein structure. PMID:22426125

Deconvolution of the role of metal and pH in metal coordinating polymers

NASA Astrophysics Data System (ADS)

Cazzell, Seth; Holten-Andersen, Niels

Nature uses metal binding amino acids to engineer both mechanical properties and structural functionality. Some examples of this metal binding behavior can be found in both mussel foot protein and DNA binding protein. The mussel byssal thread contains reversible intermolecular protein-metal bonds, allowing it to withstand harsh intertidal environments. Zinc fingers form intramolecular protein-metal bonds to stabilize the tertiary structure of DNA binding proteins, allowing specific structural functionality. Inspired by both these metal-binding materials, we present mechanical and spectroscopic characterization of a model polymer system, designed to mimic this bonding. Through these studies, we are able to answer fundamental polymer physics questions, such as the role of pH and metal to ligand ratio, illuminating both the macroscopic and microscopic material behavior. These understandings further bio-inspired engineering techniques that are used to design viscoelastic soft materials. I was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program.

Psychometric properties of the Compulsive Exercise Test in an adolescent eating disorder population.

PubMed

Formby, Pam; Watson, Hunna J; Hilyard, Anna; Martin, Kate; Egan, Sarah J

2014-12-01

The objective of this study was to evaluate the factor structure, validity, and reliability of the Compulsive Exercise Test (CET) in an adolescent clinical eating disorder population. The data source was the Helping to Outline Paediatric Eating Disorders (HOPE) Project, a prospective ongoing registry study comprising consecutive pediatric tertiary eating disorder referrals. Adolescents (N=104; 12-17years) with eating disorders completed the CET and other measures. Factor structure, convergent validity, and internal consistency were evaluated. Despite failing to identify a factor structure, the study provided clear evidence of the multidimensionality of the measure. The total score correlated significantly with measures of eating pathology, perfectionism, and frequency of exercise for shape and weight control (r=0.32-0.70, ps<0.05). More research into the multidimensional nature of compulsive exercise in clinical populations is needed. Further, research into compulsive exercise offers promise as an addition to existing cognitive behavioral models and treatments for eating disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

Contribution of long-range interactions to the secondary structure of an unfolded globin.

PubMed

Fedyukina, Daria V; Rajagopalan, Senapathy; Sekhar, Ashok; Fulmer, Eric C; Eun, Ye-Jin; Cavagnero, Silvia

2010-09-08

This work explores the effect of long-range tertiary contacts on the distribution of residual secondary structure in the unfolded state of an alpha-helical protein. N-terminal fragments of increasing length, in conjunction with multidimensional nuclear magnetic resonance, were employed. A protein representative of the ubiquitous globin fold was chosen as the model system. We found that, while most of the detectable alpha-helical population in the unfolded ensemble does not depend on the presence of the C-terminal region (corresponding to the native G and H helices), specific N-to-C long-range contacts between the H and A-B-C regions enhance the helical secondary structure content of the N terminus (A-B-C regions). The simple approach introduced here, based on the evaluation of N-terminal polypeptide fragments of increasing length, is of general applicability to identify the influence of long-range interactions in unfolded proteins. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The Unfolding and Refolding Reactions of Triosephosphate Isomerase from Trypanosoma Cruzi Follow Similar Pathways. Guanidinium Hydrochloride Studies

NASA Astrophysics Data System (ADS)

Vázquez-Contreras, Edgar; Pérez Hernández, Gerardo; Sánchez-Rebollar, Brenda Guadalupe; Chánez-Cárdenas, María Elena

2005-04-01

The unfolding and refolding reactions of Trypanosoma cruzi triosephosphate isomerase (TcTIM) was studied under equilibrium conditions at increasing guanidinium hydrochloride concentrations. The changes in activity intrinsic fluorescence and far-ultraviolet circular dichroism as a function of denaturant were used as a quaternary, tertiary and secondary structural probes respectively. The change in extrinsic ANS fluorescence intensity was also investigated. The results show that the transition between the homodimeric native enzyme to the unfolded monomers (unfolding), and its inverse reaction (refolding) are described by similar pathways and two equilibrium intermediates were detected in both reactions. The mild denaturant concentrations intermediate is active and contains significant amount of secondary and tertiary structures. The medium denaturant concentrations intermediate is inactive and able to bind the fluorescent dye. This intermediates are maybe related with those observed in the denaturation pattern of TIMs from other species; the results are discussed in this context.

