Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure

NASA Technical Reports Server (NTRS)

Komamura, K.; Shannon, R. P.; Pasipoularides, A.; Ihara, T.; Lader, A. S.; Patrick, T. A.; Bishop, S. P.; Vatner, S. F.

1992-01-01

We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.

Improved Model for Predicting the Free Energy Contribution of Dinucleotide Bulges to RNA Duplex Stability.

PubMed

Tomcho, Jeremy C; Tillman, Magdalena R; Znosko, Brent M

2015-09-01

Predicting the secondary structure of RNA is an intermediate in predicting RNA three-dimensional structure. Commonly, determining RNA secondary structure from sequence uses free energy minimization and nearest neighbor parameters. Current algorithms utilize a sequence-independent model to predict free energy contributions of dinucleotide bulges. To determine if a sequence-dependent model would be more accurate, short RNA duplexes containing dinucleotide bulges with different sequences and nearest neighbor combinations were optically melted to derive thermodynamic parameters. These data suggested energy contributions of dinucleotide bulges were sequence-dependent, and a sequence-dependent model was derived. This model assigns free energy penalties based on the identity of nucleotides in the bulge (3.06 kcal/mol for two purines, 2.93 kcal/mol for two pyrimidines, 2.71 kcal/mol for 5'-purine-pyrimidine-3', and 2.41 kcal/mol for 5'-pyrimidine-purine-3'). The predictive model also includes a 0.45 kcal/mol penalty for an A-U pair adjacent to the bulge and a -0.28 kcal/mol bonus for a G-U pair adjacent to the bulge. The new sequence-dependent model results in predicted values within, on average, 0.17 kcal/mol of experimental values, a significant improvement over the sequence-independent model. This model and new experimental values can be incorporated into algorithms that predict RNA stability and secondary structure from sequence.

High-throughput sequencing: a failure mode analysis.

PubMed

Yang, George S; Stott, Jeffery M; Smailus, Duane; Barber, Sarah A; Balasundaram, Miruna; Marra, Marco A; Holt, Robert A

2005-01-04

Basic manufacturing principles are becoming increasingly important in high-throughput sequencing facilities where there is a constant drive to increase quality, increase efficiency, and decrease operating costs. While high-throughput centres report failure rates typically on the order of 10%, the causes of sporadic sequencing failures are seldom analyzed in detail and have not, in the past, been formally reported. Here we report the results of a failure mode analysis of our production sequencing facility based on detailed evaluation of 9,216 ESTs generated from two cDNA libraries. Two categories of failures are described; process-related failures (failures due to equipment or sample handling) and template-related failures (failures that are revealed by close inspection of electropherograms and are likely due to properties of the template DNA sequence itself). Preventative action based on a detailed understanding of failure modes is likely to improve the performance of other production sequencing pipelines.

Software reliability experiments data analysis and investigation

NASA Technical Reports Server (NTRS)

Walker, J. Leslie; Caglayan, Alper K.

1991-01-01

The objectives are to investigate the fundamental reasons which cause independently developed software programs to fail dependently, and to examine fault tolerant software structures which maximize reliability gain in the presence of such dependent failure behavior. The authors used 20 redundant programs from a software reliability experiment to analyze the software errors causing coincident failures, to compare the reliability of N-version and recovery block structures composed of these programs, and to examine the impact of diversity on software reliability using subpopulations of these programs. The results indicate that both conceptually related and unrelated errors can cause coincident failures and that recovery block structures offer more reliability gain than N-version structures if acceptance checks that fail independently from the software components are available. The authors present a theory of general program checkers that have potential application for acceptance tests.

Pushover analysis of reinforced concrete frames considering shear failure at beam-column joints

NASA Astrophysics Data System (ADS)

Sung, Y. C.; Lin, T. K.; Hsiao, C. C.; Lai, M. C.

2013-09-01

Since most current seismic capacity evaluations of reinforced concrete (RC) frame structures are implemented by either static pushover analysis (PA) or dynamic time history analysis, with diverse settings of the plastic hinges (PHs) on such main structural components as columns, beams and walls, the complex behavior of shear failure at beam-column joints (BCJs) during major earthquakes is commonly neglected. This study proposes new nonlinear PA procedures that consider shear failure at BCJs and seek to assess the actual damage to RC structures. Based on the specifications of FEMA-356, a simplified joint model composed of two nonlinear cross struts placed diagonally over the location of the plastic hinge is established, allowing a sophisticated PA to be performed. To verify the validity of this method, the analytical results for the capacity curves and the failure mechanism derived from three different full-size RC frames are compared with the experimental measurements. By considering shear failure at BCJs, the proposed nonlinear analytical procedures can be used to estimate the structural behavior of RC frames, including seismic capacity and the progressive failure sequence of joints, in a precise and effective manner.

Quantitative risk assessment system (QRAS)

NASA Technical Reports Server (NTRS)

Tan, Zhibin (Inventor); Mosleh, Ali (Inventor); Weinstock, Robert M (Inventor); Smidts, Carol S (Inventor); Chang, Yung-Hsien (Inventor); Groen, Francisco J (Inventor); Swaminathan, Sankaran (Inventor)

2001-01-01

A quantitative risk assessment system (QRAS) builds a risk model of a system for which risk of failure is being assessed, then analyzes the risk of the system corresponding to the risk model. The QRAS performs sensitivity analysis of the risk model by altering fundamental components and quantifications built into the risk model, then re-analyzes the risk of the system using the modifications. More particularly, the risk model is built by building a hierarchy, creating a mission timeline, quantifying failure modes, and building/editing event sequence diagrams. Multiplicities, dependencies, and redundancies of the system are included in the risk model. For analysis runs, a fixed baseline is first constructed and stored. This baseline contains the lowest level scenarios, preserved in event tree structure. The analysis runs, at any level of the hierarchy and below, access this baseline for risk quantitative computation as well as ranking of particular risks. A standalone Tool Box capability exists, allowing the user to store application programs within QRAS.

Failure of underground concrete structures subjected to blast loadings

NASA Technical Reports Server (NTRS)

Ross, C. A.; Nash, P. T.; Griner, G. R.

1979-01-01

The response and failure of two edges of free reinforced concrete slabs subjected to intermediate blast loadings are examined. The failure of the reinforced concrete structures is defined as a condition where actual separation or fracture of the reinforcing elements has occurred. Approximate theoretical methods using stationary and moving plastic hinge mechanisms with linearly varying and time dependent loadings are developed. Equations developed to predict deflection and failure of reinforced concrete beams are presented and compared with the experimental results.

Compression failure of fibrous laminated composites in the presence of stress gradients : experiment and analysis

NASA Astrophysics Data System (ADS)

Waas, Anthony M.

A series of experiments were performed to determine the mechanism of failure in compressively loaded laminated plates in the presence of stress gradients generated by a circular cutout. Real time holographic interferometry and in-situ photomicrography of the hole surface, were used to observe the progression of failure.The test specimens are multi-layered composite flat plates, which are loaded in compression. The plates are made of two material systems, T300/BP907 and IM7/8551-7. Two different lay-ups of T300/BP907 and four different lay-ups of IM7/8551-7 are investigated.The load on the specimen is slowly increased and a series of interferograms are produced during the load cycle. These interferograms are video-recorded. The results obtained from the interferograms and photo-micrographs are substantiated by sectioning studies and ultrasonic C-scanning of some specimens which are unloaded prior to catastrophic failure, but beyond failure initiation. This is made possible by the servo-controlled loading mechanism that regulates the load application and offers the flexibility of unloading a specimen at any given instance in the loadtime history.An underlying objective of the present investigation is the identification of the physics of the failure initiation process. This required testing specimens with different stacking sequences, for a fixed hole diameter, so that consistent trends in the failure process could be identified.It is revealed that the failure is initiated as a localized instability in the 0? plies at the hole surface, approximately at right angles to the loading direction. This instability emanating at the hole edge and propagating into the interior of the specimen within the 0? plies is found to be fiber microbuckling. The microbuckling is found to occur at a local strain level of [...]8600 [mu]strain at the hole edge for the IM material system. This initial failure renders a narrow zone of fibers within the 0? plies to loose structural integrity. Subsequent to the 0?-ply failure, extensive delamination cracking is observed with increasing load. The through thickness location of these delaminations is found to depend on the position of the 0? plies.The delaminated portions spread to the undamaged areas of the laminate by a combination of delamination buckling and growth, the buckling further enhancing the growth. When the delaminated area reaches a critical size, about 75-100% of the hole radius in extent, an accelerated growth rate of the delaminated portions is observed. The culmination of this last event is the complete loss of flexural stiffness of each of the delaminated portions leading to catastrophic failure of the plate. The levels of applied load and the rate at which these events occur depend on the plate stacking sequence.A simple mechanical model is presented for the microbuckling problem. This model addresses the buckling instability of a semi-infinte layered half-plane alternatingly stacked with fibers and matrix, loaded parallel to the surface of the half-plane. The fibers are modelled using Bernoulli-Navier beam theory, and the matrix is assumed to be a linearly elastic foundation. The predicted buckling strains are found to overestimate the experimental result. However, the dependence of the buckling strain on parameters such as the fiber volume fraction, ratio of Youngs moduli of the constituents and Poisson's ratio of the matrix are obtained from the analysis. It is seen that a high fiber volume fraction, increased matrix stiffness, and perfect bonding between fiber and matrix are desirable properties for increasing the compressive strength.

Sequence-structure correlations in silk: Poly-Ala repeat of N. clavipes MaSp1 is naturally optimized at a critical length scale.

PubMed

Bratzel, Graham; Buehler, Markus J

2012-03-01

Spider silk is a self-assembling biopolymer that outperforms many known materials in terms of its mechanical performance despite being constructed from simple and inferior building blocks. While experimental studies have shown that the molecular structure of silk has a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies in particular under variations of genetic sequences have been reported. Here we report atomistic-level structures of the MaSp1 protein from the Nephila Clavipes spider dragline silk sequence, obtained using an in silico approach based on replica exchange molecular dynamics (REMD) and explicit water molecular dynamics. We apply this method to study the effects of a systematic variation of the poly-alanine repeat lengths, a parameter controlled by the genetic makeup of silk, on the resulting molecular structure of silk at the nanoscale. Confirming earlier experimental and computational work, a structural analysis reveals that poly-alanine regions in silk predominantly form distinct and orderly β-sheet crystal domains while disorderly regions are formed by glycine-rich repeats that consist of 3(10)-helix type structures and β-turns. Our predictions are directly validated against experimental data based on dihedral angle pair calculations presented in Ramachandran plots combined with an analysis of the secondary structure content. The key result of our study is our finding of a strong dependence of the resulting silk nanostructure depending on the poly-alanine length. We observe that the wildtype poly-alanine repeat length of six residues defines a critical minimum length that consistently results in clearly defined β-sheet nanocrystals. For poly-alanine lengths below six, the β-sheet nanocrystals are not well-defined or not visible at all, while for poly-alanine lengths at and above six, the characteristic nanocomposite structure of silk emerges with no significant improvement of the quality of the β-sheet nanocrystal geometry. We present a simple biophysical model that explains these computational observations based on the mechanistic insight gained from the molecular simulations. Our findings set the stage for understanding how variations in the spidroin sequence can be used to engineer the structure and thereby functional properties of this biological superfiber, and present a design strategy for the genetic optimization of spidroins for enhanced mechanical properties. The approach used here may also find application in the design of other self-assembled molecular structures and fibers and in particular biologically inspired or completely synthetic systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

Close Analysis of Texts with Structure (CATS): An Intervention to Teach Reading Comprehension to At-Risk Second Graders

ERIC Educational Resources Information Center

Williams, Joanna P.; Kao, Jenny C.; Pao, Lisa S.; Ordynans, Jill G.; Atkins, J. Grant; Cheng, Rong; DeBonis, Daniel

2016-01-01

We developed and evaluated an intervention that teaches reading comprehension via expository text structure training to second graders in urban public schools at risk for academic failure. Fifty lessons on 5 basic text structures (sequence, comparison, causation, description, and problem-solution) were embedded in a social studies curriculum that…

Observation of the initiation and progression of damage in compressively loaded composite plates containing a cutout

NASA Technical Reports Server (NTRS)

Waas, A.; Babcock, C., Jr.

1986-01-01

A series of experiments was carried out to determine the mechanism of failure in compressively loaded laminated plates with a circular cutout. Real time holographic interferometry and photomicrography are used to observe the progression of failure. These observations together with post experiment plate sectioning and deplying for interior damage observation provide useful information for modelling the failure process. It is revealed that the failure is initiated as a localised instability in the zero layers, at the hole surface. With increasing load extensive delamination cracking is observed. The progression of failure is by growth of these delaminations induced by delamination buckling. Upon reaching a critical state, catastrophic failure of the plate is observed. The levels of applied load and the rate at which these events occur depend on the plate stacking sequence.

Processing multiple non-adjacent dependencies: evidence from sequence learning

PubMed Central

de Vries, Meinou H.; Petersson, Karl Magnus; Geukes, Sebastian; Zwitserlood, Pienie; Christiansen, Morten H.

2012-01-01

Processing non-adjacent dependencies is considered to be one of the hallmarks of human language. Assuming that sequence-learning tasks provide a useful way to tap natural-language-processing mechanisms, we cross-modally combined serial reaction time and artificial-grammar learning paradigms to investigate the processing of multiple nested (A1A2A3B3B2B1) and crossed dependencies (A1A2A3B1B2B3), containing either three or two dependencies. Both reaction times and prediction errors highlighted problems with processing the middle dependency in nested structures (A1A2A3B3_B1), reminiscent of the ‘missing-verb effect’ observed in English and French, but not with crossed structures (A1A2A3B1_B3). Prior linguistic experience did not play a major role: native speakers of German and Dutch—which permit nested and crossed dependencies, respectively—showed a similar pattern of results for sequences with three dependencies. As for sequences with two dependencies, reaction times and prediction errors were similar for both nested and crossed dependencies. The results suggest that constraints on the processing of multiple non-adjacent dependencies are determined by the specific ordering of the non-adjacent dependencies (i.e. nested or crossed), as well as the number of non-adjacent dependencies to be resolved (i.e. two or three). Furthermore, these constraints may not be specific to language but instead derive from limitations on structured sequence learning. PMID:22688641

A model for the progressive failure of laminated composite structural components

NASA Technical Reports Server (NTRS)

Allen, D. H.; Lo, D. C.

1991-01-01

Laminated continuous fiber polymeric composites are capable of sustaining substantial load induced microstructural damage prior to component failure. Because this damage eventually leads to catastrophic failure, it is essential to capture the mechanics of progressive damage in any cogent life prediction model. For the past several years the authors have been developing one solution approach to this problem. In this approach the mechanics of matrix cracking and delamination are accounted for via locally averaged internal variables which account for the kinematics of microcracking. Damage progression is predicted by using phenomenologically based damage evolution laws which depend on the load history. The result is a nonlinear and path dependent constitutive model which has previously been implemented to a finite element computer code for analysis of structural components. Using an appropriate failure model, this algorithm can be used to predict component life. In this paper the model will be utilized to demonstrate the ability to predict the load path dependence of the damage and stresses in plates subjected to fatigue loading.

Domain-specific learning of grammatical structure in musical and phonological sequences.

PubMed

Bly, Benjamin Martin; Carrión, Ricardo E; Rasch, Björn

2009-01-01

Artificial grammar learning depends on acquisition of abstract structural representations rather than domain-specific representational constraints, or so many studies tell us. Using an artificial grammar task, we compared learning performance in two stimulus domains in which respondents have differing tacit prior knowledge. We found that despite grammatically identical sequence structures, learning was better for harmonically related chord sequences than for letter name sequences or harmonically unrelated chord sequences. We also found transfer effects within the musical and letter name tasks, but not across the domains. We conclude that knowledge acquired in implicit learning depends not only on abstract features of structured stimuli, but that the learning of regularities is in some respects domain-specific and strongly linked to particular features of the stimulus domain.

Global Failure Modes in High Temperature Composite Structures

NASA Technical Reports Server (NTRS)

Knauss, W. G.

1998-01-01

Composite materials have been considered for many years as the major advance in the construction of energy efficient aerospace structures. Notable advances have been made in understanding the special design considerations that set composites apart from the usual "isotropic" engineering materials such as the metals. As a result, a number of significant engineering designs have been accomplished. However, one shortcoming of the currently favored composites is their relatively unforgiving behavior with respect to failure (brittleness) under seemingly mild impact conditions and large efforts are underway to rectify that situation, much along the lines of introducing thermoplastic matrix materials. Because of their relatively more pronounced (thermo) viscoelastic behavior these materials respond with "toughness" in fracture situations. From the point of view of applications requiring material strength, this property is highly desirable. This feature impacts several important and distinct engineering problems which have been' considered under this grant and cover the 1) effect of impact damage on structural (buckling) stability of composite panels, the 2) effect of time dependence on the progression of buckling instabilities, and the 3) evolution of damage and fracture at generic thickness discontinuities in structures. The latter topic has serious implications for structural stability problems (buckling failure in reinforced shell structures) as well as failure progression in stringer-reinforced shell structures. This grant has dealt with these issues. Polymer "toughness" is usually associated with uncrosslinked or thermo-plastic polymers. But, by comparison with their thermoset counterparts they tend to exhibit more pronounced time dependent material behavior; also, that time dependence can occur at lower temperatures which places restriction in the high temperature use of these "newer and tougher" materials that are not quite so serious with the thermoset matrix materials. From a structural point of view the implications of this material behavior are potentially severe in that structural failure characteristics are no longer readily observed in short term qualification tests so characteristic for aerospace structures built from typical engineering metals.

Simplified failure sequence evaluation of reactor pressure vessel head corroding in-core instrumentation assembly

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

McVicker, J.P.; Conner, J.T.; Hasrouni, P.N.

1995-11-01

In-Core Instrumentation (ICI) assemblies located on a Reactor Pressure Vessel Head have a history of boric acid leakage. The acid tends to corrode the nuts and studs which fasten the flanges of the assembly, thereby compromising the assembly`s structural integrity. This paper provides a simplified practical approach in determining the likelihood of an undetected progressing assembly stud deterioration, which would lead to a catastrophic loss of reactor coolant. The structural behavior of the In-Core Instrumentation flanged assembly is modeled using an elastic composite section assumption, with the studs transmitting tension and the pressure sealing gasket experiencing compression. Using the abovemore » technique, one can calculate the flange relative deflection and the consequential coolant loss flow rate, as well as the stress in any stud. A solved real life example develops the expected failure sequence and discusses the exigency of leak detection for safe shutdown. In the particular case of Calvert Cliffs Nuclear Power Plant (CCNPP) it is concluded that leak detection occurs before catastrophic failure of the ICI flange assembly.« less

An experimental investigation on the three-point bending behavior of composite laminate

NASA Astrophysics Data System (ADS)

A, Azzam; W, Li

2014-08-01

The response of composite laminate structure to three-point bending load was investigated by subjecting two types of stacking sequences of composite laminate structure by using electronic universal tester (Type: WDW-20) machine. Optical microscope was selected in order to characterize bending damage, delamination, and damage shapes in composite laminate structures. The results showed that the [0/90/-45/45]2s exhibits a brittle behavior, while other laminates exhibit a progressive failure mode consisting of fiber failure, debonding (splitting), and delamination. The [45/45/90/0]2s laminate has a highly nonlinear load- displacement curve due to compressive yielding.

A Bayesian Framework for Human Body Pose Tracking from Depth Image Sequences

PubMed Central

Zhu, Youding; Fujimura, Kikuo

2010-01-01

This paper addresses the problem of accurate and robust tracking of 3D human body pose from depth image sequences. Recovering the large number of degrees of freedom in human body movements from a depth image sequence is challenging due to the need to resolve the depth ambiguity caused by self-occlusions and the difficulty to recover from tracking failure. Human body poses could be estimated through model fitting using dense correspondences between depth data and an articulated human model (local optimization method). Although it usually achieves a high accuracy due to dense correspondences, it may fail to recover from tracking failure. Alternately, human pose may be reconstructed by detecting and tracking human body anatomical landmarks (key-points) based on low-level depth image analysis. While this method (key-point based method) is robust and recovers from tracking failure, its pose estimation accuracy depends solely on image-based localization accuracy of key-points. To address these limitations, we present a flexible Bayesian framework for integrating pose estimation results obtained by methods based on key-points and local optimization. Experimental results are shown and performance comparison is presented to demonstrate the effectiveness of the proposed approach. PMID:22399933

The Thiamine-Pyrophosphate-Motif

NASA Technical Reports Server (NTRS)

Ciszak, Ewa; Dominiak, Paulina

2004-01-01

Thiamin pyrophosphate (TPP), a derivative of vitamin B1, is a cofactor for enzymes performing catalysis in pathways of energy production including the well known decarboxylation of a-keto acid dehydrogenases followed by transketolation. TPP-dependent enzymes constitute a structurally and functionally diverse group exhibiting multimeric subunit organization, multiple domains and two chemically equivalent catalytic centers. Annotation of functional TPP-dependcnt enzymes, therefore, has not been trivial due to low sequence similarity related to this complex organization. Our approach to analysis of structures of known TPP-dependent enzymes reveals for the first time features common to this group, which we have termed the TPP-motif. The TPP-motif consists of specific spatial arrangements of structural elements and their specific contacts to provide for a flip-flop, or alternate site, enzymatic mechanism of action. Analysis of structural elements entrained in the flip-flop action displayed by TPP-dependent enzymes reveals a novel definition of the common amino acid sequences. These sequences allow for annotation of TPP-dependent enzymes, thus advancing functional proteomics. Further details of three-dimensional structures of TPP-dependent enzymes will be discussed.

Implications of Secondary Aftershocks for Failure Processes

NASA Astrophysics Data System (ADS)

Gross, S. J.

2001-12-01

When a seismic sequence with more than one mainshock or an unusually large aftershock occurs, there is a compound aftershock sequence. The secondary aftershocks need not have exactly the same decay as the primary sequence, with the differences having implications for the failure process. When the stress step from the secondary mainshock is positive but not large enough to cause immediate failure of all the remaining primary aftershocks, failure processes which involve accelerating slip will produce secondary aftershocks that decay more rapidly than primary aftershocks. This is because the primary aftershocks are an accelerated version of the background seismicity, and secondary aftershocks are an accelerated version of the primary aftershocks. Real stress perturbations may be negative, and heterogeneities in mainshock stress fields mean that the real world situation is quite complicated. I will first describe and verify my picture of secondary aftershock decay with reference to a simple numerical model of slipping faults which obeys rate and state dependent friction and lacks stress heterogeneity. With such a model, it is possible to generate secondary aftershock sequences with perturbed decay patterns, quantify those patterns, and develop an analysis technique capable of correcting for the effect in real data. The secondary aftershocks are defined in terms of frequency linearized time s(T), which is equal to the number of primary aftershocks expected by a time T, $ s ≡ ∫ t=0T n(t) dt, where the start time t=0 is the time of the primary aftershock, and the primary aftershock decay function n(t) is extrapolated forward to the times of the secondary aftershocks. In the absence of secondary sequences the function s(T)$ re-scales the time so that approximately one event occurs per new time unit; the aftershock sequence is gone. If this rescaling is applied in the presence of a secondary sequence, the secondary sequence is shaped like a primary aftershock sequence, and can be fit by the same modeling techniques applied to simple sequences. The later part of the presentation will concern the decay of Hector Mine aftershocks as influenced by the Landers aftershocks. Although attempts to predict the abundance of Hector aftershocks based on stress overlap analysis are not very successful, the analysis does do a good job fitting the decay of secondary sequences.

Verification of nonlinear dynamic structural test results by combined image processing and acoustic analysis

NASA Astrophysics Data System (ADS)

Tene, Yair; Tene, Noam; Tene, G.

1993-08-01

An interactive data fusion methodology of video, audio, and nonlinear structural dynamic analysis for potential application in forensic engineering is presented. The methodology was developed and successfully demonstrated in the analysis of heavy transportable bridge collapse during preparation for testing. Multiple bridge elements failures were identified after the collapse, including fracture, cracks and rupture of high performance structural materials. Videotape recording by hand held camcorder was the only source of information about the collapse sequence. The interactive data fusion methodology resulted in extracting relevant information form the videotape and from dynamic nonlinear structural analysis, leading to full account of the sequence of events during the bridge collapse.

Combined investigation of Eddy current and ultrasonic techniques for composite materials NDE

NASA Technical Reports Server (NTRS)

Davis, C. W.; Nath, S.; Fulton, J. P.; Namkung, M.

1993-01-01

Advanced composites are not without trade-offs. Their increased designability brings an increase in the complexity of their internal geometry and, as a result, an increase in the number of failure modes associated with a defect. When two or more isotropic materials are combined in a composite, the isotropic material failure modes may also combine. In a laminate, matrix delamination, cracking and crazing, and voids and porosity, will often combine with fiber breakage, shattering, waviness, and separation to bring about ultimate structural failure. This combining of failure modes can result in defect boundaries of different sizes, corresponding to the failure of each structural component. This paper discusses a dual-technology NDE (Non Destructive Evaluation) (eddy current (EC) and ultrasonics (UT)) study of graphite/epoxy (gr/ep) laminate samples. Eddy current and ultrasonic raster (Cscan) imaging were used together to characterize the effects of mechanical impact damage, high temperature thermal damage and various types of inserts in gr/ep laminate samples of various stacking sequences.

Vulnerabilities to Rock-Slope Failure Impacts from Christchurch, NZ Case History Analysis

NASA Astrophysics Data System (ADS)

Grant, A.; Wartman, J.; Massey, C. I.; Olsen, M. J.; Motley, M. R.; Hanson, D.; Henderson, J.