Tertiary and Quaternary Ammonium-Phosphate Ionic Liquids as Lubricant Additives

DOE PAGES

Barnhill, William C.; Luo, Huimin; Meyer, III, Harry M; ...

2016-06-23

In this work we investigated the feasibility of five quaternary (aprotic) and four tertiary (protic) ammonium ionic liquids (ILs) with an identical organophosphate anion as lubricant antiwear additives. Viscosity, oil solubility, thermal stability, and corrosivity of the candidate ILs were characterized and correlated to the molecular structure. The protic group exhibits higher oil solubility than the aprotic group, and longer alkyl chains seem to provide better oil solubility and higher thermal stability. Selected ILs were applied as oil additives in steel-cast iron tribological tests and demonstrated promising anti-scuffing and anti-wear functionality. The thickness, nanostructure, coverage and composition of the tribofilmmore » formed by the besting performing IL were revealed by surface characterization for mechanistic understanding of the tribochemical interactions between the IL and metal surface. Results provide fundamental insights of the correlations among the molecular structure, physiochemical properties and lubricating performance for ammonium-phosphate ILs.« less

Tertiary and Quaternary Ammonium-Phosphate Ionic Liquids as Lubricant Additives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barnhill, William C.; Luo, Huimin; Meyer, III, Harry M

In this work we investigated the feasibility of five quaternary (aprotic) and four tertiary (protic) ammonium ionic liquids (ILs) with an identical organophosphate anion as lubricant antiwear additives. Viscosity, oil solubility, thermal stability, and corrosivity of the candidate ILs were characterized and correlated to the molecular structure. The protic group exhibits higher oil solubility than the aprotic group, and longer alkyl chains seem to provide better oil solubility and higher thermal stability. Selected ILs were applied as oil additives in steel-cast iron tribological tests and demonstrated promising anti-scuffing and anti-wear functionality. The thickness, nanostructure, coverage and composition of the tribofilmmore » formed by the besting performing IL were revealed by surface characterization for mechanistic understanding of the tribochemical interactions between the IL and metal surface. Results provide fundamental insights of the correlations among the molecular structure, physiochemical properties and lubricating performance for ammonium-phosphate ILs.« less

Late Mesozoic tectonics of the Southern-Thai Peninsula: from transpression to basins opening

NASA Astrophysics Data System (ADS)