2015-12-01

Rock-slope failures during the 2010/11 Canterbury (Christchurch), New Zealand Earthquake Sequence resulted in 5 fatalities and caused an estimated US$400 million of damage to buildings and infrastructure. Reducing losses from rock-slope failures requires consideration of both hazard (i.e. likelihood of occurrence) and risk (i.e. likelihood of losses given an occurrence). Risk assessment thus requires information on the vulnerability of structures to rock or boulder impacts. Here we present 32 case histories of structures impacted by boulders triggered during the 2010/11 Canterbury earthquake sequence, in the Port Hills region of Christchurch, New Zealand. The consequences of rock fall impacts on structures, taken as penetration distance into structures, are shown to follow a power-law distribution with impact energy. Detailed mapping of rock fall sources and paths from field mapping, aerial lidar digital elevation model (DEM) data, and high-resolution aerial imagery produced 32 well-constrained runout paths of boulders that impacted structures. Impact velocities used for structural analysis were developed using lumped mass 2-D rock fall runout models using 1-m resolution lidar elevation data. Model inputs were based on calibrated surface parameters from mapped runout paths of 198 additional boulder runouts. Terrestrial lidar scans and structure from motion (SfM) imagery generated 3-D point cloud data used to measure structural damage and impacting boulders. Combining velocity distributions from 2-D analysis and high-precision boulder dimensions, kinetic energy distributions were calculated for all impacts. Calculated impact energy versus penetration distance for all cases suggests a power-law relationship between damage and impact energy. These case histories and resulting fragility curve should serve as a foundation for future risk analysis of rock fall hazards by linking vulnerability data to the predicted energy distributions from the hazard analysis.

Cleavage of nucleic acids

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor L.; Brow, Mary Ann D.; Dahlberg, James E.

2007-12-11

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Invasive cleavage of nucleic acids

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor I.; Brow, Mary Ann D.; Dahlberg, James E.

1999-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Invasive cleavage of nucleic acids

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor I.; Brow, Mary Ann D.; Dahlberg, James E.

2002-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Cleavage of nucleic acids

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor I.; Brow; Mary Ann D.; Dahlberg, James E.

2010-11-09

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Cleavage of nucleic acids

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor I.; Brow, Mary Ann D.; Dahlberg, James E.

2000-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Nucleic acid detection assays

DOEpatents

Prudent, James R.; Hall, Jeff G.; Lyamichev, Victor I.; Brow, Mary Ann; Dahlberg, James E.

2005-04-05

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof.

Conceptual modeling of coincident failures in multiversion software

NASA Technical Reports Server (NTRS)

Littlewood, Bev; Miller, Douglas R.

1989-01-01

Recent work by Eckhardt and Lee (1985) shows that independently developed program versions fail dependently (specifically, simultaneous failure of several is greater than would be the case under true independence). The present authors show there is a precise duality between input choice and program choice in this model and consider a generalization in which different versions can be developed using diverse methodologies. The use of diverse methodologies is shown to decrease the probability of the simultaneous failure of several versions. Indeed, it is theoretically possible to obtain versions which exhibit better than independent failure behavior. The authors try to formalize the notion of methodological diversity by considering the sequence of decision outcomes that constitute a methodology. They show that diversity of decision implies likely diversity of behavior for the different verions developed under such forced diversity. For certain one-out-of-n systems the authors obtain an optimal method for allocating diversity between versions. For two-out-of-three systems there seem to be no simple optimality results which do not depend on constraints which cannot be verified in practice.

Elucidation of Peptide-Directed Palladium Surface Structure for Biologically Tunable Nanocatalysts

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

Bedford, Nicholas M.; Ramezani-Dakhel, Hadi; Slocik, Joseph M.

Peptide-enabled synthesis of inorganic nanostructures represents an avenue to access catalytic materials with tunable and optimized properties. This is achieved via peptide complexity and programmability that is missing in traditional ligands for catalytic nanomaterials. Unfortunately, there is limited information available to correlate peptide sequence to particle structure and catalytic activity to date. As such, the application of peptide-enabled nanocatalysts remains limited to trial and error approaches. In this paper, a hybrid experimental and computational approach is introduced to systematically elucidate biomolecule-dependent structure/function relationships for peptide-capped Pd nanocatalysts. Synchrotron X-ray techniques were used to uncover substantial particle surface structural disorder, whichmore » was dependent upon the amino acid sequence of the peptide capping ligand. Nanocatalyst configurations were then determined directly from experimental data using reverse Monte Carlo methods and further refined using molecular dynamics simulation, obtaining thermodynamically stable peptide-Pd nanoparticle configurations. Sequence-dependent catalytic property differences for C-C coupling and olefin hydrogenation were then eluddated by identification of the catalytic active sites at the atomic level and quantitative prediction of relative reaction rates. This hybrid methodology provides a clear route to determine peptide-dependent structure/function relationships, enabling the generation of guidelines for catalyst design through rational tailoring of peptide sequences« less

Elucidation of peptide-directed palladium surface structure for biologically tunable nanocatalysts.

PubMed

Bedford, Nicholas M; Ramezani-Dakhel, Hadi; Slocik, Joseph M; Briggs, Beverly D; Ren, Yang; Frenkel, Anatoly I; Petkov, Valeri; Heinz, Hendrik; Naik, Rajesh R; Knecht, Marc R

2015-05-26

Peptide-enabled synthesis of inorganic nanostructures represents an avenue to access catalytic materials with tunable and optimized properties. This is achieved via peptide complexity and programmability that is missing in traditional ligands for catalytic nanomaterials. Unfortunately, there is limited information available to correlate peptide sequence to particle structure and catalytic activity to date. As such, the application of peptide-enabled nanocatalysts remains limited to trial and error approaches. In this paper, a hybrid experimental and computational approach is introduced to systematically elucidate biomolecule-dependent structure/function relationships for peptide-capped Pd nanocatalysts. Synchrotron X-ray techniques were used to uncover substantial particle surface structural disorder, which was dependent upon the amino acid sequence of the peptide capping ligand. Nanocatalyst configurations were then determined directly from experimental data using reverse Monte Carlo methods and further refined using molecular dynamics simulation, obtaining thermodynamically stable peptide-Pd nanoparticle configurations. Sequence-dependent catalytic property differences for C-C coupling and olefin hydrogenation were then elucidated by identification of the catalytic active sites at the atomic level and quantitative prediction of relative reaction rates. This hybrid methodology provides a clear route to determine peptide-dependent structure/function relationships, enabling the generation of guidelines for catalyst design through rational tailoring of peptide sequences.

Optimally robust redundancy relations for failure detection in uncertain systems

NASA Technical Reports Server (NTRS)

Lou, X.-C.; Willsky, A. S.; Verghese, G. C.

1986-01-01

All failure detection methods are based, either explicitly or implicitly, on the use of redundancy, i.e. on (possibly dynamic) relations among the measured variables. The robustness of the failure detection process consequently depends to a great degree on the reliability of the redundancy relations, which in turn is affected by the inevitable presence of model uncertainties. In this paper the problem of determining redundancy relations that are optimally robust is addressed in a sense that includes several major issues of importance in practical failure detection and that provides a significant amount of intuition concerning the geometry of robust failure detection. A procedure is given involving the construction of a single matrix and its singular value decomposition for the determination of a complete sequence of redundancy relations, ordered in terms of their level of robustness. This procedure also provides the basis for comparing levels of robustness in redundancy provided by different sets of sensors.

Sequence-dependent effects in drug-DNA interaction: the crystal structure of Hoechst 33258 bound to the d(CGCAAATTTGCG)2 duplex.

PubMed Central

Spink, N; Brown, D G; Skelly, J V; Neidle, S

1994-01-01

The bis-benzimidazole drug Hoechst 33258 has been co-crystallized with the dodecanucleotide sequence d(CGCAAATTTGCG)2. The structure has been solved by molecular replacement and refined to an R factor of 18.5% for 2125 reflections collected on a Xentronics area detector. The drug is bound in the minor groove, at the five base-pair site 5'-ATTTG and is in a unique orientation. This is displaced by one base pair in the 5' direction compared to previously-determined structures of this drug with the sequence d(CGCGAATTCGCG)2. Reasons for this difference in behaviour are discussed in terms of several sequence-dependent structural features of the DNA, with particular reference to differences in propeller twist and minor-groove width. Images PMID:7515488

Fault Injection Techniques and Tools

NASA Technical Reports Server (NTRS)

Hsueh, Mei-Chen; Tsai, Timothy K.; Iyer, Ravishankar K.

1997-01-01

Dependability evaluation involves the study of failures and errors. The destructive nature of a crash and long error latency make it difficult to identify the causes of failures in the operational environment. It is particularly hard to recreate a failure scenario for a large, complex system. To identify and understand potential failures, we use an experiment-based approach for studying the dependability of a system. Such an approach is applied not only during the conception and design phases, but also during the prototype and operational phases. To take an experiment-based approach, we must first understand a system's architecture, structure, and behavior. Specifically, we need to know its tolerance for faults and failures, including its built-in detection and recovery mechanisms, and we need specific instruments and tools to inject faults, create failures or errors, and monitor their effects.

Thermal changes of the environment and their influence on reinforced concrete structures

NASA Astrophysics Data System (ADS)

Fojtik, R.; Cajka, R.

2018-04-01

The thermal expansion of concrete elements concerns both monolithic and prefabricated structures. Inappropriate design of dilation segments may cause minor but even larger failures. Critical environment factors are temperature-changing operations, such as unheated underground garages, where temperature fluctuations may occur depending on the exterior conditions. This paper numerically and experimentally analyses the thermal deformation of selected girders in the underground garages and the consequent structure failures, their causes, possible prevention and appropriate remediation.

The impact of vaccine failure rate on epidemic dynamics in responsive networks.

PubMed

Liang, Yu-Hao; Juang, Jonq

2015-04-01

An SIS model based on the microscopic Markov-chain approximation is considered in this paper. It is assumed that the individual vaccination behavior depends on the contact awareness, local and global information of an epidemic. To better simulate the real situation, the vaccine failure rate is also taken into consideration. Our main conclusions are given in the following. First, we show that if the vaccine failure rate α is zero, then the epidemic eventually dies out regardless of what the network structure is or how large the effective spreading rate and the immunization response rates of an epidemic are. Second, we show that for any positive α, there exists a positive epidemic threshold depending on an adjusted network structure, which is only determined by the structure of the original network, the positive vaccine failure rate and the immunization response rate for contact awareness. Moreover, the epidemic threshold increases with respect to the strength of the immunization response rate for contact awareness. Finally, if the vaccine failure rate and the immunization response rate for contact awareness are positive, then there exists a critical vaccine failure rate αc > 0 so that the disease free equilibrium (DFE) is stable (resp., unstable) if α < αc (resp., α > αc). Numerical simulations to see the effectiveness of our theoretical results are also provided.

Alternative model of thrust-fault propagation

NASA Astrophysics Data System (ADS)

Eisenstadt, Gloria; de Paor, Declan G.

1987-07-01

A widely accepted explanation for the geometry of thrust faults is that initial failures occur on deeply buried planes of weak rock and that thrust faults propagate toward the surface along a staircase trajectory. We propose an alternative model that applies Gretener's beam-failure mechanism to a multilayered sequence. Invoking compatibility conditions, which demand that a thrust propagate both upsection and downsection, we suggest that ramps form first, at shallow levels, and are subsequently connected by flat faults. This hypothesis also explains the formation of many minor structures associated with thrusts, such as backthrusts, wedge structures, pop-ups, and duplexes, and provides a unified conceptual framework in which to evaluate field observations.

[Progressive damage monitoring of corrugated composite skins by the FBG spectral characteristics].

PubMed

Zhang, Yong; Wang, Bang-Feng; Lu, Ji-Yun; Gu, Li-Li; Su, Yong-Gang

2014-03-01

In the present paper, a method of monitoring progressive damage of composite structures by non-uniform fiber Bragg grating (FBG) reflection spectrum is proposed. Due to the finite element analysis of corrugated composite skins specimens, the failure process under tensile load and corresponding critical failure loads of corrugated composite skin was predicated. Then, the non-uniform reflection spectrum of FBG sensor could be reconstructed and the corresponding relationship between layer failure order sequence of corrugated composite skin and FBG sensor reflection spectrums was acquired. A monitoring system based on FBG non-uniform reflection spectrum, which can be used to monitor progressive damage of corrugated composite skins, was built. The corrugated composite skins were stretched under this FBG non-uniform reflection spectrum monitoring system. The results indicate that real-time spectrums acquired by FBG non-uniform reflection spectrum monitoring system show the same trend with the reconstruction reflection spectrums. The maximum error between the corresponding failure and the predictive value is 8.6%, which proves the feasibility of using FBG sensor to monitor progressive damage of corrugated composite skin. In this method, the real-time changes in the FBG non-uniform reflection spectrum within the scope of failure were acquired through the way of monitoring and predicating, and at the same time, the progressive damage extent and layer failure sequence of corru- gated composite skin was estimated, and without destroying the structure of the specimen, the method is easy and simple to operate. The measurement and transmission section of the system are completely composed of optical fiber, which provides new ideas and experimental reference for the field of dynamic monitoring of smart skin.

High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure

PubMed Central

Rosa-Garrido, Manuel; Chapski, Douglas J.; Schmitt, Anthony D.; Kimball, Todd H.; Karbassi, Elaheh; Monte, Emma; Balderas, Enrique; Pellegrini, Matteo; Shih, Tsai-Ting; Soehalim, Elizabeth; Liem, David; Ping, Peipei; Galjart, Niels J.; Ren, Shuxun; Wang, Yibin; Ren, Bing

2017-01-01

Background: Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. Methods: To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload–induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. Results: Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. Conclusions: These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy. PMID:28802249

High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure.

PubMed

Rosa-Garrido, Manuel; Chapski, Douglas J; Schmitt, Anthony D; Kimball, Todd H; Karbassi, Elaheh; Monte, Emma; Balderas, Enrique; Pellegrini, Matteo; Shih, Tsai-Ting; Soehalim, Elizabeth; Liem, David; Ping, Peipei; Galjart, Niels J; Ren, Shuxun; Wang, Yibin; Ren, Bing; Vondriska, Thomas M

2017-10-24

Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy. © 2017 The Authors.

Himalayan Sackung and Associations to Regional Structure

NASA Astrophysics Data System (ADS)

Shroder, J. F.; Bishop, M. P.; Olsenholler, J.

2003-12-01

Recognition of sackung slope failure or deep-seated, rock-slope deformation in the Himalaya has been rather limited, in part because: (1) many geoscientists do not recognize its characteristics; (2) large-scale aerial photographs and topographic maps used to identify the characteristic surficial, topographic manifestations of the failure type are commonly low-level state secrets in that region; and (3) no systematic survey for sackung has ever been made in the Himalaya. In the Pakistani-controlled, western Himalaya, some unconventional access to aerial photographs in the Kaghan and Nanga Parbat areas allowed first recognition of several characteristic ridge-top grabens and anti-slope scarps. Later release of declassified, stereo imagery from the CORONA and KEYHOLE satellite series enabled discovery of other examples in the K2 region. Comparison of mapped sackung failures with geologic base maps has demonstrated some coincidence of sackung with various structural trends, including synformal structures in upper thrust plates or along the traces of high-angle faults. In all probability these structural trends have provided plentiful ancillary planes of weakness along which gravitationally driven sackung is facilitated. Sackung failure in the Himalaya appears to be a spatially scale-dependent manifestation of a gravitational-collapse continuum of the brittle, upper crust, mainly involving mountain ridges. In contrast, gravitational collapse of the whole range may involve some similar failures but also include listric faulting, as well as subsidence movement into zones of ductility at depth. Temporal scale dependence of sackung may also be threshold dominated, wherein initial long-continued, slow failure ultimately leads to the commonly catastrophic rock-slope collapses recently recognized throughout the western Himalaya and now differentiated from their original mismapping as glacial moraines. Such sackung in Himalayan terrain undergoing active deglaciation from global warming may increase catastrophic slope-failure hazard.

Phase dependent fracture and damage evolution of polytetrafluoroethylene (PTFE)

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

Brown, E. N.; Rae, P.; Orler, E. B.

2004-01-01

Compared with other polymers, polytetrafluoroethylene (PTFE) presents several advantages for load-bearing structural components including higher strength at elevated temperatures and higher toughness at lowered temperatures. Failure sensitive applications of PTFE include surgical implants, aerospace components, and chemical barriers. Polytetrafluoroethylene is semicrystalline in nature with their linear chains forming complicated phases near room temperature and ambient pressure. The presence of three unique phases near room temperature implies that failure during standard operating conditions may be strongly dependent on the phase. This paper presents a comprehensive and systematic study of fracture and damage evolution in PTFE to elicit the effects of temperature-inducedmore » phase on fracture mechanisms. The fracture behavior of PTFE is observed to undergo transitions from brittle-fracture below 19 C to ductile-fracture with crazing and some stable crack growth to plastic flow aver 30 C. The bulk failure properties are correlated to failure mechanisms through fractography and analysis of the crystalline structure.« less

DIVA V2.0

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

CHEN, JOANNA; SIMIRENKO, LISA; TAPASWI, MANJIRI

The DIVA software interfaces a process in which researchers design their DNA with a web-based graphical user interface, submit their designs to a central queue, and a few weeks later receive their sequence-verified clonal constructs. Each researcher independently designs the DNA to be constructed with a web-based BioCAD tool, and presses a button to submit their designs to a central queue. Researchers have web-based access to their DNA design queues, and can track the progress of their submitted designs as they progress from "evaluation", to "waiting for reagents", to "in progress", to "complete". Researchers access their completed constructs through themore » central DNA repository. Along the way, all DNA construction success/failure rates are captured in a central database. Once a design has been submitted to the queue, a small number of dedicated staff evaluate the design for feasibility and provide feedback to the responsible researcher if the design is either unreasonable (e.g., encompasses a combinatorial library of a billion constructs) or small design changes could significantly facilitate the downstream implementation process. The dedicated staff then use DNA assembly design automation software to optimize the DNA construction process for the design, leveraging existing parts from the DNA repository where possible and ordering synthetic DNA where necessary. SynTrack software manages the physical locations and availability of the various requisite reagents and process inputs (e.g., DNA templates). Once all requisite process inputs are available, the design progresses from "waiting for reagents" to "in progress" in the design queue. Human-readable and machine-parseable DNA construction protocols output by the DNA assembly design automation software are then executed by the dedicated staff exploiting lab automation devices wherever possible. Since the all employed DNA construction methods are sequence-agnostic, standardized (utilize the same enzymatic master mixes and reaction conditions), completely independent DNA construction tasks can be aggregated into the same multi-well plates and pursued in parallel. The resulting sets of cloned constructs can then be screened by high-throughput next-gen sequencing platforms for sequence correctness. A combination of long read-length (e.g., PacBio) and paired-end read platforms (e.g., Illumina) would be exploited depending the particular task at hand (e.g., PacBio might be sufficient to screen a set of pooled constructs with significant gene divergence). Post sequence verification, designs for which at least one correct clone was identified will progress to a "complete" status, while designs for which no correct clones wereidentified will progress to a "failure" status. Depending on the failure mode (e.g., no transformants), and how many prior attempts/variations of assembly protocol have been already made for a given design, subsequent attempts may be made or the design can progress to a "permanent failure" state. All success and failure rate information will be captured during the process, including at which stage a given clonal construction procedure failed (e.g., no PCR product) and what the exact failure was (e.g. assembly piece 2 missing). This success/failure rate data can be leveraged to refine the DNA assembly design process.« less

Loading direction-dependent shear behavior at different temperatures of single-layer chiral graphene sheets

NASA Astrophysics Data System (ADS)

Zhao, Yang; Dong, Shuhong; Yu, Peishi; Zhao, Junhua

2018-06-01

The loading direction-dependent shear behavior of single-layer chiral graphene sheets at different temperatures is studied by molecular dynamics (MD) simulations. Our results show that the shear properties (such as shear stress-strain curves, buckling strains, and failure strains) of chiral graphene sheets strongly depend on the loading direction due to the structural asymmetry. The maximum values of both the critical buckling shear strain and the failure strain under positive shear deformation can be around 1.4 times higher than those under negative shear deformation. For a given chiral graphene sheet, both its failure strain and failure stress decrease with increasing temperature. In particular, the amplitude to wavelength ratio of wrinkles for different chiral graphene sheets under shear deformation using present MD simulations agrees well with that from the existing theory. These findings provide physical insights into the origins of the loading direction-dependent shear behavior of chiral graphene sheets and their potential applications in nanodevices.

Modeling and Studying the Effect of Texture and Elastic Anisotropy of Copper Microstructure in Nanoscale Interconnects on Reliability in Integrated Circuits

NASA Astrophysics Data System (ADS)

Basavalingappa, Adarsh

Copper interconnects are typically polycrystalline and follow a lognormal grain size distribution. Polycrystalline copper interconnect microstructures with a lognormal grain size distribution were obtained with a Voronoi tessellation approach. The interconnect structures thus obtained were used to study grain growth mechanisms, grain boundary scattering, scattering dependent resistance of interconnects, stress evolution, vacancy migration, reliability life times, impact of orientation dependent anisotropy on various mechanisms, etc. In this work, the microstructures were used to study the impact of microstructure and elastic anisotropy of copper on thermal and electromigration induced failure. A test structure with copper and bulk moduli values was modeled to do a comparative study with the test structures with textured microstructure and elastic anisotropy. By subjecting the modeled test structure to a thermal stress by ramping temperature down from 400 °C to 100 °C, a significant variation in normal stresses and pressure were observed at the grain boundaries. This variation in normal stresses and hydrostatic stresses at the grain boundaries was found to be dependent on the orientation, dimensions, surroundings, and location of the grains. This may introduce new weak points within the metal line where normal stresses can be very high depending on the orientation of the grains leading to delamination and accumulation sites for vacancies. Further, the hydrostatic stress gradients act as a driving force for vacancy migration. The normal stresses can exceed certain grain orientation dependent critical threshold values and induce delamination at the copper and cap material interface, thereby leading to void nucleation and growth. Modeled test structures were subjected to a series of copper depositions at 250 °C followed by copper etch at 25 °C to obtain initial stress conditions. Then the modeled test structures were subjected to 100,000 hours ( 11.4 years) of simulated thermal stress at an elevated temperature of 150 °C. Vacancy migration due to concentration gradients, thermal gradients, and mechanical stress gradients were considered under the applied thermal stress. As a result, relatively high concentrations of vacancies were observed in the test structure due to a driving force caused by the pressure gradients resulting from the elastic anisotropy of copper. The grain growth mechanism was not considered in these simulations. Studies with two grain analysis demonstrated that the stress gradients developed will be severe when (100) grains are adjacent to (111) grains, therefore making them the weak points for potentially reliability failures. Ilan Blech discovered that electromigration occurs above a critical product of the current density and metal length, commonly referred as Blech condition. Electromigration stress simulations in this work were carried out by subjecting test structures to scaled current densities to overcome the Blech condition of (jL)crit for small dimensions of test structure and the low temperature stress condition used. Vacancy migration under the electromigration stress conditions was considered along with the vacancy migration induced stress evolution. A simple void growth model was used which assumes voids start to form when vacancies reach a critical level. Increase of vacancies in a localized region increases the resistance of the metal line. Considering a 10% increase in resistance as a failure criterion, the distributions of failure times were obtained for given electromigration stress conditions. Bimodal/multimodal failure distributions were obtained as a result. The sigma values were slightly lower than the ones commonly observed from experiments. The anisotropy of the elastic moduli of copper leads to the development of significantly different stress values which are dependent on the orientation of the grains. This results in some grains having higher normal stress than the others. This grain orientation dependent normal stress can reach a critical stress necessary to induce delamination at the copper and cap interface. Time taken to reach critical stress was considered as time to fail and distributions of failure times were obtained for structures with different grain orientations in the microstructure for different critical stress values. The sigma values of the failure distributions thus obtained for different constant critical stress values had a strong dependence of on the critical stress. It is therefore critical to use the appropriate critical stress value for the delamination of copper and cap interface. The critical stress necessary to overcome the local adhesion of the copper and the cap material interface is dependent on grain orientation of the copper. Simulations were carried out by considering grain orientation dependent critical normal stress values as failure criteria. The sigma value thus obtained with selected critical stress values were comparable to sigma values commonly observed from experiments.

A Procedure for Modeling Structural Component/Attachment Failure Using Transient Finite Element Analysis

NASA Technical Reports Server (NTRS)

Lovejoy, Andrew E.; Jegley, Dawn C. (Technical Monitor)

2007-01-01

Structures often comprise smaller substructures that are connected to each other or attached to the ground by a set of finite connections. Under static loading one or more of these connections may exceed allowable limits and be deemed to fail. Of particular interest is the structural response when a connection is severed (failed) while the structure is under static load. A transient failure analysis procedure was developed by which it is possible to examine the dynamic effects that result from introducing a discrete failure while a structure is under static load. The failure is introduced by replacing a connection load history by a time-dependent load set that removes the connection load at the time of failure. The subsequent transient response is examined to determine the importance of the dynamic effects by comparing the structural response with the appropriate allowables. Additionally, this procedure utilizes a standard finite element transient analysis that is readily available in most commercial software, permitting the study of dynamic failures without the need to purchase software specifically for this purpose. The procedure is developed and explained, demonstrated on a simple cantilever box example, and finally demonstrated on a real-world example, the American Airlines Flight 587 (AA587) vertical tail plane (VTP).