Sautter, Benjamin; Pubellier, Manuel; Menier, David

2015-04-01

The petroleum basins of the Southern Thailand Peninsula are poorly known and their final geometry is controlled by the Tertiary stress variations applied on pre-existing Paleozoic and Mesozoic basement structures. From the end of Mesozoic times, the arrival of Indian plate was accomodated by transpressionnal deformation along the Western Margin of Sunda Plate. Evidences of this strain are the motions along several regional strike Slip Faults (Sagaing, Three Pagodas, Mae Ping, Red River, Ranong and Klong Marui Faults) as well as compressional features (folds and thrusts) evidenced onshore. Due to changes in the boundary forces, these structures were reactivated during the Tertiary, leading to the opening of basins in this part of Sundaland. We present a structural analysis based on geomorphology, fieldwork and seismic interpretation of the Southern Thai Peninsula with emphasis on the deformation's style onshore from Ranong to Satun and offshore from Eastern Mergui to Songhkla. By analyzing morphostructures and drainage anomalies from Digital Elevation Model (SRTM and ASTER), we highlight a predominance of N-S structures in the Southern Thai Peninsula: both in the granitic belt and in the sedimentary cover. The Triassic-Jurassic (Indosinian) post-collision granitic belt is intensely fractured, with 2 penetrative directions: N140 and N50. On both sides, the sedimentary units appear folded at a large wavelength (~20km). On most of the studied outcrops, Triassic to Early Cretaceous series are gently tilted and weakly fractured whereas the Paleozoic ones shows intense fracturation and steep dipping beds. Moreover, all the Paleozoic stratas display a constant N-S S1 which does not appear in the Mezosoic sediments. Althought most of the post-Mesozoic sediments do not crop out due to thick vegetal cover, several Tertiary basins can be easily seen from seismic data both onshore and offshore. These data suggest that rifting started in the Eocene and was accommodated by large crust-scale Low Angle Normal Faults reactivating basement fabrics including intrusive edges and folds hinges. We propose a tectonic scenario for the southern Thai Peninsula according to which the northward motion of giant morphostructures (the Wharton Ridge followed by the Indian Plate) induced first right-lateral transpressionnal tectonics at the End of the Mesozoics. This system is illustrated by the 2 sets of fractures of the Indosinian Belt, the large-scale folds of Early Cretaceous Strata and the strike slip motions of the Ranong and Klong Marui Faults. Following the path of Indian Plate, a collapse of this hot and thin crust occurred accommodated via LANF's along the granitic belts and the sedimentary basement morpho-structures.

LCS-TA to identify similar fragments in RNA 3D structures.

PubMed

Wiedemann, Jakub; Zok, Tomasz; Milostan, Maciej; Szachniuk, Marta

2017-10-23

In modern structural bioinformatics, comparison of molecular structures aimed to identify and assess similarities and differences between them is one of the most commonly performed procedures. It gives the basis for evaluation of in silico predicted models. It constitutes the preliminary step in searching for structural motifs. In particular, it supports tracing the molecular evolution. Faced with an ever-increasing amount of available structural data, researchers need a range of methods enabling comparative analysis of the structures from either global or local perspective. Herein, we present a new, superposition-independent method which processes pairs of RNA 3D structures to identify their local similarities. The similarity is considered in the context of structure bending and bonds' rotation which are described by torsion angles. In the analyzed RNA structures, the method finds the longest continuous segments that show similar torsion within a user-defined threshold. The length of the segment is provided as local similarity measure. The method has been implemented as LCS-TA algorithm (Longest Continuous Segments in Torsion Angle space) and is incorporated into our MCQ4Structures application, freely available for download from http://www.cs.put.poznan.pl/tzok/mcq/ . The presented approach ties torsion-angle-based method of structure analysis with the idea of local similarity identification by handling continuous 3D structure segments. The first method, implemented in MCQ4Structures, has been successfully utilized in RNA-Puzzles initiative. The second one, originally applied in Euclidean space, is a component of LGA (Local-Global Alignment) algorithm commonly used in assessing protein models submitted to CASP. This unique combination of concepts implemented in LCS-TA provides a new perspective on structure quality assessment in local and quantitative aspect. A series of computational experiments show the first results of applying our method to comparison of RNA 3D models. LCS-TA can be used for identifying strengths and weaknesses in the prediction of RNA tertiary structures.

3D coupled heat and mass transfer processes at the scale of sedimentary basisn

NASA Astrophysics Data System (ADS)

Cacace, M.; Scheck-Wenderoth, M.; Kaiser, B. O.

2014-12-01

We use coupled 3D simulations of fluid, heat, and transport based on a 3D structural model of a complex geological setting, the Northeast German Basin (NEGB). The geological structure of the NEGB is characterized by a relatively thick layer of Permian Zechstein salt, structured in differnet diapirs (up to 5000 m thick) and pillows locally reaching nearly the surface. Salt is thermally more conductive than other sediments, hydraulically impervious but highly solvable. Thus salt structures have first order influence on the temperature distribution, the deep flow regime and the salinity of groundawater bearing aquifers. In addition, the post-Permian sedimentary sequence is vertically subdivided into several aquifers and aquitards. The shallow Quaternary to late Tertiary freshwater aquifer is separated from the underlying Mesozoic saline aquifers by an embedded Tertiary clay enriched aquitard (Rupelian Aquitard). An important feature of this aquitard is that hydraulic connections between the upper and lower aquifers exist in areas where the Rupelian Aquitard is missing (hydrogeological windows). By means of 3D numerical simulations we explore the role of heat conduction, pressure, and density driven groundwater flow as well as fluid viscosity-related and salinity-dependent effects on the resulting flow and temperature fields. Our results suggest that the regional temperature distribution within the basin results from interactions between regional pressure forces and thermal diffusion locally enhanced by thermal conductivity contrasts between the different sedimentary rocks with the highly conductive salt. Buoyancy forces triggered by temperature-dependent fluid density variations affect only locally the internal thermal configuration. Locations, geometry, and wavelengths of convective thermal anomalies are mainly controlled by the permeability field and thickness values of the respective geological layers. Numerical results from 3D thermo-haline numerical simulations suggest that hydrogeological windows act as preferential domains of hydraulic interconnectivity between the different aquifers at depth, and enable vigorous heat and mass transport which causes a mixing of warm and saline groundwater with cold and less saline groundwater within both aquifers.

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

PubMed Central

2017-01-01

Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates’ morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer’s and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer’s amyloid β and tau, Parkinson’s α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aβ, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions. PMID:28922400

Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins.

PubMed

Perez, Romel B; Tischer, Alexander; Auton, Matthew; Whitten, Steven T

2014-12-01

Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (R(h)) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PP(II)) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in R(h) were not associated with folding. The experiments showed that changes in local PP(II) structure cause changes in R(h) that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. © 2014 Wiley Periodicals, Inc.

Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins

PubMed Central

Perez, Romel B.; Tischer, Alexander; Auton, Matthew; Whitten, Steven T.

2014-01-01

Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins, mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline and alanine to glycine substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (Rh) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the glycine substitutions decreased polyproline II (PPII) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in Rh were not associated with folding. The experiments showed that changes in local PPII structure cause changes in Rh that are variable and that depend on the intrinsic chain propensities of proline and alanine residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed proline and alanine effects on the structures of intrinsically disordered proteins. PMID:25244701

European Extremely Large Telescope (E-ELT) availability stochastic model: integrating failure mode and effect analysis (FMEA), influence diagram, and Bayesian network together

NASA Astrophysics Data System (ADS)

Verzichelli, Gianluca

2016-08-01

An Availability Stochastic Model for the E-ELT has been developed in GeNIE. The latter is a Graphical User Interface (GUI) for the Structural Modeling, Inference, and Learning Engine (SMILE), originally distributed by the Decision Systems Laboratory from the University of Pittsburgh, and now being a product of Bayes Fusion, LLC. The E-ELT will be the largest optical/near-infrared telescope in the world. Its design comprises an Alt-Azimuth mount reflecting telescope with a 39-metre-diameter segmented primary mirror, a 4-metre-diameter secondary mirror, a 3.75-metre-diameter tertiary mirror, adaptive optics and multiple instruments. This paper highlights how a Model has been developed for an earlier on assessment of the Telescope Avail- ability. It also describes the modular structure and the underlying assumptions that have been adopted for developing the model and demonstrates the integration of FMEA, Influence Diagram and Bayesian Network elements. These have been considered for a better characterization of the Model inputs and outputs and for taking into account Degraded-based Reliability (DBR). Lastly, it provides an overview of how the information and knowledge captured in the model may be used for an earlier on definition of the Failure, Detection, Isolation and Recovery (FDIR) Control Strategy and the Telescope Minimum Master Equipment List (T-MMEL).

Understanding pain and coping in women with interstitial cystitis/bladder pain syndrome.