On rate-state and Coulomb failure models

USGS Publications Warehouse

Gomberg, J.; Beeler, N.; Blanpied, M.

2000-01-01

We examine the predictions of Coulomb failure stress and rate-state frictional models. We study the change in failure time (clock advance) Δt due to stress step perturbations (i.e., coseismic static stress increases) added to "background" stressing at a constant rate (i.e., tectonic loading) at time t0. The predictability of Δt implies a predictable change in seismicity rate r(t)/r0, testable using earthquake catalogs, where r0 is the constant rate resulting from tectonic stressing. Models of r(t)/r0, consistent with general properties of aftershock sequences, must predict an Omori law seismicity decay rate, a sequence duration that is less than a few percent of the mainshock cycle time and a return directly to the background rate. A Coulomb model requires that a fault remains locked during loading, that failure occur instantaneously, and that Δt is independent of t0. These characteristics imply an instantaneous infinite seismicity rate increase of zero duration. Numerical calculations of r(t)/r0 for different state evolution laws show that aftershocks occur on faults extremely close to failure at the mainshock origin time, that these faults must be "Coulomb-like," and that the slip evolution law can be precluded. Real aftershock population characteristics also may constrain rate-state constitutive parameters; a may be lower than laboratory values, the stiffness may be high, and/or normal stress may be lower than lithostatic. We also compare Coulomb and rate-state models theoretically. Rate-state model fault behavior becomes more Coulomb-like as constitutive parameter a decreases relative to parameter b. This is because the slip initially decelerates, representing an initial healing of fault contacts. The deceleration is more pronounced for smaller a, more closely simulating a locked fault. Even when the rate-state Δt has Coulomb characteristics, its magnitude may differ by some constant dependent on b. In this case, a rate-state model behaves like a modified Coulomb failure model in which the failure stress threshold is lowered due to weakening, increasing the clock advance. The deviation from a non-Coulomb response also depends on the loading rate, elastic stiffness, initial conditions, and assumptions about how state evolves.

Impact Damage and Strain Rate Effects for Toughened Epoxy Composite Structures

NASA Technical Reports Server (NTRS)

Chamis, Christos C.; Minnetyan, Levon

2006-01-01

Structural integrity of composite systems under dynamic impact loading is investigated herein. The GENOA virtual testing software environment is used to implement the effects of dynamic loading on fracture progression and damage tolerance. Combinations of graphite and glass fibers with a toughened epoxy matrix are investigated. The effect of a ceramic coating for the absorption of impact energy is also included. Impact and post impact simulations include verification and prediction of (1) Load and Impact Energy, (2) Impact Damage Size, (3) Maximum Impact Peak Load, (4) Residual Strength, (5) Maximum Displacement, (6) Contribution of Failure Modes to Failure Mechanisms, (7) Prediction of Impact Load Versus Time, and (8) Damage, and Fracture Pattern. A computer model is utilized for the assessment of structural response, progressive fracture, and defect/damage tolerance characteristics. Results show the damage progression sequence and the changes in the structural response characteristics due to dynamic impact. The fundamental premise of computational simulation is that the complete evaluation of composite fracture requires an assessment of ply and subply level damage/fracture processes as the structure is subjected to loads. Simulation results for the graphite/epoxy composite were compared with the impact and tension failure test data, correlation and verification was obtained that included: (1) impact energy, (2) damage size, (3) maximum impact peak load, (4) residual strength, (5) maximum displacement, and (6) failure mechanisms of the composite structure.

Stage Separation Failure: Model Based Diagnostics and Prognostics

NASA Technical Reports Server (NTRS)

Luchinsky, Dmitry; Hafiychuk, Vasyl; Kulikov, Igor; Smelyanskiy, Vadim; Patterson-Hine, Ann; Hanson, John; Hill, Ashley

2010-01-01

Safety of the next-generation space flight vehicles requires development of an in-flight Failure Detection and Prognostic (FD&P) system. Development of such system is challenging task that involves analysis of many hard hitting engineering problems across the board. In this paper we report progress in the development of FD&P for the re-contact fault between upper stage nozzle and the inter-stage caused by the first stage and upper stage separation failure. A high-fidelity models and analytical estimations are applied to analyze the following sequence of events: (i) structural dynamics of the nozzle extension during the impact; (ii) structural stability of the deformed nozzle in the presence of the pressure and temperature loads induced by the hot gas flow during engine start up; and (iii) the fault induced thrust changes in the steady burning regime. The diagnostic is based on the measurements of the impact torque. The prognostic is based on the analysis of the correlation between the actuator signal and fault-induced changes in the nozzle structural stability and thrust.

Enhancement of object-permanence performance in the Down's syndrome infant.

PubMed

Morss, J R

1984-01-01

Four infants with Down's syndrome (aged 19-33 months) were presented with a restructured version of an object-permanence task. Restructuring consisted of the embedding of single trials of the task within a sequence of simpler, related steps. Following failure on a standard presentation of the task, three Down's syndrome (DS) infants demonstrated success on trials embedded in the training sequence. Comparison was made with the performance of normal infants (aged 14-19 months) matched in terms of failure on the pre-test. Only two out of nine normal infants registered success on the embedded trials. Results are discussed in terms of the differences between the DS infant and the normal infant, and the former's reliance on the deliberate structuring of his learning environment by a parent or educator.

Length-scale and strain rate-dependent mechanism of defect formation and fracture in carbon nanotubes under tensile loading

NASA Astrophysics Data System (ADS)

Javvaji, Brahmanandam; Raha, S.; Mahapatra, D. Roy

2017-02-01

Electromagnetic and thermo-mechanical forces play a major role in nanotube-based materials and devices. Under high-energy electron transport or high current densities, carbon nanotubes fail via sequential fracture. The failure sequence is governed by certain length scale and flow of current. We report a unified phenomenological model derived from molecular dynamic simulation data, which successfully captures the important physics of the complex failure process. Length-scale and strain rate-dependent defect nucleation, growth, and fracture in single-walled carbon nanotubes with diameters in the range of 0.47 to 2.03 nm and length which is about 6.17 to 26.45 nm are simulated. Nanotubes with long length and small diameter show brittle fracture, while those with short length and large diameter show transition from ductile to brittle fracture. In short nanotubes with small diameters, we observe several structural transitions like Stone-Wales defect initiation, its propagation to larger void nucleation, formation of multiple chains of atoms, conversion to monatomic chain of atoms, and finally complete fracture of the carbon nanotube. Hybridization state of carbon-carbon bonds near the end cap evolves, leading to the formation of monatomic chain in short nanotubes with small diameter. Transition from ductile to brittle fracture is also observed when strain rate exceeds a critical value. A generalized analytical model of failure is established, which correlates the defect energy during the formation of atomic chain with aspect ratio of the nanotube and strain rate. Variation in the mechanical properties such as elastic modulus, tensile strength, and fracture strain with the size and strain rate shows important implications in mitigating force fields and ways to enhance the life of electronic devices and nanomaterial conversion via fracture in manufacturing.

Tensile Response of Hoop Reinforced Multiaxially Braided Thin Wall Composite Tubes

NASA Astrophysics Data System (ADS)

Roy, Sree Shankhachur; Potluri, Prasad; Soutis, Constantinos

2017-04-01

This paper presents the tensile response of thin-walled composite tubes with multi-axial fibre architecture. A hybrid braid-wound layup has the potential to optimise the composite tube properties, however, stacking sequence plays a role in the failure mechanism. A braid-winding method has been used to produce stacked overwound braid layup [(±45°/0°)5/90°4]T. Influence of stacking sequence on premature failure of hoop layers has been reported. Under tensile loading, a cross-ply composite tube with the alternate stacking of hoop and axial fibre show hoop plies splitting similar to the overwound braided composite tube. However, splitting has been restricted by the surrounding axial plies and contained between the adjacent axial fibre tows. This observation suggests hoop layers sandwiched between braid layers will improve structural integrity. A near net shape architecture with three fibre orientation in a triaxial braid will provide additional support to prevent extensive damage for plies loaded in off-axis. Several notable observations for relatively open braid structures such as tow scissoring, high Poisson's ratio and influence of axial tow crimp on the strain to failure have been reported. Digital Image Correlation (DIC) in conjunction with surface strain gauging has been employed to capture the strain pattern.

Failure analysis in the identification of synergies between cleaning monitoring methods.

PubMed

Whiteley, Greg S; Derry, Chris; Glasbey, Trevor

2015-02-01

The 4 monitoring methods used to manage the quality assurance of cleaning outcomes within health care settings are visual inspection, microbial recovery, fluorescent marker assessment, and rapid ATP bioluminometry. These methods each generate different types of information, presenting a challenge to the successful integration of monitoring results. A systematic approach to safety and quality control can be used to interrogate the known qualities of cleaning monitoring methods and provide a prospective management tool for infection control professionals. We investigated the use of failure mode and effects analysis (FMEA) for measuring failure risk arising through each cleaning monitoring method. FMEA uses existing data in a structured risk assessment tool that identifies weaknesses in products or processes. Our FMEA approach used the literature and a small experienced team to construct a series of analyses to investigate the cleaning monitoring methods in a way that minimized identified failure risks. FMEA applied to each of the cleaning monitoring methods revealed failure modes for each. The combined use of cleaning monitoring methods in sequence is preferable to their use in isolation. When these 4 cleaning monitoring methods are used in combination in a logical sequence, the failure modes noted for any 1 can be complemented by the strengths of the alternatives, thereby circumventing the risk of failure of any individual cleaning monitoring method. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

[Influence of "prehistory" of sequential movements of the right and the left hand on reproduction: coding of positions, movements and sequence structure].

PubMed

Bobrova, E V; Liakhovetskiĭ, V A; Borshchevskaia, E R

2011-01-01

The dependence of errors during reproduction of a sequence of hand movements without visual feedback on the previous right- and left-hand performance ("prehistory") and on positions in space of sequence elements (random or ordered by the explicit rule) was analyzed. It was shown that the preceding information about the ordered positions of the sequence elements was used during right-hand movements, whereas left-hand movements were performed with involvement of the information about the random sequence. The data testify to a central mechanism of the analysis of spatial structure of sequence elements. This mechanism activates movement coding specific for the left hemisphere (vector coding) in case of an ordered sequence structure and positional coding specific for the right hemisphere in case of a random sequence structure.

StralSV: assessment of sequence variability within similar 3D structures and application to polio RNA-dependent RNA polymerase.

PubMed

Zemla, Adam T; Lang, Dorothy M; Kostova, Tanya; Andino, Raul; Ecale Zhou, Carol L

2011-06-02

Most of the currently used methods for protein function prediction rely on sequence-based comparisons between a query protein and those for which a functional annotation is provided. A serious limitation of sequence similarity-based approaches for identifying residue conservation among proteins is the low confidence in assigning residue-residue correspondences among proteins when the level of sequence identity between the compared proteins is poor. Multiple sequence alignment methods are more satisfactory--still, they cannot provide reliable results at low levels of sequence identity. Our goal in the current work was to develop an algorithm that could help overcome these difficulties by facilitating the identification of structurally (and possibly functionally) relevant residue-residue correspondences between compared protein structures. Here we present StralSV (structure-alignment sequence variability), a new algorithm for detecting closely related structure fragments and quantifying residue frequency from tight local structure alignments. We apply StralSV in a study of the RNA-dependent RNA polymerase of poliovirus, and we demonstrate that the algorithm can be used to determine regions of the protein that are relatively unique, or that share structural similarity with proteins that would be considered distantly related. By quantifying residue frequencies among many residue-residue pairs extracted from local structural alignments, one can infer potential structural or functional importance of specific residues that are determined to be highly conserved or that deviate from a consensus. We further demonstrate that considerable detailed structural and phylogenetic information can be derived from StralSV analyses. StralSV is a new structure-based algorithm for identifying and aligning structure fragments that have similarity to a reference protein. StralSV analysis can be used to quantify residue-residue correspondences and identify residues that may be of particular structural or functional importance, as well as unusual or unexpected residues at a given sequence position. StralSV is provided as a web service at http://proteinmodel.org/AS2TS/STRALSV/.

Evolutionarily conserved regions and hydrophobic contacts at the superfamily level: The case of the fold-type I, pyridoxal-5′-phosphate-dependent enzymes

PubMed Central

Paiardini, Alessandro; Bossa, Francesco; Pascarella, Stefano

2004-01-01

The wealth of biological information provided by structural and genomic projects opens new prospects of understanding life and evolution at the molecular level. In this work, it is shown how computational approaches can be exploited to pinpoint protein structural features that remain invariant upon long evolutionary periods in the fold-type I, PLP-dependent enzymes. A nonredundant set of 23 superposed crystallographic structures belonging to this superfamily was built. Members of this family typically display high-structural conservation despite low-sequence identity. For each structure, a multiple-sequence alignment of orthologous sequences was obtained, and the 23 alignments were merged using the structural information to obtain a comprehensive multiple alignment of 921 sequences of fold-type I enzymes. The structurally conserved regions (SCRs), the evolutionarily conserved residues, and the conserved hydrophobic contacts (CHCs) were extracted from this data set, using both sequence and structural information. The results of this study identified a structural pattern of hydrophobic contacts shared by all of the superfamily members of fold-type I enzymes and involved in native interactions. This profile highlights the presence of a nucleus for this fold, in which residues participating in the most conserved native interactions exhibit preferential evolutionary conservation, that correlates significantly (r = 0.70) with the extent of mean hydrophobic contact value of their apolar fraction. PMID:15498941

Register of experts for information on mechanics of structural failure

NASA Technical Reports Server (NTRS)

Carpenter, J. L., Jr.; Moya, N.

1973-01-01

A list of approximately 150 experts from approximately 60 organizations who have published results of theoretical and/or experimental research related to six problem areas in the mechanics of structural failure is presented. Each author included is listed by organizational affiliation, address and principal field of expertise. The initial criteria for the selection of names for the register are recent contributions to the literature, participation in or support of relevant research programs, and referral by peers. The purpose of the register is to present, in easy reference form, sources for dependable information regarding failure modes and mechanisms of aerospace structures. The Register includes two indexes: an alphabetical listing of the experts and an alphabetical listing of the organizations with whom they are affiliated.

Sequence periodicity in nucleosomal DNA and intrinsic curvature.

PubMed

Nair, T Murlidharan

2010-05-17

Most eukaryotic DNA contained in the nucleus is packaged by wrapping DNA around histone octamers. Histones are ubiquitous and bind most regions of chromosomal DNA. In order to achieve smooth wrapping of the DNA around the histone octamer, the DNA duplex should be able to deform and should possess intrinsic curvature. The deformability of DNA is a result of the non-parallelness of base pair stacks. The stacking interaction between base pairs is sequence dependent. The higher the stacking energy the more rigid the DNA helix, thus it is natural to expect that sequences that are involved in wrapping around the histone octamer should be unstacked and possess intrinsic curvature. Intrinsic curvature has been shown to be dictated by the periodic recurrence of certain dinucleotides. Several genome-wide studies directed towards mapping of nucleosome positions have revealed periodicity associated with certain stretches of sequences. In the current study, these sequences have been analyzed with a view to understand their sequence-dependent structures. Higher order DNA structures and the distribution of molecular bend loci associated with 146 base nucleosome core DNA sequence from C. elegans and chicken have been analyzed using the theoretical model for DNA curvature. The curvature dispersion calculated by cyclically permuting the sequences revealed that the molecular bend loci were delocalized throughout the nucleosome core region and had varying degrees of intrinsic curvature. The higher order structures associated with nucleosomes of C.elegans and chicken calculated from the sequences revealed heterogeneity with respect to the deviation of the DNA axis. The results points to the possibility of context dependent curvature of varying degrees to be associated with nucleosomal DNA.

Detection of nucleic acid sequences by invader-directed cleavage

DOEpatents

Brow, Mary Ann D.; Hall, Jeff Steven Grotelueschen; Lyamichev, Victor; Olive, David Michael; Prudent, James Robert

1999-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The 5' nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof. The present invention further relates to methods and devices for the separation of nucleic acid molecules based by charge.

Sequence-Dependent Structure/Function Relationships of Catalytic Peptide-Enabled Gold Nanoparticles Generated under Ambient Synthetic Conditions.

PubMed

Bedford, Nicholas M; Hughes, Zak E; Tang, Zhenghua; Li, Yue; Briggs, Beverly D; Ren, Yang; Swihart, Mark T; Petkov, Valeri G; Naik, Rajesh R; Knecht, Marc R; Walsh, Tiffany R

2016-01-20

Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction data and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancement.

Evaluation of a Multi-Axial, Temperature, and Time Dependent (MATT) Failure Model

NASA Technical Reports Server (NTRS)

Richardson, D. E.; Anderson, G. L.; Macon, D. J.; Rudolphi, Michael (Technical Monitor)

2002-01-01

To obtain a better understanding the response of the structural adhesives used in the Space Shuttle's Reusable Solid Rocket Motor (RSRM) nozzle, an extensive effort has been conducted to characterize in detail the failure properties of these adhesives. This effort involved the development of a failure model that includes the effects of multi-axial loading, temperature, and time. An understanding of the effects of these parameters on the failure of the adhesive is crucial to the understanding and prediction of the safety of the RSRM nozzle. This paper documents the use of this newly developed multi-axial, temperature, and time (MATT) dependent failure model for modeling failure for the adhesives TIGA 321, EA913NA, and EA946. The development of the mathematical failure model using constant load rate normal and shear test data is presented. Verification of the accuracy of the failure model is shown through comparisons between predictions and measured creep and multi-axial failure data. The verification indicates that the failure model performs well for a wide range of conditions (loading, temperature, and time) for the three adhesives. The failure criterion is shown to be accurate through the glass transition for the adhesive EA946. Though this failure model has been developed and evaluated with adhesives, the concepts are applicable for other isotropic materials.

Influence of Finite Element Size in Residual Strength Prediction of Composite Structures

NASA Technical Reports Server (NTRS)

Satyanarayana, Arunkumar; Bogert, Philip B.; Karayev, Kazbek Z.; Nordman, Paul S.; Razi, Hamid

2012-01-01

The sensitivity of failure load to the element size used in a progressive failure analysis (PFA) of carbon composite center notched laminates is evaluated. The sensitivity study employs a PFA methodology previously developed by the authors consisting of Hashin-Rotem intra-laminar fiber and matrix failure criteria and a complete stress degradation scheme for damage simulation. The approach is implemented with a user defined subroutine in the ABAQUS/Explicit finite element package. The effect of element size near the notch tips on residual strength predictions was assessed for a brittle failure mode with a parametric study that included three laminates of varying material system, thickness and stacking sequence. The study resulted in the selection of an element size of 0.09 in. X 0.09 in., which was later used for predicting crack paths and failure loads in sandwich panels and monolithic laminated panels. Comparison of predicted crack paths and failure loads for these panels agreed well with experimental observations. Additionally, the element size vs. normalized failure load relationship, determined in the parametric study, was used to evaluate strength-scaling factors for three different element sizes. The failure loads predicted with all three element sizes provided converged failure loads with respect to that corresponding with the 0.09 in. X 0.09 in. element size. Though preliminary in nature, the strength-scaling concept has the potential to greatly reduce the computational time required for PFA and can enable the analysis of large scale structural components where failure is dominated by fiber failure in tension.

A Markov chain model for reliability growth and decay

NASA Technical Reports Server (NTRS)

Siegrist, K.

1982-01-01

A mathematical model is developed to describe a complex system undergoing a sequence of trials in which there is interaction between the internal states of the system and the outcomes of the trials. For example, the model might describe a system undergoing testing that is redesigned after each failure. The basic assumptions for the model are that the state of the system after a trial depends probabilistically only on the state before the trial and on the outcome of the trial and that the outcome of a trial depends probabilistically only on the state of the system before the trial. It is shown that under these basic assumptions, the successive states form a Markov chain and the successive states and outcomes jointly form a Markov chain. General results are obtained for the transition probabilities, steady-state distributions, etc. A special case studied in detail describes a system that has two possible state ('repaired' and 'unrepaired') undergoing trials that have three possible outcomes ('inherent failure', 'assignable-cause' 'failure' and 'success'). For this model, the reliability function is computed explicitly and an optimal repair policy is obtained.

Burst pressure investigation of filament wound type IV composite pressure vessel

NASA Astrophysics Data System (ADS)

Farhood, Naseer H.; Karuppanan, Saravanan; Ya, H. H.; Baharom, Mohamad Ariff

2017-12-01

Currently, composite pressure vessels (PVs) are employed in many industries such as aerospace, transportations, medical etc. Basically, the use of PVs in automotive application as a compressed natural gas (CNG) storage cylinder has been growing rapidly. Burst failure due to the laminate failure is the most critical failure mechanism for composite pressure vessels. It is predominantly caused by excessive internal pressure due to an overfilling or an overheating. In order to reduce fabrication difficulties and increase the structural efficiency, researches and studies are conducted continuously towards the proper selection of vessel design parameters. Hence, this paper is focused on the prediction of first ply failure pressure for such vessels utilizing finite element simulation based on Tsai-Wu and maximum stress failure criterions. The effects of laminate stacking sequence and orientation angle on the burst pressure were investigated in this work for a constant layered thickness PV. Two types of winding design, A [90°2/∓θ16/90°2] and B [90°2/∓θ]ns with different orientations of helical winding reinforcement were analyzed for carbon/epoxy composite material. It was found that laminate A sustained a maximum burst pressure of 55 MPa for a sequence of [90°2/∓15°16/90°2] while the laminate B returned a maximum burst pressure of 45 MPa corresponding to a stacking sequence of [90°2/±15°/90°2/±15°/90°2/±15° ....] up to 20 layers for a constant vessel thickness. For verification, a comparison was done with the literature under similar conditions of analysis and good agreement was achieved with a maximum difference of 4% and 10% for symmetrical and unsymmetrical layout, respectively.

Uncertainty and Intelligence in Computational Stochastic Mechanics

NASA Technical Reports Server (NTRS)

Ayyub, Bilal M.

1996-01-01

Classical structural reliability assessment techniques are based on precise and crisp (sharp) definitions of failure and non-failure (survival) of a structure in meeting a set of strength, function and serviceability criteria. These definitions are provided in the form of performance functions and limit state equations. Thus, the criteria provide a dichotomous definition of what real physical situations represent, in the form of abrupt change from structural survival to failure. However, based on observing the failure and survival of real structures according to the serviceability and strength criteria, the transition from a survival state to a failure state and from serviceability criteria to strength criteria are continuous and gradual rather than crisp and abrupt. That is, an entire spectrum of damage or failure levels (grades) is observed during the transition to total collapse. In the process, serviceability criteria are gradually violated with monotonically increasing level of violation, and progressively lead into the strength criteria violation. Classical structural reliability methods correctly and adequately include the ambiguity sources of uncertainty (physical randomness, statistical and modeling uncertainty) by varying amounts. However, they are unable to adequately incorporate the presence of a damage spectrum, and do not consider in their mathematical framework any sources of uncertainty of the vagueness type. Vagueness can be attributed to sources of fuzziness, unclearness, indistinctiveness, sharplessness and grayness; whereas ambiguity can be attributed to nonspecificity, one-to-many relations, variety, generality, diversity and divergence. Using the nomenclature of structural reliability, vagueness and ambiguity can be accounted for in the form of realistic delineation of structural damage based on subjective judgment of engineers. For situations that require decisions under uncertainty with cost/benefit objectives, the risk of failure should depend on the underlying level of damage and the uncertainties associated with its definition. A mathematical model for structural reliability assessment that includes both ambiguity and vagueness types of uncertainty was suggested to result in the likelihood of failure over a damage spectrum. The resulting structural reliability estimates properly represent the continuous transition from serviceability to strength limit states over the ultimate time exposure of the structure. In this section, a structural reliability assessment method based on a fuzzy definition of failure is suggested to meet these practical needs. A failure definition can be developed to indicate the relationship between failure level and structural response. In this fuzzy model, a subjective index is introduced to represent all levels of damage (or failure). This index can be interpreted as either a measure of failure level or a measure of a degree of belief in the occurrence of some performance condition (e.g., failure). The index allows expressing the transition state between complete survival and complete failure for some structural response based on subjective evaluation and judgment.

Escherichia coli DNA polymerase I can disrupt G-quadruplex structures during DNA replication.

PubMed

Teng, Fang-Yuan; Hou, Xi-Miao; Fan, San-Hong; Rety, Stephane; Dou, Shuo-Xing; Xi, Xu-Guang

2017-12-01

Non-canonical four-stranded G-quadruplex (G4) DNA structures can form in G-rich sequences that are widely distributed throughout the genome. The presence of G4 structures can impair DNA replication by hindering the progress of replicative polymerases (Pols), and failure to resolve these structures can lead to genetic instability. In the present study, we combined different approaches to address the question of whether and how Escherichia coli Pol I resolves G4 obstacles during DNA replication and/or repair. We found that E. coli Pol I-catalyzed DNA synthesis could be arrested by G4 structures at low protein concentrations and the degree of inhibition was strongly dependent on the stability of the G4 structures. Interestingly, at high protein concentrations, E. coli Pol I was able to overcome some kinds of G4 obstacles without the involvement of other molecules and could achieve complete replication of G4 DNA. Mechanistic studies suggested that multiple Pol I proteins might be implicated in G4 unfolding, and the disruption of G4 structures requires energy derived from dNTP hydrolysis. The present work not only reveals an unrealized function of E. coli Pol I, but also presents a possible mechanism by which G4 structures can be resolved during DNA replication and/or repair in E. coli. © 2017 Federation of European Biochemical Societies.

Progressive failure site generation in AlGaN/GaN high electron mobility transistors under OFF-state stress: Weibull statistics and temperature dependence

NASA Astrophysics Data System (ADS)

Sun, Huarui; Bajo, Miguel Montes; Uren, Michael J.; Kuball, Martin

2015-01-01

Gate leakage degradation of AlGaN/GaN high electron mobility transistors under OFF-state stress is investigated using a combination of electrical, optical, and surface morphology characterizations. The generation of leakage "hot spots" at the edge of the gate is found to be strongly temperature accelerated. The time for the formation of each failure site follows a Weibull distribution with a shape parameter in the range of 0.7-0.9 from room temperature up to 120 °C. The average leakage per failure site is only weakly temperature dependent. The stress-induced structural degradation at the leakage sites exhibits a temperature dependence in the surface morphology, which is consistent with a surface defect generation process involving temperature-associated changes in the breakdown sites.

Flight Test of an Adaptive Controller and Simulated Failure/Damage on the NASA NF-15B

NASA Technical Reports Server (NTRS)

Buschbacher, Mark; Maliska, Heather

2006-01-01

The method of flight-testing the Intelligent Flight Control System (IFCS) Second Generation (Gen-2) project on the NASA NF-15B is herein described. The Gen-2 project objective includes flight-testing a dynamic inversion controller augmented by a direct adaptive neural network to demonstrate performance improvements in the presence of simulated failure/damage. The Gen-2 objectives as implemented on the NASA NF-15B created challenges for software design, structural loading limitations, and flight test operations. Simulated failure/damage is introduced by modifying control surface commands, therefore requiring structural loads measurements. Flight-testing began with the validation of a structural loads model. Flight-testing of the Gen-2 controller continued, using test maneuvers designed in a sequenced approach. Success would clear the new controller with respect to dynamic response, simulated failure/damage, and with adaptation on and off. A handling qualities evaluation was conducted on the capability of the Gen-2 controller to restore aircraft response in the presence of a simulated failure/damage. Control room monitoring of loads sensors, flight dynamics, and controller adaptation, in addition to postflight data comparison to the simulation, ensured a safe methodology of buildup testing. Flight-testing continued without major incident to accomplish the project objectives, successfully uncovering strengths and weaknesses of the Gen-2 control approach in flight.

StralSV: assessment of sequence variability within similar 3D structures and application to polio RNA-dependent RNA polymerase

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

Zemla, A; Lang, D; Kostova, T

2010-11-29

Most of the currently used methods for protein function prediction rely on sequence-based comparisons between a query protein and those for which a functional annotation is provided. A serious limitation of sequence similarity-based approaches for identifying residue conservation among proteins is the low confidence in assigning residue-residue correspondences among proteins when the level of sequence identity between the compared proteins is poor. Multiple sequence alignment methods are more satisfactory - still, they cannot provide reliable results at low levels of sequence identity. Our goal in the current work was to develop an algorithm that could overcome these difficulties and facilitatemore » the identification of structurally (and possibly functionally) relevant residue-residue correspondences between compared protein structures. Here we present StralSV, a new algorithm for detecting closely related structure fragments and quantifying residue frequency from tight local structure alignments. We apply StralSV in a study of the RNA-dependent RNA polymerase of poliovirus and demonstrate that the algorithm can be used to determine regions of the protein that are relatively unique or that shared structural similarity with structures that are distantly related. By quantifying residue frequencies among many residue-residue pairs extracted from local alignments, one can infer potential structural or functional importance of specific residues that are determined to be highly conserved or that deviate from a consensus. We further demonstrate that considerable detailed structural and phylogenetic information can be derived from StralSV analyses. StralSV is a new structure-based algorithm for identifying and aligning structure fragments that have similarity to a reference protein. StralSV analysis can be used to quantify residue-residue correspondences and identify residues that may be of particular structural or functional importance, as well as unusual or unexpected residues at a given sequence position.« less

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure.

PubMed

Guo, Cathy A; Guo, Shaodong

2017-06-01

The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function. © 2017 Society for Endocrinology.

Sequencing of Dust Filter Production Process Using Design Structure Matrix (DSM)

NASA Astrophysics Data System (ADS)

Sari, R. M.; Matondang, A. R.; Syahputri, K.; Anizar; Siregar, I.; Rizkya, I.; Ursula, C.

2018-01-01

Metal casting company produces machinery spare part for manufactures. One of the product produced is dust filter. Most of palm oil mill used this product. Since it is used in most of palm oil mill, company often have problems to address this product. One of problem is the disordered of production process. It carried out by the job sequencing. The important job that should be solved first, least implement, while less important job and could be completed later, implemented first. Design Structure Matrix (DSM) used to analyse and determine priorities in the production process. DSM analysis is sort of production process through dependency sequencing. The result of dependency sequences shows the sequence process according to the inter-process linkage considering before and after activities. Finally, it demonstrates their activities to the coupled activities for metal smelting, refining, grinding, cutting container castings, metal expenditure of molds, metal casting, coating processes, and manufacture of molds of sand.

Numerical simulation of the fatigue behavior of additive manufactured titanium porous lattice structures.

PubMed

Zargarian, A; Esfahanian, M; Kadkhodapour, J; Ziaei-Rad, S

2016-03-01

In this paper, the effects of cell geometry and relative density on the high-cycle fatigue behavior of Titanium scaffolds produced by selective laser melting and electron beam melting techniques were numerically investigated by finite element analysis. The regular titanium lattice samples with three different unit cell geometries, namely, diamond, rhombic dodecahedron and truncated cuboctahedron, and the relative density range of 0.1-0.3 were analyzed under uniaxial cyclic compressive loading. A failure event based algorithm was employed to simulate fatigue failure in the cellular material. Stress-life approach was used to model fatigue failure of both bulk (struts) and cellular material. The predicted fatigue life and the damage pattern of all three structures were found to be in good agreement with the experimental fatigue investigations published in the literature. The results also showed that the relationship between fatigue strength and cycles to failure obeyed the power law. The coefficient of power function was shown to depend on relative density, geometry and fatigue properties of the bulk material while the exponent was only dependent on the fatigue behavior of the bulk material. The results also indicated the failure surface at an angle of 45° to the loading direction. Copyright © 2015 Elsevier B.V. All rights reserved.

Structure and energetic basis of overrepresented λ light chain in systemic light chain amyloidosis patients.

PubMed

Zhao, Jun; Zhang, Baohong; Zhu, Jianwei; Nussinov, Ruth; Ma, Buyong

2018-06-01

Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the κ light-chain is dominant (λ/κ=1:2) in healthy individuals, λ is highly overrepresented (λ/κ=3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that λ light-chains prefer misfolded dimer conformation, while κ chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. Copyright © 2017 Elsevier B.V. All rights reserved.

Sequence periodicity in nucleosomal DNA and intrinsic curvature

PubMed Central

2010-01-01

Background Most eukaryotic DNA contained in the nucleus is packaged by wrapping DNA around histone octamers. Histones are ubiquitous and bind most regions of chromosomal DNA. In order to achieve smooth wrapping of the DNA around the histone octamer, the DNA duplex should be able to deform and should possess intrinsic curvature. The deformability of DNA is a result of the non-parallelness of base pair stacks. The stacking interaction between base pairs is sequence dependent. The higher the stacking energy the more rigid the DNA helix, thus it is natural to expect that sequences that are involved in wrapping around the histone octamer should be unstacked and possess intrinsic curvature. Intrinsic curvature has been shown to be dictated by the periodic recurrence of certain dinucleotides. Several genome-wide studies directed towards mapping of nucleosome positions have revealed periodicity associated with certain stretches of sequences. In the current study, these sequences have been analyzed with a view to understand their sequence-dependent structures. Results Higher order DNA structures and the distribution of molecular bend loci associated with 146 base nucleosome core DNA sequence from C. elegans and chicken have been analyzed using the theoretical model for DNA curvature. The curvature dispersion calculated by cyclically permuting the sequences revealed that the molecular bend loci were delocalized throughout the nucleosome core region and had varying degrees of intrinsic curvature. Conclusions The higher order structures associated with nucleosomes of C.elegans and chicken calculated from the sequences revealed heterogeneity with respect to the deviation of the DNA axis. The results points to the possibility of context dependent curvature of varying degrees to be associated with nucleosomal DNA. PMID:20487515

Sequence-Dependent Structure/Function Relationships of Catalytic Peptide-Enabled Gold Nanoparticles Generated under Ambient Synthetic Conditions

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

Bedford, Nicholas M.; Hughes, Zak E.; Tang, Zhenghua

Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction datamore » and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancement.« less

NMR studies on the structure and dynamics of lac operator DNA

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

Lee, S.C.

Nuclear Magnetic Resonance spectroscopy was used to elucidate the relationships between structure, dynamics and function of the gene regulatory sequence corresponding to the lactose operon operator of Escherichia coli. The length of the DNA fragments examined varied from 13 to 36 base pair, containing all or part of the operator sequence. These DNA fragments are either derived genetically or synthesized chemically. Resonances of the imino protons were assigned by one dimensional inter-base pair nuclear Overhauser enhancement (NOE) measurements. Imino proton exchange rates were measured by saturation recovery methods. Results from the kinetic measurements show an interesting dynamic heterogeneity with amore » maximum opening rate centered about a GTG/CAC sequence which correlates with the biological function of the operator DNA. This particular three base pair sequence occurs frequently and often symmetrically in prokaryotic nd eukaryotic DNA sites where one anticipates specific protein interaction for gene regulation. The observed sequence dependent imino proton exchange rate may be a reflection of variation of the local structure of regulatory DNA. The results also indicate that the observed imino proton exchange rates are length dependent.« less

Register of experts for information on mechanics of structural failure

NASA Technical Reports Server (NTRS)

Carpenter, J. L., Jr.; Stuhrke, W. F.

1975-01-01

This register is comprised of a list of approximately 300 experts from approximately 90 organizations who have published results of theoretical and/or experimental research related to six problem areas in the mechanics of structural failure: (1) life prediction for structural materials, (2) fracture toughness testing, (3) fracture mechanics analysis; (4) hydrogen embrittlement; (5) protective coatings; and (6) composite materials. The criteria for the selection of names for the register are recent contributions to the literature, participation in or support of relevant research programs, and referral by peers. Each author included is listed by organizational affiliation, address, and principal field of expertise. The purpose of the register is to present, in easy reference form, sources for dependable information regarding failure modes and mechanisms of aerospace structures. The register includes two indexes; an alphabetical listing of the experts and an alphabetical listing of the organizations with whom they are affiliated.

Membrane raft association is a determinant of plasma membrane localization.

PubMed

Diaz-Rohrer, Blanca B; Levental, Kandice R; Simons, Kai; Levental, Ilya

2014-06-10

The lipid raft hypothesis proposes lateral domains driven by preferential interactions between sterols, sphingolipids, and specific proteins as a central mechanism for the regulation of membrane structure and function; however, experimental limitations in defining raft composition and properties have prevented unequivocal demonstration of their functional relevance. Here, we establish a quantitative, functional relationship between raft association and subcellular protein sorting. By systematic mutation of the transmembrane and juxtamembrane domains of a model transmembrane protein, linker for activation of T-cells (LAT), we generated a panel of variants possessing a range of raft affinities. These mutations revealed palmitoylation, transmembrane domain length, and transmembrane sequence to be critical determinants of membrane raft association. Moreover, plasma membrane (PM) localization was strictly dependent on raft partitioning across the entire panel of unrelated mutants, suggesting that raft association is necessary and sufficient for PM sorting of LAT. Abrogation of raft partitioning led to mistargeting to late endosomes/lysosomes because of a failure to recycle from early endosomes. These findings identify structural determinants of raft association and validate lipid-driven domain formation as a mechanism for endosomal protein sorting.

Membrane raft association is a determinant of plasma membrane localization

PubMed Central

Diaz-Rohrer, Blanca B.; Levental, Kandice R.; Simons, Kai; Levental, Ilya

2014-01-01

The lipid raft hypothesis proposes lateral domains driven by preferential interactions between sterols, sphingolipids, and specific proteins as a central mechanism for the regulation of membrane structure and function; however, experimental limitations in defining raft composition and properties have prevented unequivocal demonstration of their functional relevance. Here, we establish a quantitative, functional relationship between raft association and subcellular protein sorting. By systematic mutation of the transmembrane and juxtamembrane domains of a model transmembrane protein, linker for activation of T-cells (LAT), we generated a panel of variants possessing a range of raft affinities. These mutations revealed palmitoylation, transmembrane domain length, and transmembrane sequence to be critical determinants of membrane raft association. Moreover, plasma membrane (PM) localization was strictly dependent on raft partitioning across the entire panel of unrelated mutants, suggesting that raft association is necessary and sufficient for PM sorting of LAT. Abrogation of raft partitioning led to mistargeting to late endosomes/lysosomes because of a failure to recycle from early endosomes. These findings identify structural determinants of raft association and validate lipid-driven domain formation as a mechanism for endosomal protein sorting. PMID:24912166

Sequence-similar, structure-dissimilar protein pairs in the PDB.

PubMed

Kosloff, Mickey; Kolodny, Rachel

2008-05-01

It is often assumed that in the Protein Data Bank (PDB), two proteins with similar sequences will also have similar structures. Accordingly, it has proved useful to develop subsets of the PDB from which "redundant" structures have been removed, based on a sequence-based criterion for similarity. Similarly, when predicting protein structure using homology modeling, if a template structure for modeling a target sequence is selected by sequence alone, this implicitly assumes that all sequence-similar templates are equivalent. Here, we show that this assumption is often not correct and that standard approaches to create subsets of the PDB can lead to the loss of structurally and functionally important information. We have carried out sequence-based structural superpositions and geometry-based structural alignments of a large number of protein pairs to determine the extent to which sequence similarity ensures structural similarity. We find many examples where two proteins that are similar in sequence have structures that differ significantly from one another. The source of the structural differences usually has a functional basis. The number of such proteins pairs that are identified and the magnitude of the dissimilarity depend on the approach that is used to calculate the differences; in particular sequence-based structure superpositioning will identify a larger number of structurally dissimilar pairs than geometry-based structural alignments. When two sequences can be aligned in a statistically meaningful way, sequence-based structural superpositioning provides a meaningful measure of structural differences. This approach and geometry-based structure alignments reveal somewhat different information and one or the other might be preferable in a given application. Our results suggest that in some cases, notably homology modeling, the common use of nonredundant datasets, culled from the PDB based on sequence, may mask important structural and functional information. We have established a data base of sequence-similar, structurally dissimilar protein pairs that will help address this problem (http://luna.bioc.columbia.edu/rachel/seqsimstrdiff.htm).

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

Fedorenko, V.K.; Sergeev, V.V.; Shkanov, I.N.

The influence of the structural, phase, and size factors, and the bonding of hard tungsten alloys to titanium alloy bases on the mechanism by which the system fails under alternating loads is studied. The failure mechanism of materials with detonation coatings applied by different methods is discussed in regard to the classical sequence of fatigue phenomena, i.e., hardening-softening and crack nucleation and growth.

Progressive failure site generation in AlGaN/GaN high electron mobility transistors under OFF-state stress: Weibull statistics and temperature dependence

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

Sun, Huarui, E-mail: huarui.sun@bristol.ac.uk; Bajo, Miguel Montes; Uren, Michael J.

2015-01-26

Gate leakage degradation of AlGaN/GaN high electron mobility transistors under OFF-state stress is investigated using a combination of electrical, optical, and surface morphology characterizations. The generation of leakage “hot spots” at the edge of the gate is found to be strongly temperature accelerated. The time for the formation of each failure site follows a Weibull distribution with a shape parameter in the range of 0.7–0.9 from room temperature up to 120 °C. The average leakage per failure site is only weakly temperature dependent. The stress-induced structural degradation at the leakage sites exhibits a temperature dependence in the surface morphology, which ismore » consistent with a surface defect generation process involving temperature-associated changes in the breakdown sites.« less

Complex structural behavior of oligopurine-oligopyrimidine sequence cloned within the supercoiled plasmid.

PubMed Central

Parniewski, P; Galazka, G; Wilk, A; Klysik, J

1989-01-01

Synthetic sequence GATCC(AG)7ATCG(AT)4CG(AG)7 was cloned into plasmid and its structural behavior under the influence of supercoiling was analysed by chemical modification at variety of experimental conditions. It was found that this sequence adopts at least two different non-B conformations depending on -delta and pH values. Moreover, 12 nucleotide long non-pur.pyr spacer region separating two identical (AG)7 blocks does not provide a significant energy barrier protecting against unusual structures formation. Images PMID:2644622

Sequence-Mandated, Distinct Assembly of Giant Molecules

DOE PAGES

Zhang, Wei; Lu, Xinlin; Mao, Jialin; ...

2017-10-24

Although controlling the primary structure of synthetic polymers is itself a great challenge, the potential of sequence control for tailoring hierarchical structures remains to be exploited, especially in the creation of new and unconventional phases. A series of model amphiphilic chain-like giant molecules was designed and synthesized by interconnecting both hydrophobic and hydrophilic molecular nanoparticles in precisely defined sequence and composition to investigate their sequence-dependent phase structures. Not only compositional variation changed the self-assembled supramolecular phases, but also specific sequences induce unconventional phase formation, including Frank-Kasper phases. The formation mechanism was attributed to the conformational change driven by the collectivemore » hydrogen bonding and the sequence-mandated topology of the molecules. Lastly, these results show that sequence control in synthetic polymers can have a dramatic impact on polymer properties and self-assembly.« less

Sequence-Mandated, Distinct Assembly of Giant Molecules

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

Zhang, Wei; Lu, Xinlin; Mao, Jialin

Although controlling the primary structure of synthetic polymers is itself a great challenge, the potential of sequence control for tailoring hierarchical structures remains to be exploited, especially in the creation of new and unconventional phases. A series of model amphiphilic chain-like giant molecules was designed and synthesized by interconnecting both hydrophobic and hydrophilic molecular nanoparticles in precisely defined sequence and composition to investigate their sequence-dependent phase structures. Not only compositional variation changed the self-assembled supramolecular phases, but also specific sequences induce unconventional phase formation, including Frank-Kasper phases. The formation mechanism was attributed to the conformational change driven by the collectivemore » hydrogen bonding and the sequence-mandated topology of the molecules. Lastly, these results show that sequence control in synthetic polymers can have a dramatic impact on polymer properties and self-assembly.« less

Predicting PDZ domain mediated protein interactions from structure

PubMed Central

2013-01-01

Background PDZ domains are structural protein domains that recognize simple linear amino acid motifs, often at protein C-termini, and mediate protein-protein interactions (PPIs) in important biological processes, such as ion channel regulation, cell polarity and neural development. PDZ domain-peptide interaction predictors have been developed based on domain and peptide sequence information. Since domain structure is known to influence binding specificity, we hypothesized that structural information could be used to predict new interactions compared to sequence-based predictors. Results We developed a novel computational predictor of PDZ domain and C-terminal peptide interactions using a support vector machine trained with PDZ domain structure and peptide sequence information. Performance was estimated using extensive cross validation testing. We used the structure-based predictor to scan the human proteome for ligands of 218 PDZ domains and show that the predictions correspond to known PDZ domain-peptide interactions and PPIs in curated databases. The structure-based predictor is complementary to the sequence-based predictor, finding unique known and novel PPIs, and is less dependent on training–testing domain sequence similarity. We used a functional enrichment analysis of our hits to create a predicted map of PDZ domain biology. This map highlights PDZ domain involvement in diverse biological processes, some only found by the structure-based predictor. Based on this analysis, we predict novel PDZ domain involvement in xenobiotic metabolism and suggest new interactions for other processes including wound healing and Wnt signalling. Conclusions We built a structure-based predictor of PDZ domain-peptide interactions, which can be used to scan C-terminal proteomes for PDZ interactions. We also show that the structure-based predictor finds many known PDZ mediated PPIs in human that were not found by our previous sequence-based predictor and is less dependent on training–testing domain sequence similarity. Using both predictors, we defined a functional map of human PDZ domain biology and predict novel PDZ domain function. Users may access our structure-based and previous sequence-based predictors at http://webservice.baderlab.org/domains/POW. PMID:23336252

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

Dana L. Kelly

Typical engineering systems in applications with high failure consequences such as nuclear reactor plants often employ redundancy and diversity of equipment in an effort to lower the probability of failure and therefore risk. However, it has long been recognized that dependencies exist in these redundant and diverse systems. Some dependencies, such as common sources of electrical power, are typically captured in the logic structure of the risk model. Others, usually referred to as intercomponent dependencies, are treated implicitly by introducing one or more statistical parameters into the model. Such common-cause failure models have limitations in a simulation environment. In addition,more » substantial subjectivity is associated with parameter estimation for these models. This paper describes an approach in which system performance is simulated by drawing samples from the joint distributions of dependent variables. The approach relies on the notion of a copula distribution, a notion which has been employed by the actuarial community for ten years or more, but which has seen only limited application in technological risk assessment. The paper also illustrates how equipment failure data can be used in a Bayesian framework to estimate the parameter values in the copula model. This approach avoids much of the subjectivity required to estimate parameters in traditional common-cause failure models. Simulation examples are presented for failures in time. The open-source software package R is used to perform the simulations. The open-source software package WinBUGS is used to perform the Bayesian inference via Markov chain Monte Carlo sampling.« less

Streptococcal phosphoenolpyruvate-sugar phosphotransferase system: amino acid sequence and site of ATP-dependent phosphorylation of HPr

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

Deutscher, J.; Pevec, B.; Beyreuther, K.

1986-10-21

The amino acid sequence of histidine-containing protein (HPr) from Streptococcus faecalis has been determined by direct Edman degradation of intact HPr and by amino acid sequence analysis of tryptic peptides, V8 proteolyptic peptides, thermolytic peptides, and cyanogen bromide cleavage products. HPr from S. faecalis was found to contain 89 amino acid residues, corresponding to a molecular weight of 9438. The amino acid sequence of HPr from S. faecalis shows extended homology to the primary structure of HPr proteins from other bacteria. Besides the phosphoenolpyruvate-dependent phosphorylation of a histidyl residue in HPr, catalyzed by enzyme I of the bacterial phosphotransferase system,more » HPr was also found to be phosphorylated at a seryl residue in an ATP-dependent protein kinase catalyzed reaction. The site of ATP-dependent phosphorylation in HPr of S faecalis has now been determined. (/sup 32/P)P-Ser-HPr was digested with three different proteases, and in each case, a single labeled peptide was isolated. Following digestion with subtilisin, they obtained a peptide with the sequence -(P)Ser-Ile-Met-. Using chymotrypsin, they isolated a peptide with the sequence -Ser-Val-Asn-Leu-Lys-(P)Ser-Ile-Met-Gly-Val-Met-. The longest labeled peptide was obtained with V8 staphylococcal protease. According to amino acid analysis, this peptide contained 36 out of the 89 amino acid residues of HPr. The following sequence of 12 amino acid residues of the V8 peptide was determined: -Tyr-Lys-Gly-Lys-Ser-Val-Asn-Leu-Lys-(P)Ser-Ile-Met-. Thus, the site of ATP-dependent phosphorylation was determined to be Ser-46 within the primary structure of HPr.« less

Sequence-dependent DNA deformability studied using molecular dynamics simulations.

PubMed

Fujii, Satoshi; Kono, Hidetoshi; Takenaka, Shigeori; Go, Nobuhiro; Sarai, Akinori

2007-01-01

Proteins recognize specific DNA sequences not only through direct contact between amino acids and bases, but also indirectly based on the sequence-dependent conformation and deformability of the DNA (indirect readout). We used molecular dynamics simulations to analyze the sequence-dependent DNA conformations of all 136 possible tetrameric sequences sandwiched between CGCG sequences. The deformability of dimeric steps obtained by the simulations is consistent with that by the crystal structures. The simulation results further showed that the conformation and deformability of the tetramers can highly depend on the flanking base pairs. The conformations of xATx tetramers show the most rigidity and are not affected by the flanking base pairs and the xYRx show by contrast the greatest flexibility and change their conformations depending on the base pairs at both ends, suggesting tetramers with the same central dimer can show different deformabilities. These results suggest that analysis of dimeric steps alone may overlook some conformational features of DNA and provide insight into the mechanism of indirect readout during protein-DNA recognition. Moreover, the sequence dependence of DNA conformation and deformability may be used to estimate the contribution of indirect readout to the specificity of protein-DNA recognition as well as nucleosome positioning and large-scale behavior of nucleic acids.

Micromechanics Fatigue Damage Analysis Modeling for Fabric Reinforced Ceramic Matrix Composites

NASA Technical Reports Server (NTRS)

Min, J. B.; Xue, D.; Shi, Y.

2013-01-01

A micromechanics analysis modeling method was developed to analyze the damage progression and fatigue failure of fabric reinforced composite structures, especially for the brittle ceramic matrix material composites. A repeating unit cell concept of fabric reinforced composites was used to represent the global composite structure. The thermal and mechanical properties of the repeating unit cell were considered as the same as those of the global composite structure. The three-phase micromechanics, the shear-lag, and the continuum fracture mechanics models were integrated with a statistical model in the repeating unit cell to predict the progressive damages and fatigue life of the composite structures. The global structure failure was defined as the loss of loading capability of the repeating unit cell, which depends on the stiffness reduction due to material slice failures and nonlinear material properties in the repeating unit cell. The present methodology is demonstrated with the analysis results evaluated through the experimental test performed with carbon fiber reinforced silicon carbide matrix plain weave composite specimens.