PubMed

Katz, Laura; Tripp, Dean A; Carr, Lesley K; Mayer, Robert; Moldwin, Robert M; Nickel, J Curtis

2017-08-01

To examine a self-regulation and coping model for interstitial cystitis/bladder pain syndrome (IC/BPS) that may help us understand the pain experience of patients with chronic IC/BPS. The model tested illness perceptions, illness-focused coping, emotional regulation, mental health and disability in a stepwise method using factor analysis and structural equation modelling. Step 1, explored the underlying constructs. Step 2, confirmed the measurement models to determine the structure/composition of the main constructs. Step 3, evaluated the model fit and specified pathways in the proposed IC/BPS self-regulation model. In all, 217 female patients with urologist diagnosed IC/BPS were recruited and diagnosed across tertiary care centres in North America. The data were collected through self-report questionnaires. An IC/BPS self-regulation model was supported. Physical disability was worsened by patient's negative perception of their illness, attempts to cope using illness-focused coping and poorer emotional regulation. Mental health was supported by perceptions that individuals could do something about their illness, using wellness-focused behavioural strategies and adaptive emotion regulation. The results clarify the complex and unique process of self-regulation in women with IC/BPS, implicating cognitive and coping targets, and highlighting emotional regulation. This knowledge should help clinicians understand and manage these patients' distress and disability. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Deformation of allochthonous salt and evolution of related salt-structural systems, eastern Louisiana Gulf Coast

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schuster, D.C.

1996-12-31

Salt tectonics in the northern Gulf of Mexico involves both vertical diapirism and lateral silling or flow of salt into wings and tablets (sheets). Combinations of these two modes of salt deformation, concurrent with sediment loading and salt evacuation, have produced complex structures in the coastal and offshore region of southeastern Louisiana, a prolific oil and gas province. Many large growth faults and salt domes in the study area root into intra-Tertiary salt welds that were formerly occupied by allochthonous salt tablets. Two end-member structural systems involving evacuation of former tabular salt are recognized: roho systems and stepped counter-regional systems.more » Both end-member systems share a similar multi-staged evolution, including (1) initial formation of a south-leaning salt dome or wall sourced from the Jurassic salt level; (2) progressive development into a semi-tabular allochthonous salt body; and (3) subsequent loading, evacuation, and displacement of the tabular salt into secondary domes. In both systems, it is not uncommon to find salt displaced as much as 16-24 km south of its autochthonous source, connected by a horizontal salt weld to an updip, deflated counter-regional feeder. Although both end-member structural systems may originate before loading of allochthonous salt having grossly similar geometry, their final structural configurations after loading and salt withdrawal are distinctly different. Roho systems are characterized by large-displacement, listric, south-dipping growth faults that sole into intra-Tertiary salt welds marked by high-amplitude reflections continuous with residual salt masses. Salt from the former salt tablets has been loaded and squeezed laterally and downdip. Stepped counter-regional systems, in contrast, comprise large salt domes and adjacent large-displacement, north-dipping growth faults that sole into intra-Tertiary salt welds before stepping down again farther north.« less

Predictive Structure and Topology of Peroxisomal ATP-Binding Cassette (ABC) Transporters

PubMed Central

Andreoletti, Pierre; Raas, Quentin; Gondcaille, Catherine; Cherkaoui-Malki, Mustapha; Trompier, Doriane; Savary, Stéphane

2017-01-01

The peroxisomal ATP-binding Cassette (ABC) transporters, which are called ABCD1, ABCD2 and ABCD3, are transmembrane proteins involved in the transport of various lipids that allow their degradation inside the organelle. Defective ABCD1 leads to the accumulation of very long-chain fatty acids and is associated with a complex and severe neurodegenerative disorder called X-linked adrenoleukodystrophy (X-ALD). Although the nucleotide-binding domain is highly conserved and characterized within the ABC transporters family, solid data are missing for the transmembrane domain (TMD) of ABCD proteins. The lack of a clear consensus on the secondary and tertiary structure of the TMDs weakens any structure-function hypothesis based on the very diverse ABCD1 mutations found in X-ALD patients. Therefore, we first reinvestigated thoroughly the structure-function data available and performed refined alignments of ABCD protein sequences. Based on the 2.85  Å resolution crystal structure of the mitochondrial ABC transporter ABCB10, here we propose a structural model of peroxisomal ABCD proteins that specifies the position of the transmembrane and coupling helices, and highlight functional motifs and putative important amino acid residues. PMID:28737695