A graphical language for reliability model generation

NASA Technical Reports Server (NTRS)

Howell, Sandra V.; Bavuso, Salvatore J.; Haley, Pamela J.

1990-01-01

A graphical interface capability of the hybrid automated reliability predictor (HARP) is described. The graphics-oriented (GO) module provides the user with a graphical language for modeling system failure modes through the selection of various fault tree gates, including sequence dependency gates, or by a Markov chain. With this graphical input language, a fault tree becomes a convenient notation for describing a system. In accounting for any sequence dependencies, HARP converts the fault-tree notation to a complex stochastic process that is reduced to a Markov chain which it can then solve for system reliability. The graphics capability is available for use on an IBM-compatible PC, a Sun, and a VAX workstation. The GO module is written in the C programming language and uses the Graphical Kernel System (GKS) standard for graphics implementation. The PC, VAX, and Sun versions of the HARP GO module are currently in beta-testing.

DAMP-Mediated Innate Immune Failure and Pneumonia after Trauma

DTIC Science & Technology

2017-10-01

Correlation Between Chemotaxis and Ca2+ release AUC ND6 ND3 ND4 ND5 COX1 6 similarity of amino acid sequences based upon their component residues. We used... correlation to chemotaxis studies. These findings give us confidence that our mechanistic studies in mice can be able be used translationally to...evaluated time-dependent changes in peripheral blood in trauma patients to identify changes correlated with infection. Methods: Total leukocytes were

Quantification of loading in biomechanical testing: the influence of dissection sequence.

PubMed

Funabashi, Martha; El-Rich, Marwan; Prasad, Narasimha; Kawchuk, Gregory N

2015-09-18

Sequential dissection is a technique used to investigate loads experienced by articular tissues. When the joint of interest is tested in an unconstrained manner, its kinematics change with each tissue removal. To address this limitation, sufficiently rigid robots are used to constrain joint kinematics. While this approach can quantify loads experienced by each tissue, it does not assure similar results when removal order is changed. Specifically, structure loading is assumed to be independent of removal order if the structure behaves linearly (i.e. principle of superposition applies), but dependent on removal order when response is affected by material and/or geometry nonlinearities and/or viscoelasticiy (e.g. biological tissues). Therefore, this experiment was conducted to evaluate if structure loading created through robotic testing is dependent on the order in which connectors are removed. Six identical models were 3D printed. Each model was composed of 2 rigid bodies and 3 connecting structures with nonlinear time-dependent behavior. To these models, pure rotations were applied about a predefined static center of rotation using a parallel robot. A unique dissection sequence was used for each of the six models and the same movements applied robotically after each dissection. When comparing the moments experienced by each structure between different removal sequences, a statistically significant difference (p<0.05) was observed. These results suggest that even in an optimized environment, the sequence in which nonlinear viscoelastic structures are removed influence model loading. These findings support prior work suggesting that tissue loads obtained from robotic testing are specific to removal order. Copyright © 2015 Elsevier Ltd. All rights reserved.

Algorithm to determine the percolation largest component in interconnected networks.

PubMed

Schneider, Christian M; Araújo, Nuno A M; Herrmann, Hans J

2013-04-01

Interconnected networks have been shown to be much more vulnerable to random and targeted failures than isolated ones, raising several interesting questions regarding the identification and mitigation of their risk. The paradigm to address these questions is the percolation model, where the resilience of the system is quantified by the dependence of the size of the largest cluster on the number of failures. Numerically, the major challenge is the identification of this cluster and the calculation of its size. Here, we propose an efficient algorithm to tackle this problem. We show that the algorithm scales as O(NlogN), where N is the number of nodes in the network, a significant improvement compared to O(N(2)) for a greedy algorithm, which permits studying much larger networks. Our new strategy can be applied to any network topology and distribution of interdependencies, as well as any sequence of failures.

Spatio-temporal propagation of cascading overload failures in spatially embedded networks

NASA Astrophysics Data System (ADS)

Zhao, Jichang; Li, Daqing; Sanhedrai, Hillel; Cohen, Reuven; Havlin, Shlomo

2016-01-01

Different from the direct contact in epidemics spread, overload failures propagate through hidden functional dependencies. Many studies focused on the critical conditions and catastrophic consequences of cascading failures. However, to understand the network vulnerability and mitigate the cascading overload failures, the knowledge of how the failures propagate in time and space is essential but still missing. Here we study the spatio-temporal propagation behaviour of cascading overload failures analytically and numerically on spatially embedded networks. The cascading overload failures are found to spread radially from the centre of the initial failure with an approximately constant velocity. The propagation velocity decreases with increasing tolerance, and can be well predicted by our theoretical framework with one single correction for all the tolerance values. This propagation velocity is found similar in various model networks and real network structures. Our findings may help to predict the dynamics of cascading overload failures in realistic systems.

Spatio-temporal propagation of cascading overload failures in spatially embedded networks

PubMed Central

Zhao, Jichang; Li, Daqing; Sanhedrai, Hillel; Cohen, Reuven; Havlin, Shlomo

2016-01-01

Different from the direct contact in epidemics spread, overload failures propagate through hidden functional dependencies. Many studies focused on the critical conditions and catastrophic consequences of cascading failures. However, to understand the network vulnerability and mitigate the cascading overload failures, the knowledge of how the failures propagate in time and space is essential but still missing. Here we study the spatio-temporal propagation behaviour of cascading overload failures analytically and numerically on spatially embedded networks. The cascading overload failures are found to spread radially from the centre of the initial failure with an approximately constant velocity. The propagation velocity decreases with increasing tolerance, and can be well predicted by our theoretical framework with one single correction for all the tolerance values. This propagation velocity is found similar in various model networks and real network structures. Our findings may help to predict the dynamics of cascading overload failures in realistic systems. PMID:26754065

Molecular phylogeny of 21 tropical bamboo species reconstructed by integrating non-coding internal transcribed spacer (ITS1 and 2) sequences and their consensus secondary structure.

PubMed

Ghosh, Jayadri Sekhar; Bhattacharya, Samik; Pal, Amita

2017-06-01

The unavailability of the reproductive structure and unpredictability of vegetative characters for the identification and phylogenetic study of bamboo prompted the application of molecular techniques for greater resolution and consensus. We first employed internal transcribed spacer (ITS1, 5.8S rRNA and ITS2) sequences to construct the phylogenetic tree of 21 tropical bamboo species. While the sequence alone could grossly reconstruct the traditional phylogeny amongst the 21-tropical species studied, some anomalies were encountered that prompted a further refinement of the phylogenetic analyses. Therefore, we integrated the secondary structure of the ITS sequences to derive individual sequence-structure matrix to gain more resolution on the phylogenetic reconstruction. The results showed that ITS sequence-structure is the reliable alternative to the conventional phenotypic method for the identification of bamboo species. The best-fit topology obtained by the sequence-structure based phylogeny over the sole sequence based one underscores closer clustering of all the studied Bambusa species (Sub-tribe Bambusinae), while Melocanna baccifera, which belongs to Sub-Tribe Melocanneae, disjointedly clustered as an out-group within the consensus phylogenetic tree. In this study, we demonstrated the dependability of the combined (ITS sequence+structure-based) approach over the only sequence-based analysis for phylogenetic relationship assessment of bamboo.

Loss of control air at Browns Ferry Unit One: accident sequence analysis

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

Harrington, R.M.; Hodge, S.A.

1986-04-01

This study describes the predicted response of the Browns Ferry Nuclear Plant to a postulated complete failure of plant control air. The failure of plant control air cascades to include the loss of drywell control air at Units 1 and 2. Nevertheless, this is a benign accident unless compounded by simultaneous failures in the turbine-driven high pressure injection systems. Accident sequence calculations are presented for Loss of Control Air sequences with assumed failure upon demand of the Reactor Core Isolation Cooling (RCIC) and the High Pressure Coolant Injection (HPCI) at Unit 1. Sequences with and without operator action are considered.more » Results show that the operators can prevent core uncovery if they take action to utilize the Control Rod Drive Hydraulic System as a backup high pressure injection system.« less

A Generative Angular Model of Protein Structure Evolution

PubMed Central

Golden, Michael; García-Portugués, Eduardo; Sørensen, Michael; Mardia, Kanti V.; Hamelryck, Thomas; Hein, Jotun

2017-01-01

Abstract Recently described stochastic models of protein evolution have demonstrated that the inclusion of structural information in addition to amino acid sequences leads to a more reliable estimation of evolutionary parameters. We present a generative, evolutionary model of protein structure and sequence that is valid on a local length scale. The model concerns the local dependencies between sequence and structure evolution in a pair of homologous proteins. The evolutionary trajectory between the two structures in the protein pair is treated as a random walk in dihedral angle space, which is modeled using a novel angular diffusion process on the two-dimensional torus. Coupling sequence and structure evolution in our model allows for modeling both “smooth” conformational changes and “catastrophic” conformational jumps, conditioned on the amino acid changes. The model has interpretable parameters and is comparatively more realistic than previous stochastic models, providing new insights into the relationship between sequence and structure evolution. For example, using the trained model we were able to identify an apparent sequence–structure evolutionary motif present in a large number of homologous protein pairs. The generative nature of our model enables us to evaluate its validity and its ability to simulate aspects of protein evolution conditioned on an amino acid sequence, a related amino acid sequence, a related structure or any combination thereof. PMID:28453724

3D FSE Cube and VIPR-aTR 3.0 Tesla magnetic resonance imaging predicts canine cranial cruciate ligament structural properties.

PubMed

Racette, Molly; Al saleh, Habib; Waller, Kenneth R; Bleedorn, Jason A; McCabe, Ronald P; Vanderby, Ray; Markel, Mark D; Brounts, Sabrina H; Block, Walter F; Muir, Peter

2016-03-01

Estimation of cranial cruciate ligament (CrCL) structural properties in client-owned dogs with incipient cruciate rupture would be advantageous. The objective of this study was to determine whether magnetic resonance imaging (MRI) measurement of normal CrCL volume in an ex-vivo canine model predicts structural properties. Stifles from eight dogs underwent 3.0 Tesla 3D MRI. CrCL volume and normalized median grayscale values were determined using 3D Fast Spin Echo (FSE) Cube and Vastly under-sampled Isotropic PRojection (VIPR)-alternative repetition time (aTR) sequences. Stifles were then mechanically tested. After joint laxity testing, CrCL structural properties were determined, including displacement at yield, yield load, load to failure, and stiffness. Yield load and load to failure (R(2)=0.56, P <0.01) were correlated with CrCL volume determined by VIPR-aTR. Yield load was also correlated with CrCL volume determined by 3D FSE Cube (R(2)=0.32, P <0.05). Structural properties were not related to median grayscale values. Joint laxity and CrCL stiffness were not related to MRI parameters, but displacement at yield load was related to CrCL volume for both sequences during testing (R(2)>0.57, P <0.005). In conclusion, 3D MRI offers a predictive method for estimating canine CrCL structural properties. 3D MRI may be useful for monitoring CrCL properties in clinical trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Functional specificity of a Hox protein mediated by the recognition of minor groove structure.

PubMed

Joshi, Rohit; Passner, Jonathan M; Rohs, Remo; Jain, Rinku; Sosinsky, Alona; Crickmore, Michael A; Jacob, Vinitha; Aggarwal, Aneel K; Honig, Barry; Mann, Richard S

2007-11-02

The recognition of specific DNA-binding sites by transcription factors is a critical yet poorly understood step in the control of gene expression. Members of the Hox family of transcription factors bind DNA by making nearly identical major groove contacts via the recognition helices of their homeodomains. In vivo specificity, however, often depends on extended and unstructured regions that link Hox homeodomains to a DNA-bound cofactor, Extradenticle (Exd). Using a combination of structure determination, computational analysis, and in vitro and in vivo assays, we show that Hox proteins recognize specific Hox-Exd binding sites via residues located in these extended regions that insert into the minor groove but only when presented with the correct DNA sequence. Our results suggest that these residues, which are conserved in a paralog-specific manner, confer specificity by recognizing a sequence-dependent DNA structure instead of directly reading a specific DNA sequence.

Fluorescent DNA-templated silver nanoclusters

NASA Astrophysics Data System (ADS)

Lin, Ruoqian

Because of the ultra-small size and biocompatibility of silver nanoclusters, they have attracted much research interest for their applications in biolabeling. Among the many ways of synthesizing silver nanoclusters, DNA templated method is particularly attractive---the high tunability of DNA sequences provides another degree of freedom for controlling the chemical and photophysical properties. However, systematic studies about how DNA sequences and concentrations are controlling the photophysical properties are still lacking. The aim of this thesis is to investigate the binding mechanisms of silver clusters binding and single stranded DNAs. Here in this thesis, we report synthesis and characterization of DNA-templated silver nanoclusters and provide a systematic interrogation of the effects of DNA concentrations and sequences, including lengths and secondary structures. We performed a series of syntheses utilizing five different sequences to explore the optimal synthesis condition. By characterizing samples with UV-vis and fluorescence spectroscopy, we achieved the most proper reactants ratio and synthesis conditions. Two of them were chosen for further concentration dependence studies and sequence dependence studies. We found that cytosine-rich sequences are more likely to produce silver nanoclusters with stronger fluorescence signals; however, sequences with hairpin secondary structures are more capable in stabilizing silver nanoclusters. In addition, the fluorescence peak emission intensities and wavelengths of the DNA templated silver clusters have sequence dependent fingerprints. This potentially can be applied to sequence sensing in the future. However all the current conclusions are not warranted; there is still difficulty in formulating general rules in DNA strand design and silver nanocluster production. Further investigation of more sequences could solve these questions in the future.

SMARTIV: combined sequence and structure de-novo motif discovery for in-vivo RNA binding data.

PubMed

Polishchuk, Maya; Paz, Inbal; Yakhini, Zohar; Mandel-Gutfreund, Yael

2018-05-25

Gene expression regulation is highly dependent on binding of RNA-binding proteins (RBPs) to their RNA targets. Growing evidence supports the notion that both RNA primary sequence and its local secondary structure play a role in specific Protein-RNA recognition and binding. Despite the great advance in high-throughput experimental methods for identifying sequence targets of RBPs, predicting the specific sequence and structure binding preferences of RBPs remains a major challenge. We present a novel webserver, SMARTIV, designed for discovering and visualizing combined RNA sequence and structure motifs from high-throughput RNA-binding data, generated from in-vivo experiments. The uniqueness of SMARTIV is that it predicts motifs from enriched k-mers that combine information from ranked RNA sequences and their predicted secondary structure, obtained using various folding methods. Consequently, SMARTIV generates Position Weight Matrices (PWMs) in a combined sequence and structure alphabet with assigned P-values. SMARTIV concisely represents the sequence and structure motif content as a single graphical logo, which is informative and easy for visual perception. SMARTIV was examined extensively on a variety of high-throughput binding experiments for RBPs from different families, generated from different technologies, showing consistent and accurate results. Finally, SMARTIV is a user-friendly webserver, highly efficient in run-time and freely accessible via http://smartiv.technion.ac.il/.

The molecular genetic makeup of acute lymphoblastic leukemia.

PubMed

Mullighan, Charles G

2012-01-01

Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.

Analysis of Tsunamigenic Coastal Rock Slope Failures Triggered by the 2007 Earthquake in the Chilean Fjordland

NASA Astrophysics Data System (ADS)

Sepulveda, S. A.; Serey, A.; Hermanns, R. L.; Redfield, T. F.; Oppikofer, T.; Duhart, P.

2011-12-01

The fjordland of the Chilean Patagonia is subject to active tectonics, with large magnitude subduction earthquakes, such as the M 9.5 1960 earthquake, and shallow crustal earthquakes along the regional Liquiñe-Ofqui Fault Zone (LOFZ). One of the latter (M 6.2) struck the Aysen Fjord region (45.5 S) on the 21st of April 2007, triggering dozens of landslides in the epicentral area along the fjord coast and surroundings. The largest rock slides and rock avalanches induced a local tsunami that together with debris flows caused ten fatalities and severely damaged several salmon farms, the most important economic activity of the area. Multi-scale studies of the landslides triggered during the Aysen earthquake have been carried out, including landslide mapping and classification, slope stability back-analyses and structural and geomorphological mapping of the largest failures from field surveys and high-resolution digital surface models created from terrestrial laser scanning. The failures included rock slides, rock avalanches, rock-soil slides, soil slides and debris flows. The largest rock avalanche had a volume of over 20 million cubic metres. The landslides affected steep slopes of intrusive rocks of the North Patagonian batholith covered by a thin layer of volcanic soils, which supports a high forest. The results of geotechnical analyses suggest a site effect due to topographic amplification on the generation of the landslides, with peak ground accelerations that may have reached between about 1.0 and 2.0 g for rock avalanches and between 0.6 and 1.0 g for shallow rock-soil slides, depending on the amount of assumed vertical acceleration and the applied method (limit equilibrium and Newmark). Attenuation relationships for shallow crustal seismicity indicate accelerations below 0.5 g for earthquakes of a similar magnitude and epicentral distances. Detailed field structural analyses of the largest rock avalanche in Punta Cola indicate a key role in the failure mechanics of brittle faults and jointing related to the LOFZ. The basal failure plane closely followed an older (epidote chlorite facies) thrust fault. Later fracture patterns suggest the thrust relaxed under gravitational stress following rock column uplift. Failure probably utilized a combination of these structures. Digital geomorphic models allowed establishing a sequence of events during failure which together make up the complex rock avalanche deposit. The volume of each individual slide could be more accurately determined. These and ongoing studies will allow a unique characterization of earthquake-induced slope failures in fjord coastal environments, providing new tools for landslide, seismic and tsunami hazard assessment in Patagonia and similar geomorphological settings around the world. This work was funded by Fondecyt project 11070107, the International Center for Geohazards, the Millenium Nucleus 'International Earthquake Research Center Montessus de Ballore', FNDR-Project 'Geological-Mining Environmental Research in Aysen' of the Chilean Government and the Andean Geothermal Center of Excellence.

The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+-dependent cell adhesion.

PubMed Central

Ringwald, M; Schuh, R; Vestweber, D; Eistetter, H; Lottspeich, F; Engel, J; Dölz, R; Jähnig, F; Epplen, J; Mayer, S

1987-01-01

We have determined the amino acid sequence of the Ca2+-dependent cell adhesion molecule uvomorulin as it appears on the cell surface. The extracellular part of the molecule exhibits three internally repeated domains of 112 residues which are most likely generated by gene duplication. Each of the repeated domains contains two highly conserved units which could represent putative Ca2+-binding sites. Secondary structure predictions suggest that the putative Ca2+-binding units are located in external loops at the surface of the protein. The protein sequence exhibits a single membrane-spanning region and a cytoplasmic domain. Sequence comparison reveals extensive homology to the chicken L-CAM. Both uvomorulin and L-CAM are identical in 65% of their entire amino acid sequence suggesting a common origin for both CAMs. Images Fig. 1. Fig. 4. Fig. 7. PMID:3501370

Underwound DNA under Tension: Structure, Elasticity, and Sequence-Dependent Behaviors

NASA Astrophysics Data System (ADS)

Sheinin, Maxim Y.; Forth, Scott; Marko, John F.; Wang, Michelle D.

2011-09-01

DNA melting under torsion plays an important role in a wide variety of cellular processes. In the present Letter, we have investigated DNA melting at the single-molecule level using an angular optical trap. By directly measuring force, extension, torque, and angle of DNA, we determined the structural and elastic parameters of torsionally melted DNA. Our data reveal that under moderate forces, the melted DNA assumes a left-handed structure as opposed to an open bubble conformation and is highly torsionally compliant. We have also discovered that at low forces melted DNA properties are highly dependent on DNA sequence. These results provide a more comprehensive picture of the global DNA force-torque phase diagram.

Productive mRNA stem loop-mediated transcriptional slippage: Crucial features in common with intrinsic terminators.

PubMed

Penno, Christophe; Sharma, Virag; Coakley, Arthur; O'Connell Motherway, Mary; van Sinderen, Douwe; Lubkowska, Lucyna; Kireeva, Maria L; Kashlev, Mikhail; Baranov, Pavel V; Atkins, John F

2015-04-21

Escherichia coli and yeast DNA-dependent RNA polymerases are shown to mediate efficient nascent transcript stem loop formation-dependent RNA-DNA hybrid realignment. The realignment was discovered on the heteropolymeric sequence T5C5 and yields transcripts lacking a C residue within a corresponding U5C4. The sequence studied is derived from a Roseiflexus insertion sequence (IS) element where the resulting transcriptional slippage is required for transposase synthesis. The stability of the RNA structure, the proximity of the stem loop to the slippage site, the length and composition of the slippage site motif, and the identity of its 3' adjacent nucleotides (nt) are crucial for transcripts lacking a single C. In many respects, the RNA structure requirements for this slippage resemble those for hairpin-dependent transcription termination. In a purified in vitro system, the slippage efficiency ranges from 5% to 75% depending on the concentration ratios of the nucleotides specified by the slippage sequence and the 3' nt context. The only previous proposal of stem loop mediated slippage, which was in Ebola virus expression, was based on incorrect data interpretation. We propose a mechanical slippage model involving the RNAP translocation state as the main motor in slippage directionality and efficiency. It is distinct from previously described models, including the one proposed for paramyxovirus, where following random movement efficiency is mainly dependent on the stability of the new realigned hybrid. In broadening the scope for utilization of transcription slippage for gene expression, the stimulatory structure provides parallels with programmed ribosomal frameshifting at the translation level.

p53 Specifically Binds Triplex DNA In Vitro and in Cells

PubMed Central

Brázdová, Marie; Tichý, Vlastimil; Helma, Robert; Bažantová, Pavla; Polášková, Alena; Krejčí, Aneta; Petr, Marek; Navrátilová, Lucie; Tichá, Olga; Nejedlý, Karel; Bennink, Martin L.; Subramaniam, Vinod; Bábková, Zuzana; Martínek, Tomáš; Lexa, Matej; Adámik, Matej

2016-01-01

Triplex DNA is implicated in a wide range of biological activities, including regulation of gene expression and genomic instability leading to cancer. The tumor suppressor p53 is a central regulator of cell fate in response to different type of insults. Sequence and structure specific modes of DNA recognition are core attributes of the p53 protein. The focus of this work is the structure-specific binding of p53 to DNA containing triplex-forming sequences in vitro and in cells and the effect on p53-driven transcription. This is the first DNA binding study of full-length p53 and its deletion variants to both intermolecular and intramolecular T.A.T triplexes. We demonstrate that the interaction of p53 with intermolecular T.A.T triplex is comparable to the recognition of CTG-hairpin non-B DNA structure. Using deletion mutants we determined the C-terminal DNA binding domain of p53 to be crucial for triplex recognition. Furthermore, strong p53 recognition of intramolecular T.A.T triplexes (H-DNA), stabilized by negative superhelicity in plasmid DNA, was detected by competition and immunoprecipitation experiments, and visualized by AFM. Moreover, chromatin immunoprecipitation revealed p53 binding T.A.T forming sequence in vivo. Enhanced reporter transactivation by p53 on insertion of triplex forming sequence into plasmid with p53 consensus sequence was observed by luciferase reporter assays. In-silico scan of human regulatory regions for the simultaneous presence of both consensus sequence and T.A.T motifs identified a set of candidate p53 target genes and p53-dependent activation of several of them (ABCG5, ENOX1, INSR, MCC, NFAT5) was confirmed by RT-qPCR. Our results show that T.A.T triplex comprises a new class of p53 binding sites targeted by p53 in a DNA structure-dependent mode in vitro and in cells. The contribution of p53 DNA structure-dependent binding to the regulation of transcription is discussed. PMID:27907175

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis.

PubMed

Du, Yushen; Wu, Nicholas C; Jiang, Lin; Zhang, Tianhao; Gong, Danyang; Shu, Sara; Wu, Ting-Ting; Sun, Ren

2016-11-01

Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available. To fully comprehend the diverse functions of a protein, it is essential to understand the functionality of individual residues. Current methods are highly dependent on evolutionary sequence conservation, which is usually limited by sampling size. Sequence conservation-based methods are further confounded by structural constraints and multifunctionality of proteins. Here we present a method that can systematically identify and annotate functional residues of a given protein. We used a high-throughput functional profiling platform to identify essential residues. Coupling it with homologous-structure comparison, we were able to annotate multiple functions of proteins. We demonstrated the method with the PB1 protein of influenza A virus and identified novel functional residues in addition to its canonical function as an RNA-dependent RNA polymerase. Not limited to virology, this method is generally applicable to other proteins that can be functionally selected and about which homologous-structure information is available. Copyright © 2016 Du et al.

Sequence and Structure Dependent DNA-DNA Interactions

NASA Astrophysics Data System (ADS)

Kopchick, Benjamin; Qiu, Xiangyun

Molecular forces between dsDNA strands are largely dominated by electrostatics and have been extensively studied. Quantitative knowledge has been accumulated on how DNA-DNA interactions are modulated by varied biological constituents such as ions, cationic ligands, and proteins. Despite its central role in biology, the sequence of DNA has not received substantial attention and ``random'' DNA sequences are typically used in biophysical studies. However, ~50% of human genome is composed of non-random-sequence DNAs, particularly repetitive sequences. Furthermore, covalent modifications of DNA such as methylation play key roles in gene functions. Such DNAs with specific sequences or modifications often take on structures other than the canonical B-form. Here we present series of quantitative measurements of the DNA-DNA forces with the osmotic stress method on different DNA sequences, from short repeats to the most frequent sequences in genome, and to modifications such as bromination and methylation. We observe peculiar behaviors that appear to be strongly correlated with the incurred structural changes. We speculate the causalities in terms of the differences in hydration shell and DNA surface structures.

Length-independent structural similarities enrich the antibody CDR canonical class model.

PubMed

Nowak, Jaroslaw; Baker, Terry; Georges, Guy; Kelm, Sebastian; Klostermann, Stefan; Shi, Jiye; Sridharan, Sudharsan; Deane, Charlotte M

2016-01-01

Complementarity-determining regions (CDRs) are antibody loops that make up the antigen binding site. Here, we show that all CDR types have structurally similar loops of different lengths. Based on these findings, we created length-independent canonical classes for the non-H3 CDRs. Our length variable structural clusters show strong sequence patterns suggesting either that they evolved from the same original structure or result from some form of convergence. We find that our length-independent method not only clusters a larger number of CDRs, but also predicts canonical class from sequence better than the standard length-dependent approach. To demonstrate the usefulness of our findings, we predicted cluster membership of CDR-L3 sequences from 3 next-generation sequencing datasets of the antibody repertoire (over 1,000,000 sequences). Using the length-independent clusters, we can structurally classify an additional 135,000 sequences, which represents a ∼20% improvement over the standard approach. This suggests that our length-independent canonical classes might be a highly prevalent feature of antibody space, and could substantially improve our ability to accurately predict the structure of novel CDRs identified by next-generation sequencing.

Sequence dependent aggregation of peptides and fibril formation

NASA Astrophysics Data System (ADS)

Hung, Nguyen Ba; Le, Duy-Manh; Hoang, Trinh X.

2017-09-01

Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study the aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different numbers of peptides. Fibril-like ordered aggregates are found for several sequences that contain the common HPH pattern, while other sequences may form helix bundles or disordered aggregates. A wide variation of the aggregation transition temperatures among sequences, even among those of the same hydrophobic fraction, indicates that not all sequences undergo aggregation at a presumable physiological temperature. The transition is found to be the most cooperative for sequences forming fibril-like structures. For a fibril-prone sequence, it is shown that fibril formation follows the nucleation and growth mechanism. Interestingly, a binary mixture of peptides of an aggregation-prone and a non-aggregation-prone sequence shows the association and conversion of the latter to the fibrillar structure. Our study highlights the role of a sequence in selecting fibril-like aggregates and also the impact of a structural template on fibril formation by peptides of unrelated sequences.

Scaling effects in the static and dynamic response of graphite-epoxy beam-columns. Ph.D. Thesis - Virginia Polytechnic Inst. and State Univ.

NASA Technical Reports Server (NTRS)

Jackson, Karen E.

1990-01-01

Scale model technology represents one method of investigating the behavior of advanced, weight-efficient composite structures under a variety of loading conditions. It is necessary, however, to understand the limitations involved in testing scale model structures before the technique can be fully utilized. These limitations, or scaling effects, are characterized. in the large deflection response and failure of composite beams. Scale model beams were loaded with an eccentric axial compressive load designed to produce large bending deflections and global failure. A dimensional analysis was performed on the composite beam-column loading configuration to determine a model law governing the system response. An experimental program was developed to validate the model law under both static and dynamic loading conditions. Laminate stacking sequences including unidirectional, angle ply, cross ply, and quasi-isotropic were tested to examine a diversity of composite response and failure modes. The model beams were loaded under scaled test conditions until catastrophic failure. A large deflection beam solution was developed to compare with the static experimental results and to analyze beam failure. Also, the finite element code DYCAST (DYnamic Crash Analysis of STructure) was used to model both the static and impulsive beam response. Static test results indicate that the unidirectional and cross ply beam responses scale as predicted by the model law, even under severe deformations. In general, failure modes were consistent between scale models within a laminate family; however, a significant scale effect was observed in strength. The scale effect in strength which was evident in the static tests was also observed in the dynamic tests. Scaling of load and strain time histories between the scale model beams and the prototypes was excellent for the unidirectional beams, but inconsistent results were obtained for the angle ply, cross ply, and quasi-isotropic beams. Results show that valuable information can be obtained from testing on scale model composite structures, especially in the linear elastic response region. However, due to scaling effects in the strength behavior of composite laminates, caution must be used in extrapolating data taken from a scale model test when that test involves failure of the structure.

Influence of DNA sequence on the structure of minicircles under torsional stress

PubMed Central

Wang, Qian; Irobalieva, Rossitza N.; Chiu, Wah; Schmid, Michael F.; Fogg, Jonathan M.; Zechiedrich, Lynn

2017-01-01

Abstract The sequence dependence of the conformational distribution of DNA under various levels of torsional stress is an important unsolved problem. Combining theory and coarse-grained simulations shows that the DNA sequence and a structural correlation due to topology constraints of a circle are the main factors that dictate the 3D structure of a 336 bp DNA minicircle under torsional stress. We found that DNA minicircle topoisomers can have multiple bend locations under high torsional stress and that the positions of these sharp bends are determined by the sequence, and by a positive mechanical correlation along the sequence. We showed that simulations and theory are able to provide sequence-specific information about individual DNA minicircles observed by cryo-electron tomography (cryo-ET). We provided a sequence-specific cryo-ET tomogram fitting of DNA minicircles, registering the sequence within the geometric features. Our results indicate that the conformational distribution of minicircles under torsional stress can be designed, which has important implications for using minicircle DNA for gene therapy. PMID:28609782

Structure and Sequence Search on Aptamer-Protein Docking

NASA Astrophysics Data System (ADS)

Xiao, Jiajie; Bonin, Keith; Guthold, Martin; Salsbury, Freddie

2015-03-01

Interactions between proteins and deoxyribonucleic acid (DNA) play a significant role in the living systems, especially through gene regulation. However, short nucleic acids sequences (aptamers) with specific binding affinity to specific proteins exhibit clinical potential as therapeutics. Our capillary and gel electrophoresis selection experiments show that specific sequences of aptamers can be selected that bind specific proteins. Computationally, given the experimentally-determined structure and sequence of a thrombin-binding aptamer, we can successfully dock the aptamer onto thrombin in agreement with experimental structures of the complex. In order to further study the conformational flexibility of this thrombin-binding aptamer and to potentially develop a predictive computational model of aptamer-binding, we use GPU-enabled molecular dynamics simulations to both examine the conformational flexibility of the aptamer in the absence of binding to thrombin, and to determine our ability to fold an aptamer. This study should help further de-novo predictions of aptamer sequences by enabling the study of structural and sequence-dependent effects on aptamer-protein docking specificity.

Optimization design of strong and tough nacreous nanocomposites through tuning characteristic lengths

NASA Astrophysics Data System (ADS)

Ni, Yong; Song, Zhaoqiang; Jiang, Hongyuan; Yu, Shu-Hong; He, Linghui

2015-08-01

How nacreous nanocomposites with optimal combinations of stiffness, strength and toughness depend on constituent property and microstructure parameters is studied using a nonlinear shear-lag model. We show that the interfacial elasto-plasticity and the overlapping length between bricks dependent on the brick size and brick staggering mode significantly affect the nonuniformity of the shear stress, the stress-transfer efficiency and thus the failure path. There are two characteristic lengths at which the strength and toughness are optimized respectively. Simultaneous optimization of the strength and toughness is achieved by matching these lengths as close as possible in the nacreous nanocomposite with regularly staggered brick-and-mortar (BM) structure where simultaneous uniform failures of the brick and interface occur. In the randomly staggered BM structure, as the overlapping length is distributed, the nacreous nanocomposite turns the simultaneous uniform failure into progressive interface or brick failure with moderate decrease of the strength and toughness. Specifically there is a parametric range at which the strength and toughness are insensitive to the brick staggering randomness. The obtained results propose a parametric selection guideline based on the length matching for rational design of nacreous nanocomposites. Such guideline explains why nacre is strong and tough while most artificial nacreous nanocomposites aere not.

A concept for fault tolerant design and improved availability of active composite elastic structures

NASA Astrophysics Data System (ADS)

Soeffker, D.; Wolters, K.; Krajcin, I.

2005-05-01

New functionalities, higher comfort and increasing performance requirements are often be solved by adding new technologies to existing (passive) solutions. Monitoring and control approaches uses additional sensors and actuators, new materials, microprocessors and new devices realizing new and improved functionalities. Two effects are becoming more and more interesting: (1) the lifetime of new actuators/materials strongly depends on the usage-history, (2) the functionality of the new composed systems depends on the fully functionality of all elements. In the consequence, the availability of such new systems is decreased by the number of elements and depends strongly on the use. These effects are known and act against new developments improving performance behavior also in mechanical engineering, automotive systems etc. This will be also the case for multifunctional composite or compound systems such as piezomaterials, magnetostrictive alloys or smart memory alloys (SMA) and is actually within the focus of the Structural-Health-Monitoring (SHM)-community. This contribution explains a new and systematically structured methodological approach to avoid and eliminate failures in mechatronical systems in an integrated and intelligent way to achieve a desirable or required amount of utilization in compliance with a defined failure rate. The result is an enhancement of the dependability of such a system.

Overcoming Sequence Misalignments with Weighted Structural Superposition

PubMed Central

Khazanov, Nickolay A.; Damm-Ganamet, Kelly L.; Quang, Daniel X.; Carlson, Heather A.

2012-01-01

An appropriate structural superposition identifies similarities and differences between homologous proteins that are not evident from sequence alignments alone. We have coupled our Gaussian-weighted RMSD (wRMSD) tool with a sequence aligner and seed extension (SE) algorithm to create a robust technique for overlaying structures and aligning sequences of homologous proteins (HwRMSD). HwRMSD overcomes errors in the initial sequence alignment that would normally propagate into a standard RMSD overlay. SE can generate a corrected sequence alignment from the improved structural superposition obtained by wRMSD. HwRMSD’s robust performance and its superiority over standard RMSD are demonstrated over a range of homologous proteins. Its better overlay results in corrected sequence alignments with good agreement to HOMSTRAD. Finally, HwRMSD is compared to established structural alignment methods: FATCAT, SSM, CE, and Dalilite. Most methods are comparable at placing residue pairs within 2 Å, but HwRMSD places many more residue pairs within 1 Å, providing a clear advantage. Such high accuracy is essential in drug design, where small distances can have a large impact on computational predictions. This level of accuracy is also needed to correct sequence alignments in an automated fashion, especially for omics-scale analysis. HwRMSD can align homologs with low sequence identity and large conformational differences, cases where both sequence-based and structural-based methods may fail. The HwRMSD pipeline overcomes the dependency of structural overlays on initial sequence pairing and removes the need to determine the best sequence-alignment method, substitution matrix, and gap parameters for each unique pair of homologs. PMID:22733542

Test and Analysis Correlation of a Large-Scale, Orthogrid-Stiffened Metallic Cylinder without Weld Lands

NASA Technical Reports Server (NTRS)

Rudd, Michelle T.; Hilburger, Mark W.; Lovejoy, Andrew E.; Lindell, Michael C.; Gardner, Nathaniel W.; Schultz, Marc R.

2018-01-01

The NASA Engineering Safety Center (NESC) Shell Buckling Knockdown Factor Project (SBKF) was established in 2007 by the NESC with the primary objective to develop analysis-based buckling design factors and guidelines for metallic and composite launch-vehicle structures.1 A secondary objective of the project is to advance technologies that have the potential to increase the structural efficiency of launch-vehicles. The SBKF Project has determined that weld-land stiffness discontinuities can significantly reduce the buckling load of a cylinder. In addition, the welding process can introduce localized geometric imperfections that can further exacerbate the inherent buckling imperfection sensitivity of the cylinder. Therefore, single-piece barrel fabrication technologies can improve structural efficiency by eliminating these weld-land issues. As part of this effort, SBKF partnered with the Advanced Materials and Processing Branch (AMPB) at NASA Langley Research Center (LaRC), the Mechanical and Fabrication Branch at NASA Marshall Space Flight Center (MSFC), and ATI Forged Products to design and fabricate an 8-ft-diameter orthogrid-stiffened seamless metallic cylinder. The cylinder was subjected to seven subcritical load sequences (load levels that are not intended to induce test article buckling or material failure) and one load sequence to failure. The purpose of this test effort was to demonstrate the potential benefits of building cylindrical structures with no weld lands using the flow-formed manufacturing process. This seamless barrel is the ninth 8-ft-diameter metallic barrel and the first single-piece metallic structure to be tested under this program.

Mechanics-based statistics of failure risk of quasibrittle structures and size effect on safety factors.

PubMed

Bazant, Zdenĕk P; Pang, Sze-Dai

2006-06-20

In mechanical design as well as protection from various natural hazards, one must ensure an extremely low failure probability such as 10(-6). How to achieve that goal is adequately understood only for the limiting cases of brittle or ductile structures. Here we present a theory to do that for the transitional class of quasibrittle structures, having brittle constituents and characterized by nonnegligible size of material inhomogeneities. We show that the probability distribution of strength of the representative volume element of material is governed by the Maxwell-Boltzmann distribution of atomic energies and the stress dependence of activation energy barriers; that it is statistically modeled by a hierarchy of series and parallel couplings; and that it consists of a broad Gaussian core having a grafted far-left power-law tail with zero threshold and amplitude depending on temperature and load duration. With increasing structure size, the Gaussian core shrinks and Weibull tail expands according to the weakest-link model for a finite chain of representative volume elements. The model captures experimentally observed deviations of the strength distribution from Weibull distribution and of the mean strength scaling law from a power law. These deviations can be exploited for verification and calibration. The proposed theory will increase the safety of concrete structures, composite parts of aircraft or ships, microelectronic components, microelectromechanical systems, prosthetic devices, etc. It also will improve protection against hazards such as landslides, avalanches, ice breaks, and rock or soil failures.

Complete mitochondrial genome sequence of the heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus).

PubMed

Hu, Bo; Liu, Dong-Xing; Zhang, Yu-Qing; Song, Jian-Tao; Ji, Xian-Fei; Hou, Zhi-Qiang; Zhang, Zhen-Hai

2016-05-01

In this study we sequenced the complete mitochondrial genome sequencing of a heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus) for the first time. The total length of the mitogenome was 16,267 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region.

Electromigration resistance in a short three-contact interconnect tree

NASA Astrophysics Data System (ADS)

Chang, C. W.; Choi, Z.-S.; Thompson, C. V.; Gan, C. L.; Pey, K. L.; Choi, W. K.; Hwang, N.

2006-05-01

Electromigration has been characterized in via-terminated interconnect lines with additional vias in the middle, creating two adjacent segments that can be stressed independently. The mortality of a segment was found to depend on the direction and magnitude of the current in the adjacent segment, confirming that there is not a fixed value of the product of the current density and segment length, jL, that defines immortality in individual segments that are part of a multisegment interconnect tree. Instead, it is found that the probability of failure of a multisegment tree increases with the increasing value of an effective jL product defined in earlier work. However, contrary to expectations, the failures were still observed when (jL)eff was less than the critical jL product for which lines were found to be immortal in single-segment test structures. It is argued that this is due to reservoir effects associated with unstressed segments or due to liner failure at the central via. Multisegment test structures are therefore shown to reveal more types of failure mechanisms and mortality conditions that are not found in tests with single-segment structures.

Thermal Cycling Fatigue in DIPs Mounted with Eutectic Tin-Lead Solder Joints in Stub and Gullwing Geometries

NASA Technical Reports Server (NTRS)

Winslow, J. W.; Silveira, C. de

1993-01-01

It has long been known that solder joints under mechanical stress are subject to failure. In early electronic systems, such failures were avoided primarily by avoiding the use of solder as a mechanical structural component. The rule was first to make sound wire connections that did not depend mechanically on solder, and only then to solder them. Careful design and miniaturization in modern electronic systems limits the mechanical stresses exerted on solder joints to values less than their yield points, and these joints have become integral parts of the mechanical structures. Unfortunately, while these joints are strong enough when new, they have proven vulnerable to fatigue failures as they age. Details of the fatigue process are poorly understood, making predictions of expected lifetimes difficult.

Slow Crack Growth and Fatigue Life Prediction of Ceramic Components Subjected to Variable Load History

NASA Technical Reports Server (NTRS)

Jadaan, Osama

2001-01-01

Present capabilities of the NASA CARES/Life (Ceramic Analysis and Reliability Evaluation of Structures/Life) code include probabilistic life prediction of ceramic components subjected to fast fracture, slow crack growth (stress corrosion), and cyclic fatigue failure modes. Currently, this code has the capability to compute the time-dependent reliability of ceramic structures subjected to simple time-dependent loading. For example, in slow crack growth (SCG) type failure conditions CARES/Life can handle the cases of sustained and linearly increasing time-dependent loads, while for cyclic fatigue applications various types of repetitive constant amplitude loads can be accounted for. In real applications applied loads are rarely that simple, but rather vary with time in more complex ways such as, for example, engine start up, shut down, and dynamic and vibrational loads. In addition, when a given component is subjected to transient environmental and or thermal conditions, the material properties also vary with time. The objective of this paper is to demonstrate a methodology capable of predicting the time-dependent reliability of components subjected to transient thermomechanical loads that takes into account the change in material response with time. In this paper, the dominant delayed failure mechanism is assumed to be SCG. This capability has been added to the NASA CARES/Life (Ceramic Analysis and Reliability Evaluation of Structures/Life) code, which has also been modified to have the ability of interfacing with commercially available FEA codes executed for transient load histories. An example involving a ceramic exhaust valve subjected to combustion cycle loads is presented to demonstrate the viability of this methodology and the CARES/Life program.

Methods for Joining of Rails : Survey Report

DOT National Transportation Integrated Search

1977-07-01

The performance of track structures depends greatly on the integrity of the connections between rail sections. Because the majority of service and detected rail failures occur at joints, particularly conventional bolted joints, this survey was conduc...

Carbon Fiber Strand Tensile Failure Dynamic Event Characterization

NASA Technical Reports Server (NTRS)

Johnson, Kenneth L.; Reeder, James

2016-01-01

There are few if any clear, visual, and detailed images of carbon fiber strand failures under tension useful for determining mechanisms, sequences of events, different types of failure modes, etc. available to researchers. This makes discussion of physics of failure difficult. It was also desired to find out whether the test article-to-test rig interface (grip) played a part in some failures. These failures have nothing to do with stress rupture failure, thus representing a source of waste for the larger 13-00912 investigation into that specific failure type. Being able to identify or mitigate any competing failure modes would improve the value of the 13-00912 test data. The beginnings of the solution to these problems lay in obtaining images of strand failures useful for understanding physics of failure and the events leading up to failure. Necessary steps include identifying imaging techniques that result in useful data, using those techniques to home in on where in a strand and when in the sequence of events one should obtain imaging data.

Compression Fracture of CFRP Laminates Containing Stress Intensifications.

PubMed

Leopold, Christian; Schütt, Martin; Liebig, Wilfried V; Philipkowski, Timo; Kürten, Jonas; Schulte, Karl; Fiedler, Bodo

2017-09-05

For brittle fracture behaviour of carbon fibre reinforced plastics (CFRP) under compression, several approaches exist, which describe different mechanisms during failure, especially at stress intensifications. The failure process is not only initiated by the buckling fibres, but a shear driven fibre compressive failure beneficiaries or initiates the formation of fibres into a kink-band. Starting from this kink-band further damage can be detected, which leads to the final failure. The subject of this work is an experimental investigation on the influence of ply thickness and stacking sequence in quasi-isotropic CFRP laminates containing stress intensifications under compression loading. Different effects that influence the compression failure and the role the stacking sequence has on damage development and the resulting compressive strength are identified and discussed. The influence of stress intensifications is investigated in detail at a hole in open hole compression (OHC) tests. A proposed interrupted test approach allows identifying the mechanisms of damage initiation and propagation from the free edge of the hole by causing a distinct damage state and examine it at a precise instant of time during fracture process. Compression after impact (CAI) tests are executed in order to compare the OHC results to a different type of stress intensifications. Unnotched compression tests are carried out for comparison as a reference. With this approach, a more detailed description of the failure mechanisms during the sudden compression failure of CFRP is achieved. By microscopic examination of single plies from various specimens, the different effects that influence the compression failure are identified. First damage of fibres occurs always in 0°-ply. Fibre shear failure leads to local microbuckling and the formation and growth of a kink-band as final failure mechanisms. The formation of a kink-band and finally steady state kinking is shifted to higher compressive strains with decreasing ply thickness. Final failure mode in laminates with stress intensification depends on ply thickness. In thick or inner plies, damage initiates as shear failure and fibre buckling into the drilled hole. The kink-band orientation angle is changing with increasing strain. In outer or thin plies shear failure of single fibres is observed as first damage and the kink-band orientation angle is constant until final failure. Decreasing ply thickness increases the unnotched compressive strength. When stress intensifications are present, the position of the 0°-layer is critical for stability under compression and is thus more important than the ply thickness. Central 0°-layers show best results for OHC and CAI strength due to higher bending stiffness and better supporting effect of the adjacent layers.

Compression Fracture of CFRP Laminates Containing Stress Intensifications

PubMed Central

Schütt, Martin; Philipkowski, Timo; Kürten, Jonas; Schulte, Karl

2017-01-01

For brittle fracture behaviour of carbon fibre reinforced plastics (CFRP) under compression, several approaches exist, which describe different mechanisms during failure, especially at stress intensifications. The failure process is not only initiated by the buckling fibres, but a shear driven fibre compressive failure beneficiaries or initiates the formation of fibres into a kink-band. Starting from this kink-band further damage can be detected, which leads to the final failure. The subject of this work is an experimental investigation on the influence of ply thickness and stacking sequence in quasi-isotropic CFRP laminates containing stress intensifications under compression loading. Different effects that influence the compression failure and the role the stacking sequence has on damage development and the resulting compressive strength are identified and discussed. The influence of stress intensifications is investigated in detail at a hole in open hole compression (OHC) tests. A proposed interrupted test approach allows identifying the mechanisms of damage initiation and propagation from the free edge of the hole by causing a distinct damage state and examine it at a precise instant of time during fracture process. Compression after impact (CAI) tests are executed in order to compare the OHC results to a different type of stress intensifications. Unnotched compression tests are carried out for comparison as a reference. With this approach, a more detailed description of the failure mechanisms during the sudden compression failure of CFRP is achieved. By microscopic examination of single plies from various specimens, the different effects that influence the compression failure are identified. First damage of fibres occurs always in 0°-ply. Fibre shear failure leads to local microbuckling and the formation and growth of a kink-band as final failure mechanisms. The formation of a kink-band and finally steady state kinking is shifted to higher compressive strains with decreasing ply thickness. Final failure mode in laminates with stress intensification depends on ply thickness. In thick or inner plies, damage initiates as shear failure and fibre buckling into the drilled hole. The kink-band orientation angle is changing with increasing strain. In outer or thin plies shear failure of single fibres is observed as first damage and the kink-band orientation angle is constant until final failure. Decreasing ply thickness increases the unnotched compressive strength. When stress intensifications are present, the position of the 0°-layer is critical for stability under compression and is thus more important than the ply thickness. Central 0°-layers show best results for OHC and CAI strength due to higher bending stiffness and better supporting effect of the adjacent layers. PMID:28872623

Evolution of ribozymes in the presence of a mineral surface

PubMed Central

Stephenson, James D.; Popović, Milena; Bristow, Thomas F.

2016-01-01

Mineral surfaces are often proposed as the sites of critical processes in the emergence of life. Clay minerals in particular are thought to play significant roles in the origin of life including polymerizing, concentrating, organizing, and protecting biopolymers. In these scenarios, the impact of minerals on biopolymer folding is expected to influence evolutionary processes. These processes include both the initial emergence of functional structures in the presence of the mineral and the subsequent transition away from the mineral-associated niche. The initial evolution of function depends upon the number and distribution of sequences capable of functioning in the presence of the mineral, and the transition to new environments depends upon the overlap between sequences that evolve on the mineral surface and sequences that can perform the same functions in the mineral's absence. To examine these processes, we evolved self-cleaving ribozymes in vitro in the presence or absence of Na-saturated montmorillonite clay mineral particles. Starting from a shared population of random sequences, RNA populations were evolved in parallel, along separate evolutionary trajectories. Comparative sequence analysis and activity assays show that the impact of this clay mineral on functional structure selection was minimal; it neither prevented common structures from emerging, nor did it promote the emergence of new structures. This suggests that montmorillonite does not improve RNA's ability to evolve functional structures; however, it also suggests that RNAs that do evolve in contact with montmorillonite retain the same structures in mineral-free environments, potentially facilitating an evolutionary transition away from a mineral-associated niche. PMID:27793980

Agenesis of the ductus venosus-A case with favorable outcome after early signs of cardiac failure.

PubMed

Hofmann, Sigrun R; Heilmann, Antje; Häusler, Hans J; Kamin, Gabriele; Nitzsche, Katharina I

2013-01-01

Absence of the ductus venosus (ADV) is a rare vascular anomaly. Its prognosis depends on the pathway of the umbilical flow to the systemic venous circulation, and the presence or absence of associated structural or chromosomal anomalies, sometimes resulting in hydrops fetalis. In cases with isolated ADV in the absence of associated anomalies, survival rates are as high as 85%, depending on the shunt situation. Here, we report a patient with ADV and extrahepatic umbilical vein drainage with favorable outcome after intrauterine reversal of early signs of cardiac failure. Diagnosis was made after the appearance of moderate cardiomegaly in the 25th gestational week. Thus, in the case of cardiomegaly with or without further signs of cardiac failure, ultrasound imaging of the venous duct should be considered. Copyright © 2012 Wiley Periodicals, Inc.

Detection and molecular identification of leishmania RNA virus (LRV) in Iranian Leishmania species.