Strategy for the management of substance use disorders in the State of Punjab: Developing a structural model of state-level de-addiction services in the health sector (the “Punjab model”)

PubMed Central

Basu, Debasish; Avasthi, Ajit

2015-01-01

Background: Substance use disorders are believed to have become rampant in the State of Punjab, causing substantive loss to the person, the family, the society, and the state. The situation is likely to worsen further if a structured, government-level, state-wide de-addiction service is not put into place. Aims: The aim was to describe a comprehensive structural model of de-addiction service in the State of Punjab (the “Pyramid model” or “Punjab model”), which is primarily concerned with demand reduction, particularly that part which is concerned with identification, treatment, and aftercare of substance users. Materials and Methods: At the behest of the Punjab Government, this model was developed by the authors after a detailed study of the current scenario, critical and exhaustive look at the existing guidelines, policies, books, web resources, government documents, and the like in this area, a check of the ground reality in terms of existing infrastructural and manpower resources, and keeping pragmatism and practicability in mind. Several rounds of meetings with the government officials and other important stakeholders helped to refine the model further. Results: Our model envisages structural innovation and renovations within the existing state healthcare infrastructure. We formulated a “Pyramid model,” later renamed as “Punjab model,” where there is a broad community base for early identification and outpatient level treatment at the primary care level, both outpatient and inpatient care at the secondary care level, and comprehensive management for more difficult cases at the tertiary care level. A separate de-addiction system for the prisons was also developed. Each of these structural elements was described and refined in details, with the aim of uniform, standardized, and easily accessible care across the state. Conclusions: If the “Punjab model” succeeds, it can provide useful models for other states or even at the national level. PMID:25657452

Structure and tectonics of the northwestern United States from EarthScope USArray magnetotelluric data

USGS Publications Warehouse

Bedrosian, Paul A.; Feucht, Daniel W.

2014-01-01

The magnetotelluric component of the EarthScope USArray program has covered over 35% of the continental United States. Resistivity tomography models derived from these data image lithospheric structure and provide constraints on the distribution of fluids and melt within the lithosphere. We present a three-dimensional resistivity model of the northwestern United States which provides new insight into the tectonic assembly of western North America from the Archean to present. Comparison with seismic tomography models reveals regions of correlated and anti-correlated resistivity and velocity that help identify thermal and compositional variations within the lithosphere. Recent (Neogene) tectonic features reflected in the model include the subducting Juan de Fuca–Gorda plate which can be traced beneath the forearc to more than 100 km depth, high lithospheric conductivity along the Snake River Plain, and pronounced lower-crustal and upper-mantle conductivity beneath the Basin and Range. The latter is abruptly terminated to the northwest by the Klamath–Blue Mountains Lineament, which we interpret as an important structure during and since the Mesozoic assembly of the region. This boundary is interpreted to separate hot extended lithosphere from colder, less extended lithosphere. The western edge of Proterozoic North America, as indicated by the Cretaceous initial 87Sr/86Sr = 0.706 contour, is clearly reflected in the resistivity model. We further image an Archean crustal block (“Pend Oreille block”) straddling the Washington/Idaho border, which we speculate separated from the Archean Medicine Hat block in the Proterozoic. Finally, in the modern Cascades forearc, the geometry and internal structure of the Eocene Siletz terrane is reflected in the resistivity model. The apparent eastern edge of the Siletz terrane under the Cascades arc suggests that pre-Tertiary rocks fill the Washington and Oregon back-arc.