PubMed

Hajjaran, Homa; Mahdi, Maryam; Mohebali, Mehdi; Samimi-Rad, Katayoun; Ataei-Pirkooh, Angila; Kazemi-Rad, Elham; Naddaf, Saied Reza; Raoofian, Reza

2016-12-01

Leishmania RNA virus (LRV) was first detected in members of the subgenus Leishmania (Viannia), and later, the virulence and metastasis of the New World species were attributed to this virus. The data on the presence of LRV in Old World species are confined to Leishmania major and a few Leishmania aethiopica isolates. The aim of this study was to survey the presence of LRV in various Iranian Leishmania species originating from patients and animal reservoir hosts. Genomic nucleic acids were extracted from 50 cultured isolates belonging to the species Leishmania major, Leishmania tropica, and Leishmania infantum. A partial sequence of the viral RNA-dependent RNA polymerase (RdRp) gene was amplified, sequenced and compared with appropriate sequences from the GenBank database. We detected the virus in two parasite specimens: an isolate of L. infantum derived from a visceral leishmaniasis (VL) patient who was unresponsive to meglumine antimoniate treatment, and an L. major isolate originating from a great gerbil, Rhombomys opimus. The Iranian LRV sequences showed the highest similarities to an Old World L. major LRV2 and were genetically distant from LRV1 isolates detected in New World Leishmania parasites. We could not attribute treatment failure in VL patient to the presence of LRV due to the limited number of specimens analyzed. Further studies with inclusion of more clinical samples are required to elucidate the potential role of LRVs in pathogenesis or treatment failure of Old World leishmaniasis.

Methodology Development for Passive Component Reliability Modeling in a Multi-Physics Simulation Environment

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

Aldemir, Tunc; Denning, Richard; Catalyurek, Umit

Reduction in safety margin can be expected as passive structures and components undergo degradation with time. Limitations in the traditional probabilistic risk assessment (PRA) methodology constrain its value as an effective tool to address the impact of aging effects on risk and for quantifying the impact of aging management strategies in maintaining safety margins. A methodology has been developed to address multiple aging mechanisms involving large numbers of components (with possibly statistically dependent failures) within the PRA framework in a computationally feasible manner when the sequencing of events is conditioned on the physical conditions predicted in a simulation environment, suchmore » as the New Generation System Code (NGSC) concept. Both epistemic and aleatory uncertainties can be accounted for within the same phenomenological framework and maintenance can be accounted for in a coherent fashion. The framework accommodates the prospective impacts of various intervention strategies such as testing, maintenance, and refurbishment. The methodology is illustrated with several examples.« less

Effect of temperature on composite sandwich structures subjected to low velocity impact. [aircraft construction materials

NASA Technical Reports Server (NTRS)

Sharma, A. V.

1980-01-01

The effect of low velocity projectile impact on sandwich-type structural components was investigated. The materials used in the fabrication of the impact surface were graphite-, Kevlar-, and boron-fibers with appropriate epoxy matrices. The testing of the specimens was performed at moderately low- and high-temperatures as well as at room temperature to assess the impact-initiated strength degradation of the laminates. Eleven laminates with different stacking sequences, orientations, and thicknesses were tested. The low energy projectile impact is considered to simulate the damage caused by runway debris, the dropping of the hand tools during servicing, etc., on the secondary aircraft structures fabricated with the composite materials. The results show the preload and the impact energy combinations necessary to cause catastrophic failure in the laminates tested. A set of faired curves indicating the failure thresholds is shown separately for the tension-and compression-loaded laminates. The specific-strengths and -modulii for the various laminates tested are also given.

Pairwise Sequence Alignment Library

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

Jeff Daily, PNNL

2015-05-20

Vector extensions, such as SSE, have been part of the x86 CPU since the 1990s, with applications in graphics, signal processing, and scientific applications. Although many algorithms and applications can naturally benefit from automatic vectorization techniques, there are still many that are difficult to vectorize due to their dependence on irregular data structures, dense branch operations, or data dependencies. Sequence alignment, one of the most widely used operations in bioinformatics workflows, has a computational footprint that features complex data dependencies. The trend of widening vector registers adversely affects the state-of-the-art sequence alignment algorithm based on striped data layouts. Therefore, amore » novel SIMD implementation of a parallel scan-based sequence alignment algorithm that can better exploit wider SIMD units was implemented as part of the Parallel Sequence Alignment Library (parasail). Parasail features: Reference implementations of all known vectorized sequence alignment approaches. Implementations of Smith Waterman (SW), semi-global (SG), and Needleman Wunsch (NW) sequence alignment algorithms. Implementations across all modern CPU instruction sets including AVX2 and KNC. Language interfaces for C/C++ and Python.« less

Surveying unsteady flows by means of movie sequences - A case study

NASA Astrophysics Data System (ADS)

Freymuth, P.; Bank, W.; Finaish, F.

Photographic surveying techniques and their results are presented for vortical pattern development in unsteady two-dimensional flows, which depends on a multitude of parameters that have heretofore hampered broad investigation, in order to delineate the more important parametric dependencies. Samples are given from 100 films representing over 2000 sequences consisting of 400,000 photographic frames. Attention is given to the problems posed by resolution of time and lateral dimensions, spanwise vortical structure, and the dependence of angle of attack on Reynolds number and flow geometry.

PSS-3D1D: an improved 3D1D profile method of protein fold recognition for the annotation of twilight zone sequences.

PubMed

Ganesan, K; Parthasarathy, S

2011-12-01

Annotation of any newly determined protein sequence depends on the pairwise sequence identity with known sequences. However, for the twilight zone sequences which have only 15-25% identity, the pair-wise comparison methods are inadequate and the annotation becomes a challenging task. Such sequences can be annotated by using methods that recognize their fold. Bowie et al. described a 3D1D profile method in which the amino acid sequences that fold into a known 3D structure are identified by their compatibility to that known 3D structure. We have improved the above method by using the predicted secondary structure information and employ it for fold recognition from the twilight zone sequences. In our Protein Secondary Structure 3D1D (PSS-3D1D) method, a score (w) for the predicted secondary structure of the query sequence is included in finding the compatibility of the query sequence to the known fold 3D structures. In the benchmarks, the PSS-3D1D method shows a maximum of 21% improvement in predicting correctly the α + β class of folds from the sequences with twilight zone level of identity, when compared with the 3D1D profile method. Hence, the PSS-3D1D method could offer more clues than the 3D1D method for the annotation of twilight zone sequences. The web based PSS-3D1D method is freely available in the PredictFold server at http://bioinfo.bdu.ac.in/servers/ .

De Novo Protein Structure Prediction

NASA Astrophysics Data System (ADS)

Hung, Ling-Hong; Ngan, Shing-Chung; Samudrala, Ram

An unparalleled amount of sequence data is being made available from large-scale genome sequencing efforts. The data provide a shortcut to the determination of the function of a gene of interest, as long as there is an existing sequenced gene with similar sequence and of known function. This has spurred structural genomic initiatives with the goal of determining as many protein folds as possible (Brenner and Levitt, 2000; Burley, 2000; Brenner, 2001; Heinemann et al., 2001). The purpose of this is twofold: First, the structure of a gene product can often lead to direct inference of its function. Second, since the function of a protein is dependent on its structure, direct comparison of the structures of gene products can be more sensitive than the comparison of sequences of genes for detecting homology. Presently, structural determination by crystallography and NMR techniques is still slow and expensive in terms of manpower and resources, despite attempts to automate the processes. Computer structure prediction algorithms, while not providing the accuracy of the traditional techniques, are extremely quick and inexpensive and can provide useful low-resolution data for structure comparisons (Bonneau and Baker, 2001). Given the immense number of structures which the structural genomic projects are attempting to solve, there would be a considerable gain even if the computer structure prediction approach were applicable to a subset of proteins.

OARSI Clinical Trials Recommendations for Hip Imaging in Osteoarthritis

PubMed Central

Gold, Garry E.; Cicuttini, Flavia; Crema, Michel D.; Eckstein, Felix; Guermazi, Ali; Kijowski, Richard; Link, Thomas M.; Maheu, Emmanuel; Martel-Pelletier, Johanne; Miller, Colin G.; Pelletier, Jean-Pierre; Peterfy, Charles G.; Potter, Hollis G.; Roemer, Frank W.; Hunter, David. J

2015-01-01

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/ techniques (including guidance on positioning for radiography, sequence/protocol recommendations/ hardware for MRI); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/ control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations. PMID:25952344

Discriminating between stabilizing and destabilizing protein design mutations via recombination and simulation.

PubMed

Johnson, Lucas B; Gintner, Lucas P; Park, Sehoo; Snow, Christopher D

2015-08-01

Accuracy of current computational protein design (CPD) methods is limited by inherent approximations in energy potentials and sampling. These limitations are often used to qualitatively explain design failures; however, relatively few studies provide specific examples or quantitative details that can be used to improve future CPD methods. Expanding the design method to include a library of sequences provides data that is well suited for discriminating between stabilizing and destabilizing design elements. Using thermophilic endoglucanase E1 from Acidothermus cellulolyticus as a model enzyme, we computationally designed a sequence with 60 mutations. The design sequence was rationally divided into structural blocks and recombined with the wild-type sequence. Resulting chimeras were assessed for activity and thermostability. Surprisingly, unlike previous chimera libraries, regression analysis based on one- and two-body effects was not sufficient for predicting chimera stability. Analysis of molecular dynamics simulations proved helpful in distinguishing stabilizing and destabilizing mutations. Reverting to the wild-type amino acid at destabilized sites partially regained design stability, and introducing predicted stabilizing mutations in wild-type E1 significantly enhanced thermostability. The ability to isolate stabilizing and destabilizing elements in computational design offers an opportunity to interpret previous design failures and improve future CPD methods. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

STAT1:DNA sequence-dependent binding modulation by phosphorylation, protein:protein interactions and small-molecule inhibition

PubMed Central

Bonham, Andrew J.; Wenta, Nikola; Osslund, Leah M.; Prussin, Aaron J.; Vinkemeier, Uwe; Reich, Norbert O.

2013-01-01

The DNA-binding specificity and affinity of the dimeric human transcription factor (TF) STAT1, were assessed by total internal reflectance fluorescence protein-binding microarrays (TIRF-PBM) to evaluate the effects of protein phosphorylation, higher-order polymerization and small-molecule inhibition. Active, phosphorylated STAT1 showed binding preferences consistent with prior characterization, whereas unphosphorylated STAT1 showed a weak-binding preference for one-half of the GAS consensus site, consistent with recent models of STAT1 structure and function in response to phosphorylation. This altered-binding preference was further tested by use of the inhibitor LLL3, which we show to disrupt STAT1 binding in a sequence-dependent fashion. To determine if this sequence-dependence is specific to STAT1 and not a general feature of human TF biology, the TF Myc/Max was analysed and tested with the inhibitor Mycro3. Myc/Max inhibition by Mycro3 is sequence independent, suggesting that the sequence-dependent inhibition of STAT1 may be specific to this system and a useful target for future inhibitor design. PMID:23180800

Position-specific automated processing of V3 env ultra-deep pyrosequencing data for predicting HIV-1 tropism

PubMed Central

Jeanne, Nicolas; Saliou, Adrien; Carcenac, Romain; Lefebvre, Caroline; Dubois, Martine; Cazabat, Michelle; Nicot, Florence; Loiseau, Claire; Raymond, Stéphanie; Izopet, Jacques; Delobel, Pierre

2015-01-01

HIV-1 coreceptor usage must be accurately determined before starting CCR5 antagonist-based treatment as the presence of undetected minor CXCR4-using variants can cause subsequent virological failure. Ultra-deep pyrosequencing of HIV-1 V3 env allows to detect low levels of CXCR4-using variants that current genotypic approaches miss. However, the computation of the mass of sequence data and the need to identify true minor variants while excluding artifactual sequences generated during amplification and ultra-deep pyrosequencing is rate-limiting. Arbitrary fixed cut-offs below which minor variants are discarded are currently used but the errors generated during ultra-deep pyrosequencing are sequence-dependant rather than random. We have developed an automated processing of HIV-1 V3 env ultra-deep pyrosequencing data that uses biological filters to discard artifactual or non-functional V3 sequences followed by statistical filters to determine position-specific sensitivity thresholds, rather than arbitrary fixed cut-offs. It allows to retain authentic sequences with point mutations at V3 positions of interest and discard artifactual ones with accurate sensitivity thresholds. PMID:26585833

Position-specific automated processing of V3 env ultra-deep pyrosequencing data for predicting HIV-1 tropism.

PubMed

Jeanne, Nicolas; Saliou, Adrien; Carcenac, Romain; Lefebvre, Caroline; Dubois, Martine; Cazabat, Michelle; Nicot, Florence; Loiseau, Claire; Raymond, Stéphanie; Izopet, Jacques; Delobel, Pierre

2015-11-20

HIV-1 coreceptor usage must be accurately determined before starting CCR5 antagonist-based treatment as the presence of undetected minor CXCR4-using variants can cause subsequent virological failure. Ultra-deep pyrosequencing of HIV-1 V3 env allows to detect low levels of CXCR4-using variants that current genotypic approaches miss. However, the computation of the mass of sequence data and the need to identify true minor variants while excluding artifactual sequences generated during amplification and ultra-deep pyrosequencing is rate-limiting. Arbitrary fixed cut-offs below which minor variants are discarded are currently used but the errors generated during ultra-deep pyrosequencing are sequence-dependant rather than random. We have developed an automated processing of HIV-1 V3 env ultra-deep pyrosequencing data that uses biological filters to discard artifactual or non-functional V3 sequences followed by statistical filters to determine position-specific sensitivity thresholds, rather than arbitrary fixed cut-offs. It allows to retain authentic sequences with point mutations at V3 positions of interest and discard artifactual ones with accurate sensitivity thresholds.

Does an inter-flaw length control the accuracy of rupture forecasting in geological materials?

NASA Astrophysics Data System (ADS)

Vasseur, Jérémie; Wadsworth, Fabian B.; Heap, Michael J.; Main, Ian G.; Lavallée, Yan; Dingwell, Donald B.

2017-10-01

Multi-scale failure of porous materials is an important phenomenon in nature and in material physics - from controlled laboratory tests to rockbursts, landslides, volcanic eruptions and earthquakes. A key unsolved research question is how to accurately forecast the time of system-sized catastrophic failure, based on observations of precursory events such as acoustic emissions (AE) in laboratory samples, or, on a larger scale, small earthquakes. Until now, the length scale associated with precursory events has not been well quantified, resulting in forecasting tools that are often unreliable. Here we test the hypothesis that the accuracy of the forecast failure time depends on the inter-flaw distance in the starting material. We use new experimental datasets for the deformation of porous materials to infer the critical crack length at failure from a static damage mechanics model. The style of acceleration of AE rate prior to failure, and the accuracy of forecast failure time, both depend on whether the cracks can span the inter-flaw length or not. A smooth inverse power-law acceleration of AE rate to failure, and an accurate forecast, occurs when the cracks are sufficiently long to bridge pore spaces. When this is not the case, the predicted failure time is much less accurate and failure is preceded by an exponential AE rate trend. Finally, we provide a quantitative and pragmatic correction for the systematic error in the forecast failure time, valid for structurally isotropic porous materials, which could be tested against larger-scale natural failure events, with suitable scaling for the relevant inter-flaw distances.

The Advanced Glaucoma Intervention Study (AGIS): 13. Comparison of treatment outcomes within race: 10-year results.

PubMed

Ederer, Fred; Gaasterland, Douglas A; Dally, Leonard G; Kim, Jonghyeon; VanVeldhuisen, Paul C; Blackwell, Beth; Prum, Bruce; Shafranov, George; Allen, Robert C; Beck, Allen

2004-04-01

To present for black and white patients with medically uncontrolled glaucoma 10-year results of treatment with 1 of 2 randomly assigned surgical intervention sequences. Randomized clinical trial. Three hundred thirty-two black patients (451 eyes) and 249 white patients (325 eyes). Eyes had glaucoma that could not be controlled with medications alone. Eyes were randomly assigned to 1 of 2 sequences: argon laser trabeculoplasty (ALT)-trabeculectomy-trabeculectomy (ATT) or trabeculectomy-ALT-trabeculectomy (TAT). Second and third interventions were offered after failure of the preceding intervention. Minimum required intraocular pressure (IOP) for intervention failure ranged upward from 18 mmHg, the value depending on whether recent optic disc or visual field (VF) deterioration occurred, and on the magnitude of the field defect. Patients were observed every 6 months, with total potential follow-up ranging from 8 years, 4 months to 13 years. The averages over follow-up of (1) the percentage of eyes having moderate loss of VF and (2) the percentage of eyes having moderate loss of visual acuity (VA). Race-treatment interactions in VF and VA loss are significant for the 2 main outcome measures; therefore, results of treatment sequence differences are presented by race. In black patients the average percent of eyes with VF loss was less in the ATT sequence than in the TAT sequence, a difference that is not statistically significant at any visit. In white patients, conversely, after 18 months the average percent of eyes with VF loss was less in the TAT sequence, a difference that increases and is statistically significant in years 8 to 10. In both black and white patients, the average percent of eyes with VA loss was less in the ATT sequence; this difference is statistically significant throughout 10 follow-up years in black patients and is statistically significant only for the first year in white patients. In both black and white patients, average IOP reductions were greater in the TAT sequence, though the TAT-ATT difference was substantially greater in white patients. In both black and white patients, first-intervention failure rates were substantially lower for trabeculectomy than for trabeculoplasty. Ten-year cumulative incidence of unilateral VF impairment comparable to legal blindness was modest in eyes of black (ATT 11.9%, TAT 18.5%) and white (ATT 9.9%, TAT 7.3%) patients. Although IOP was lowered in both sequences in black and white patients with medically uncontrolled glaucoma, long-term visual function outcomes were better for the ATT sequence in black patients and better for the TAT sequence in white patients.

Shale Failure Mechanics and Intervention Measures in Underground Coal Mines: Results From 50 Years of Ground Control Safety Research

PubMed Central

2015-01-01

Ground control research in underground coal mines has been ongoing for over 50 years. One of the most problematic issues in underground coal mines is roof failures associated with weak shale. This paper will present a historical narrative on the research the National Institute for Occupational Safety and Health has conducted in relation to rock mechanics and shale. This paper begins by first discussing how shale is classified in relation to coal mining. Characterizing and planning for weak roof sequences is an important step in developing an engineering solution to prevent roof failures. Next, the failure mechanics associated with the weak characteristics of shale will be discussed. Understanding these failure mechanics also aids in applying the correct engineering solutions. The various solutions that have been implemented in the underground coal mining industry to control the different modes of failure will be summarized. Finally, a discussion on current and future research relating to rock mechanics and shale is presented. The overall goal of the paper is to share the collective ground control experience of controlling roof structures dominated by shale rock in underground coal mining. PMID:26549926

Shale Failure Mechanics and Intervention Measures in Underground Coal Mines: Results From 50 Years of Ground Control Safety Research.

PubMed

Murphy, M M

2016-02-01

Ground control research in underground coal mines has been ongoing for over 50 years. One of the most problematic issues in underground coal mines is roof failures associated with weak shale. This paper will present a historical narrative on the research the National Institute for Occupational Safety and Health has conducted in relation to rock mechanics and shale. This paper begins by first discussing how shale is classified in relation to coal mining. Characterizing and planning for weak roof sequences is an important step in developing an engineering solution to prevent roof failures. Next, the failure mechanics associated with the weak characteristics of shale will be discussed. Understanding these failure mechanics also aids in applying the correct engineering solutions. The various solutions that have been implemented in the underground coal mining industry to control the different modes of failure will be summarized. Finally, a discussion on current and future research relating to rock mechanics and shale is presented. The overall goal of the paper is to share the collective ground control experience of controlling roof structures dominated by shale rock in underground coal mining.

Shale Failure Mechanics and Intervention Measures in Underground Coal Mines: Results From 50 Years of Ground Control Safety Research

NASA Astrophysics Data System (ADS)

Murphy, M. M.

2016-02-01

Ground control research in underground coal mines has been ongoing for over 50 years. One of the most problematic issues in underground coal mines is roof failures associated with weak shale. This paper will present a historical narrative on the research the National Institute for Occupational Safety and Health has conducted in relation to rock mechanics and shale. This paper begins by first discussing how shale is classified in relation to coal mining. Characterizing and planning for weak roof sequences is an important step in developing an engineering solution to prevent roof failures. Next, the failure mechanics associated with the weak characteristics of shale will be discussed. Understanding these failure mechanics also aids in applying the correct engineering solutions. The various solutions that have been implemented in the underground coal mining industry to control the different modes of failure will be summarized. Finally, a discussion on current and future research relating to rock mechanics and shale is presented. The overall goal of the paper is to share the collective ground control experience of controlling roof structures dominated by shale rock in underground coal mining.

Contingency Table Browser - prediction of early stage protein structure.

PubMed

Kalinowska, Barbara; Krzykalski, Artur; Roterman, Irena

2015-01-01

The Early Stage (ES) intermediate represents the starting structure in protein folding simulations based on the Fuzzy Oil Drop (FOD) model. The accuracy of FOD predictions is greatly dependent on the accuracy of the chosen intermediate. A suitable intermediate can be constructed using the sequence-structure relationship information contained in the so-called contingency table - this table expresses the likelihood of encountering various structural motifs for each tetrapeptide fragment in the amino acid sequence. The limited accuracy with which such structures could previously be predicted provided the motivation for a more indepth study of the contingency table itself. The Contingency Table Browser is a tool which can visualize, search and analyze the table. Our work presents possible applications of Contingency Table Browser, among them - analysis of specific protein sequences from the point of view of their structural ambiguity.

Iterative refinement of structure-based sequence alignments by Seed Extension

PubMed Central

Kim, Changhoon; Tai, Chin-Hsien; Lee, Byungkook

2009-01-01

Background Accurate sequence alignment is required in many bioinformatics applications but, when sequence similarity is low, it is difficult to obtain accurate alignments based on sequence similarity alone. The accuracy improves when the structures are available, but current structure-based sequence alignment procedures still mis-align substantial numbers of residues. In order to correct such errors, we previously explored the possibility of replacing the residue-based dynamic programming algorithm in structure alignment procedures with the Seed Extension algorithm, which does not use a gap penalty. Here, we describe a new procedure called RSE (Refinement with Seed Extension) that iteratively refines a structure-based sequence alignment. Results RSE uses SE (Seed Extension) in its core, which is an algorithm that we reported recently for obtaining a sequence alignment from two superimposed structures. The RSE procedure was evaluated by comparing the correctly aligned fractions of residues before and after the refinement of the structure-based sequence alignments produced by popular programs. CE, DaliLite, FAST, LOCK2, MATRAS, MATT, TM-align, SHEBA and VAST were included in this analysis and the NCBI's CDD root node set was used as the reference alignments. RSE improved the average accuracy of sequence alignments for all programs tested when no shift error was allowed. The amount of improvement varied depending on the program. The average improvements were small for DaliLite and MATRAS but about 5% for CE and VAST. More substantial improvements have been seen in many individual cases. The additional computation times required for the refinements were negligible compared to the times taken by the structure alignment programs. Conclusion RSE is a computationally inexpensive way of improving the accuracy of a structure-based sequence alignment. It can be used as a standalone procedure following a regular structure-based sequence alignment or to replace the traditional iterative refinement procedures based on residue-level dynamic programming algorithm in many structure alignment programs. PMID:19589133

Identification of a conserved branched RNA structure that functions as a factor-independent terminator.

PubMed

Johnson, Christopher M; Chen, Yuqing; Lee, Heejin; Ke, Ailong; Weaver, Keith E; Dunny, Gary M

2014-03-04

Anti-Q is a small RNA encoded on pCF10, an antibiotic resistance plasmid of Enterococcus faecalis, which negatively regulates conjugation of the plasmid. In this study we sought to understand how Anti-Q is generated relative to larger transcripts of the same operon. We found that Anti-Q folds into a branched structure that functions as a factor-independent terminator. In vitro and in vivo, termination is dependent on the integrity of this structure as well as the presence of a 3' polyuridine tract, but is not dependent on other downstream sequences. In vitro, terminated transcripts are released from RNA polymerase after synthesis. In vivo, a mutant with reduced termination efficiency demonstrated loss of tight control of conjugation function. A search of bacterial genomes revealed the presence of sequences that encode Anti-Q-like RNA structures. In vitro and in vivo experiments demonstrated that one of these functions as a terminator. This work reveals a previously unappreciated flexibility in the structure of factor-independent terminators and identifies a mechanism for generation of functional small RNAs; it should also inform annotation of bacterial sequence features, such as terminators, functional sRNAs, and operons.

Identification of a conserved branched RNA structure that functions as a factor-independent terminator

PubMed Central

Johnson, Christopher M.; Chen, Yuqing; Lee, Heejin; Ke, Ailong; Weaver, Keith E.; Dunny, Gary M.

2014-01-01

Anti-Q is a small RNA encoded on pCF10, an antibiotic resistance plasmid of Enterococcus faecalis, which negatively regulates conjugation of the plasmid. In this study we sought to understand how Anti-Q is generated relative to larger transcripts of the same operon. We found that Anti-Q folds into a branched structure that functions as a factor-independent terminator. In vitro and in vivo, termination is dependent on the integrity of this structure as well as the presence of a 3′ polyuridine tract, but is not dependent on other downstream sequences. In vitro, terminated transcripts are released from RNA polymerase after synthesis. In vivo, a mutant with reduced termination efficiency demonstrated loss of tight control of conjugation function. A search of bacterial genomes revealed the presence of sequences that encode Anti-Q–like RNA structures. In vitro and in vivo experiments demonstrated that one of these functions as a terminator. This work reveals a previously unappreciated flexibility in the structure of factor-independent terminators and identifies a mechanism for generation of functional small RNAs; it should also inform annotation of bacterial sequence features, such as terminators, functional sRNAs, and operons. PMID:24550474

Static Strength of Adhesively-bonded Woven Fabric Kenaf Composite Plates

NASA Astrophysics Data System (ADS)

Hilton, Ahmad; Lee, Sim Yee; Supar, Khairi

2017-06-01

Natural fibers are potentially used as reinforcing materials and combined with epoxy resin as matrix system to form a superior specific strength (or stiffness) materials known as composite materials. The advantages of implementing natural fibers such as kenaf fibers are renewable, less hazardous during fabrication and handling process; and relatively cheap compared to synthetic fibers. The aim of current work is to conduct a parametric study on static strength of adhesively bonded woven fabric kenaf composite plates. Fabrication of composite panels were conducted using hand lay-up techniques, with variation of stacking sequence, over-lap length, joint types and lay-up types as identified in testing series. Quasi-static testing was carried out using mechanical testing following code of practice. Load-displacement profiles were analyzed to study its structural response prior to ultimate failures. It was found that cross-ply lay-up demonstrates better static strength compared to quasi-isotropic lay-up counterparts due to larger volume of 0° plies exhibited in cross-ply lay-up. Consequently, larger overlap length gives better joining strength, as expected, however this promotes to weight penalty in the joining structure. Most samples showed failures within adhesive region known as cohesive failure modes, however, few sample demonstrated interface failure. Good correlations of parametric study were found and discussed in the respective section.

[Sequential course and prospective management of ifosfamide-induced multi-organ toxicity].

PubMed

Mollenkopf, A; du Bois, A; Meerpohl, H G

1996-10-01

We report on an 66-year old female in whom we diagnosed uterine carcinosarcoma and concurrent breast cancer. As first-line treatment the patient received ifosfamide 4.8 mg/m2 body surface. During her second course of chemotherapy she developed sequentially life-threatening toxicities; severe emesis followed by nephrotoxicity, neurotoxicity and myelosuppression. Early prophylactic administration of rhG-CSF (Filgrastim) helped to overcome severe, potentially fatal myelosuppression. The course of severe toxicities following high doses of ifosfamide might reflect a dependent sequence, where one organ failure causes a subsequent organ failure. Prophylactic treatment of anticipated toxicity should be considered for the management of severe ifosfamide-induced toxicity. Such treatment may consist of sufficient antiemesis, sufficient hydration, as well as a therapy with methylene blue in case of severe neurotoxicity.

Role of Sequence and Structural Polymorphism on the Mechanical Properties of Amyloid Fibrils

PubMed Central

Kim, Jae In; Na, Sungsoo; Eom, Kilho

2014-01-01

Amyloid fibrils playing a critical role in disease expression, have recently been found to exhibit the excellent mechanical properties such as elastic modulus in the order of 10 GPa, which is comparable to that of other mechanical proteins such as microtubule, actin filament, and spider silk. These remarkable mechanical properties of amyloid fibrils are correlated with their functional role in disease expression. This suggests the importance in understanding how these excellent mechanical properties are originated through self-assembly process that may depend on the amino acid sequence. However, the sequence-structure-property relationship of amyloid fibrils has not been fully understood yet. In this work, we characterize the mechanical properties of human islet amyloid polypeptide (hIAPP) fibrils with respect to their molecular structures as well as their amino acid sequence by using all-atom explicit water molecular dynamics (MD) simulation. The simulation result suggests that the remarkable bending rigidity of amyloid fibrils can be achieved through a specific self-aggregation pattern such as antiparallel stacking of β strands (peptide chain). Moreover, we have shown that a single point mutation of hIAPP chain constituting a hIAPP fibril significantly affects the thermodynamic stability of hIAPP fibril formed by parallel stacking of peptide chain, and that a single point mutation results in a significant change in the bending rigidity of hIAPP fibrils formed by antiparallel stacking of β strands. This clearly elucidates the role of amino acid sequence on not only the equilibrium conformations of amyloid fibrils but also their mechanical properties. Our study sheds light on sequence-structure-property relationships of amyloid fibrils, which suggests that the mechanical properties of amyloid fibrils are encoded in their sequence-dependent molecular architecture. PMID:24551113

Using chaos to generate variations on movement sequences

NASA Astrophysics Data System (ADS)

Bradley, Elizabeth; Stuart, Joshua

1998-12-01

We describe a method for introducing variations into predefined motion sequences using a chaotic symbol-sequence reordering technique. A progression of symbols representing the body positions in a dance piece, martial arts form, or other motion sequence is mapped onto a chaotic trajectory, establishing a symbolic dynamics that links the movement sequence and the attractor structure. A variation on the original piece is created by generating a trajectory with slightly different initial conditions, inverting the mapping, and using special corpus-based graph-theoretic interpolation schemes to smooth any abrupt transitions. Sensitive dependence guarantees that the variation is different from the original; the attractor structure and the symbolic dynamics guarantee that the two resemble one another in both aesthetic and mathematical senses.

Sequence-dependent modelling of local DNA bending phenomena: curvature prediction and vibrational analysis.

PubMed

Vlahovicek, K; Munteanu, M G; Pongor, S

1999-01-01

Bending is a local conformational micropolymorphism of DNA in which the original B-DNA structure is only distorted but not extensively modified. Bending can be predicted by simple static geometry models as well as by a recently developed elastic model that incorporate sequence dependent anisotropic bendability (SDAB). The SDAB model qualitatively explains phenomena including affinity of protein binding, kinking, as well as sequence-dependent vibrational properties of DNA. The vibrational properties of DNA segments can be studied by finite element analysis of a model subjected to an initial bending moment. The frequency spectrum is obtained by applying Fourier analysis to the displacement values in the time domain. This analysis shows that the spectrum of the bending vibrations quite sensitively depends on the sequence, for example the spectrum of a curved sequence is characteristically different from the spectrum of straight sequence motifs of identical basepair composition. Curvature distributions are genome-specific, and pronounced differences are found between protein-coding and regulatory regions, respectively, that is, sites of extreme curvature and/or bendability are less frequent in protein-coding regions. A WWW server is set up for the prediction of curvature and generation of 3D models from DNA sequences (http:@www.icgeb.trieste.it/dna).

Detection of nucleic acids by multiple sequential invasive cleavages

DOEpatents

Hall, Jeff G.; Lyamichev, Victor I.; Mast, Andrea L.; Brow, Mary Ann D.

1999-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof. The present invention further relates to methods and devices for the separation of nucleic acid molecules based on charge. The present invention also provides methods for the detection of non-target cleavage products via the formation of a complete and activated protein binding region. The invention further provides sensitive and specific methods for the detection of human cytomegalovirus nucleic acid in a sample.

Nucleic acid detection kits

DOEpatents

Hall, Jeff G.; Lyamichev, Victor I.; Mast, Andrea L.; Brow, Mary Ann; Kwiatkowski, Robert W.; Vavra, Stephanie H.

2005-03-29

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof. The present invention further relates to methods and devices for the separation of nucleic acid molecules based on charge. The present invention also provides methods for the detection of non-target cleavage products via the formation of a complete and activated protein binding region. The invention further provides sensitive and specific methods for the detection of nucleic acid from various viruses in a sample.

Detection of nucleic acids by multiple sequential invasive cleavages 02

DOEpatents

Hall, Jeff G.; Lyamichev, Victor I.; Mast, Andrea L.; Brow, Mary Ann D.

2002-01-01

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof. The present invention further relates to methods and devices for the separation of nucleic acid molecules based on charge. The present invention also provides methods for the detection of non-target cleavage products via the formation of a complete and activated protein binding region. The invention further provides sensitive and specific methods for the detection of human cytomegalovirus nucleic acid in a sample.

Detection of nucleic acids by multiple sequential invasive cleavages

DOEpatents

Hall, Jeff G; Lyamichev, Victor I; Mast, Andrea L; Brow, Mary Ann D

2012-10-16

The present invention relates to means for the detection and characterization of nucleic acid sequences, as well as variations in nucleic acid sequences. The present invention also relates to methods for forming a nucleic acid cleavage structure on a target sequence and cleaving the nucleic acid cleavage structure in a site-specific manner. The structure-specific nuclease activity of a variety of enzymes is used to cleave the target-dependent cleavage structure, thereby indicating the presence of specific nucleic acid sequences or specific variations thereof. The present invention further relates to methods and devices for the separation of nucleic acid molecules based on charge. The present invention also provides methods for the detection of non-target cleavage products via the formation of a complete and activated protein binding region. The invention further provides sensitive and specific methods for the detection of human cytomegalovirus nucleic acid in a sample.

Contingent plan structures for spacecraft

NASA Technical Reports Server (NTRS)

Drummond, M.; Currie, K.; Tate, A.

1987-01-01

Most current AI planners build partially ordered plan structures which delay decisions on action ordering. Such structures cannot easily represent contingent actions. A representation which can is presented. The representation has some other useful features: it provides a good account of the causal structure of a plan, can be used to describe disjunctive actions, and it offers a planner the opportunity of even less commitment than the classical partial order on actions. The use of this representation is demonstrated in an on-board spacecraft activity sequencing problem. Contingent plan execution in a spacecraft context highlights the requirements for a fully disjunctive representation, since communication delays often prohibit extensive ground-based accounting for remotely sensed information and replanning on execution failure.

A Novel Bioinformatics Strategy to Analyze Microbial Big Sequence Data for Efficient Knowledge Discovery: Batch-Learning Self-Organizing Map (BLSOM).

PubMed

Iwasaki, Yuki; Abe, Takashi; Wada, Kennosuke; Wada, Yoshiko; Ikemura, Toshimichi

2013-11-20

With the remarkable increase of genomic sequence data of microorganisms, novel tools are needed for comprehensive analyses of the big sequence data available. The self-organizing map (SOM) is an effective tool for clustering and visualizing high-dimensional data, such as oligonucleotide composition on one map. By modifying the conventional SOM, we developed batch-learning SOM (BLSOM), which allowed classification of sequence fragments (e.g., 1 kb) according to phylotypes, solely depending on oligonucleotide composition. Metagenomics studies of uncultivable microorganisms in clinical and environmental samples should allow extensive surveys of genes important in life sciences. BLSOM is most suitable for phylogenetic assignment of metagenomic sequences, because fragmental sequences can be clustered according to phylotypes, solely depending on oligonucleotide composition. We first constructed oligonucleotide BLSOMs for all available sequences from genomes of known species, and by mapping metagenomic sequences on these large-scale BLSOMs, we can predict phylotypes of individual metagenomic sequences, revealing a microbial community structure of uncultured microorganisms, including viruses. BLSOM has shown that influenza viruses isolated from humans and birds clearly differ in oligonucleotide composition. Based on this host-dependent oligonucleotide composition, we have proposed strategies for predicting directional changes of virus sequences and for surveilling potentially hazardous strains when introduced into humans from non-human sources.

In vitro fluorescence studies of transcription factor IIB-DNA interaction.

PubMed

Górecki, Andrzej; Figiel, Małgorzata; Dziedzicka-Wasylewska, Marta

2015-01-01

General transcription factor TFIIB is one of the basal constituents of the preinitiation complex of eukaryotic RNA polymerase II, acting as a bridge between the preinitiation complex and the polymerase, and binding promoter DNA in an asymmetric manner, thereby defining the direction of the transcription. Methods of fluorescence spectroscopy together with circular dichroism spectroscopy were used to observe conformational changes in the structure of recombinant human TFIIB after binding to specific DNA sequence. To facilitate the exploration of the structural changes, several site-directed mutations have been introduced altering the fluorescence properties of the protein. Our observations showed that binding of specific DNA sequences changed the protein structure and dynamics, and TFIIB may exist in two conformational states, which can be described by a different microenvironment of W52. Fluorescence studies using both intrinsic and exogenous fluorophores showed that these changes significantly depended on the recognition sequence and concerned various regions of the protein, including those interacting with other transcription factors and RNA polymerase II. DNA binding can cause rearrangements in regions of proteins interacting with the polymerase in a manner dependent on the recognized sequences, and therefore, influence the gene expression.

Cost-effective sequencing of full-length cDNA clones powered by a de novo-reference hybrid assembly.

PubMed

Kuroshu, Reginaldo M; Watanabe, Junichi; Sugano, Sumio; Morishita, Shinichi; Suzuki, Yutaka; Kasahara, Masahiro

2010-05-07

Sequencing full-length cDNA clones is important to determine gene structures including alternative splice forms, and provides valuable resources for experimental analyses to reveal the biological functions of coded proteins. However, previous approaches for sequencing cDNA clones were expensive or time-consuming, and therefore, a fast and efficient sequencing approach was demanded. We developed a program, MuSICA 2, that assembles millions of short (36-nucleotide) reads collected from a single flow cell lane of Illumina Genome Analyzer to shotgun-sequence approximately 800 human full-length cDNA clones. MuSICA 2 performs a hybrid assembly in which an external de novo assembler is run first and the result is then improved by reference alignment of shotgun reads. We compared the MuSICA 2 assembly with 200 pooled full-length cDNA clones finished independently by the conventional primer-walking using Sanger sequencers. The exon-intron structure of the coding sequence was correct for more than 95% of the clones with coding sequence annotation when we excluded cDNA clones insufficiently represented in the shotgun library due to PCR failure (42 out of 200 clones excluded), and the nucleotide-level accuracy of coding sequences of those correct clones was over 99.99%. We also applied MuSICA 2 to full-length cDNA clones from Toxoplasma gondii, to confirm that its ability was competent even for non-human species. The entire sequencing and shotgun assembly takes less than 1 week and the consumables cost only approximately US$3 per clone, demonstrating a significant advantage over previous approaches.

Mechanical responses of a-axis GaN nanowires under axial loads

NASA Astrophysics Data System (ADS)

Wang, R. J.; Wang, C. Y.; Feng, Y. T.; Tang, Chun

2018-03-01

Gallium nitride (GaN) nanowires (NWs) hold technological significance as functional components in emergent nano-piezotronics. However, the examination of their mechanical responses, especially the mechanistic understanding of behavior beyond elasticity (at failure) remains limited due to the constraints of in situ experimentation. We therefore performed simulations of the molecular dynamics (MD) of the mechanical behavior of [1\\bar{2}10]-oriented GaN NWs subjected to tension or compression loading until failure. The mechanical properties and critical deformation processes are characterized in relation to NW sizes and loading conditions. Detailed examinations revealed that the failure mechanisms are size-dependent and controlled by the dislocation mobility on shuffle-set pyramidal planes. The size dependence of the elastic behavior is also examined in terms of the surface structure determined modification of Young’s modulus. In addition, a comparison with c-axis NWs is made to show how size-effect trends vary with the growth orientation of NWs.

A continuum model for damage evolution in laminated composites

NASA Technical Reports Server (NTRS)

Lo, D. C.; Allen, D. H.; Harris, C. E.

1991-01-01

The accumulation of matrix cracking is examined using continuum damage mechanics lamination theory. A phenomenologically based damage evolutionary relationship is proposed for matrix cracking in continuous fiber reinforced laminated composites. The use of material dependent properties and damage dependent laminate averaged ply stresses in this evolutionary relationship permits its application independently of the laminate stacking sequence. Several load histories are applied to crossply laminates using this model, and the results are compared to published experimental data. The stress redistribution among the plies during the accumulation of matrix damage is also examined. It is concluded that characteristics of the stress redistribution process could assist in the analysis of the progressive failure process in laminated composites.

The right inferior frontal gyrus processes nested non-local dependencies in music.

PubMed

Cheung, Vincent K M; Meyer, Lars; Friederici, Angela D; Koelsch, Stefan

2018-02-28

Complex auditory sequences known as music have often been described as hierarchically structured. This permits the existence of non-local dependencies, which relate elements of a sequence beyond their temporal sequential order. Previous studies in music have reported differential activity in the inferior frontal gyrus (IFG) when comparing regular and irregular chord-transitions based on theories in Western tonal harmony. However, it is unclear if the observed activity reflects the interpretation of hierarchical structure as the effects are confounded by local irregularity. Using functional magnetic resonance imaging (fMRI), we found that violations to non-local dependencies in nested sequences of three-tone musical motifs in musicians elicited increased activity in the right IFG. This is in contrast to similar studies in language which typically report the left IFG in processing grammatical syntax. Effects of increasing auditory working demands are moreover reflected by distributed activity in frontal and parietal regions. Our study therefore demonstrates the role of the right IFG in processing non-local dependencies in music, and suggests that hierarchical processing in different cognitive domains relies on similar mechanisms that are subserved by domain-selective neuronal subpopulations.

Torque measurements reveal sequence-specific cooperative transitions in supercoiled DNA

PubMed Central

Oberstrass, Florian C.; Fernandes, Louis E.; Bryant, Zev

2012-01-01

B-DNA becomes unstable under superhelical stress and is able to adopt a wide range of alternative conformations including strand-separated DNA and Z-DNA. Localized sequence-dependent structural transitions are important for the regulation of biological processes such as DNA replication and transcription. To directly probe the effect of sequence on structural transitions driven by torque, we have measured the torsional response of a panel of DNA sequences using single molecule assays that employ nanosphere rotational probes to achieve high torque resolution. The responses of Z-forming d(pGpC)n sequences match our predictions based on a theoretical treatment of cooperative transitions in helical polymers. “Bubble” templates containing 50–100 bp mismatch regions show cooperative structural transitions similar to B-DNA, although less torque is required to disrupt strand–strand interactions. Our mechanical measurements, including direct characterization of the torsional rigidity of strand-separated DNA, establish a framework for quantitative predictions of the complex torsional response of arbitrary sequences in their biological context. PMID:22474350

Power law tails in phylogenetic systems.

PubMed

Qin, Chongli; Colwell, Lucy J

2018-01-23

Covariance analysis of protein sequence alignments uses coevolving pairs of sequence positions to predict features of protein structure and function. However, current methods ignore the phylogenetic relationships between sequences, potentially corrupting the identification of covarying positions. Here, we use random matrix theory to demonstrate the existence of a power law tail that distinguishes the spectrum of covariance caused by phylogeny from that caused by structural interactions. The power law is essentially independent of the phylogenetic tree topology, depending on just two parameters-the sequence length and the average branch length. We demonstrate that these power law tails are ubiquitous in the large protein sequence alignments used to predict contacts in 3D structure, as predicted by our theory. This suggests that to decouple phylogenetic effects from the interactions between sequence distal sites that control biological function, it is necessary to remove or down-weight the eigenvectors of the covariance matrix with largest eigenvalues. We confirm that truncating these eigenvectors improves contact prediction.

Cascading failures in interdependent networks with finite functional components

NASA Astrophysics Data System (ADS)

Di Muro, M. A.; Buldyrev, S. V.; Stanley, H. E.; Braunstein, L. A.

2016-10-01

We present a cascading failure model of two interdependent networks in which functional nodes belong to components of size greater than or equal to s . We find theoretically and via simulation that in complex networks with random dependency links the transition is first order for s ≥3 and continuous for s =2 . We also study interdependent lattices with a distance constraint r in the dependency links and find that increasing r moves the system from a regime without a phase transition to one with a second-order transition. As r continues to increase, the system collapses in a first-order transition. Each regime is associated with a different structure of domain formation of functional nodes.

Variation of Time Domain Failure Probabilities of Jack-up with Wave Return Periods

NASA Astrophysics Data System (ADS)

Idris, Ahmad; Harahap, Indra S. H.; Ali, Montassir Osman Ahmed

2018-04-01

This study evaluated failure probabilities of jack up units on the framework of time dependent reliability analysis using uncertainty from different sea states representing different return period of the design wave. Surface elevation for each sea state was represented by Karhunen-Loeve expansion method using the eigenfunctions of prolate spheroidal wave functions in order to obtain the wave load. The stochastic wave load was propagated on a simplified jack up model developed in commercial software to obtain the structural response due to the wave loading. Analysis of the stochastic response to determine the failure probability in excessive deck displacement in the framework of time dependent reliability analysis was performed by developing Matlab codes in a personal computer. Results from the study indicated that the failure probability increases with increase in the severity of the sea state representing a longer return period. Although the results obtained are in agreement with the results of a study of similar jack up model using time independent method at higher values of maximum allowable deck displacement, it is in contrast at lower values of the criteria where the study reported that failure probability decreases with increase in the severity of the sea state.

Orion Burn Management, Nominal and Response to Failures

NASA Technical Reports Server (NTRS)

Odegard, Ryan; Goodman, John L.; Barrett, Charles P.; Pohlkamp, Kara; Robinson, Shane

2016-01-01

An approach for managing Orion on-orbit burn execution is described for nominal and failure response scenarios. The burn management strategy for Orion takes into account per-burn variations in targeting, timing, and execution; crew and ground operator intervention and overrides; defined burn failure triggers and responses; and corresponding on-board software sequencing functionality. Burn-to- burn variations are managed through the identification of specific parameters that may be updated for each progressive burn. Failure triggers and automatic responses during the burn timeframe are defined to provide safety for the crew in the case of vehicle failures, along with override capabilities to ensure operational control of the vehicle. On-board sequencing software provides the timeline coordination for performing the required activities related to targeting, burn execution, and responding to burn failures.

Polytypism in the ground state structure of the Lennard-Jonesium.

PubMed

Pártay, Lívia B; Ortner, Christoph; Bartók, Albert P; Pickard, Chris J; Csányi, Gábor

2017-07-26

We present a systematic study of the stability of nineteen different periodic structures using the finite range Lennard-Jones potential model discussing the effects of pressure, potential truncation, cutoff distance and Lennard-Jones exponents. The structures considered are the hexagonal close packed (hcp), face centred cubic (fcc) and seventeen other polytype stacking sequences, such as dhcp and 9R. We found that at certain pressure and cutoff distance values, neither fcc nor hcp is the ground state structure as previously documented, but different polytypic sequences. This behaviour shows a strong dependence on the way the tail of the potential is truncated.

Learning Temporal Statistics for Sensory Predictions in Aging.

PubMed

Luft, Caroline Di Bernardi; Baker, Rosalind; Goldstone, Aimee; Zhang, Yang; Kourtzi, Zoe

2016-03-01

Predicting future events based on previous knowledge about the environment is critical for successful everyday interactions. Here, we ask which brain regions support our ability to predict the future based on implicit knowledge about the past in young and older age. Combining behavioral and fMRI measurements, we test whether training on structured temporal sequences improves the ability to predict upcoming sensory events; we then compare brain regions involved in learning predictive structures between young and older adults. Our behavioral results demonstrate that exposure to temporal sequences without feedback facilitates the ability of young and older adults to predict the orientation of an upcoming stimulus. Our fMRI results provide evidence for the involvement of corticostriatal regions in learning predictive structures in both young and older learners. In particular, we showed learning-dependent fMRI responses for structured sequences in frontoparietal regions and the striatum (putamen) for young adults. However, for older adults, learning-dependent activations were observed mainly in subcortical (putamen, thalamus) regions but were weaker in frontoparietal regions. Significant correlations of learning-dependent behavioral and fMRI changes in these regions suggest a strong link between brain activations and behavioral improvement rather than general overactivation. Thus, our findings suggest that predicting future events based on knowledge of temporal statistics engages brain regions involved in implicit learning in both young and older adults.

Design and Optimization of a Composite Canard Control Surface of an Advanced Fighter Aircraft under Static Loading

NASA Astrophysics Data System (ADS)

Shrivastava, Sachin; Mohite, P. M.

2015-01-01

The minimization of weight and maximization of payload is an ever challenging design procedure for air vehicles. The present study has been carried out with an objective to redesign control surface of an advanced all-metallic fighter aircraft. In this study, the structure made up of high strength aluminum, titanium and ferrous alloys has been attempted to replace by carbon fiber composite (CFC) skin, ribs and stiffeners. This study presents an approach towards development of a methodology for optimization of first-ply failure index (FI) in unidirectional fibrous laminates using Genetic-Algorithms (GA) under quasi-static loading. The GAs, by the application of its operators like reproduction, cross-over, mutation and elitist strategy, optimize the ply-orientations in laminates so as to have minimum FI of Tsai-Wu first-ply failure criterion. The GA optimization procedure has been implemented in MATLAB and interfaced with commercial software ABAQUS using python scripting. FI calculations have been carried out in ABAQUS with user material subroutine (UMAT). The GA's application gave reasonably well-optimized ply-orientations combination at a faster convergence rate. However, the final optimized sequence of ply-orientations is obtained by tweaking the sequences given by GA's based on industrial practices and experience, whenever needed. The present study of conversion of an all metallic structure to partial CFC structure has led to 12% of weight reduction. Therefore, the approach proposed here motivates designer to use CFC with a confidence.

COMPUTER SIMULATION STUDY OF AMYLOID FIBRIL FORMATION BY PALINDROMIC SEQUENCES IN PRION PEPTIDES

PubMed Central

Wagoner, Victoria; Cheon, Mookyung; Chang, Iksoo; Hall, Carol

2011-01-01

We simulate the aggregation of large systems containing palindromic peptides from the Syrian hamster prion protein SHaPrP 113–120 (AGAAAAGA) and the mouse prion protein MoPrP 111–120 (VAGAAAAGAV) and eight sequence variations: GAAAAAAG, (AG)4, A8, GAAAGAAA, A10, V10, GAVAAAAVAG, and VAVAAAAVAV The first two peptides are thought to act as the Velcro that holds the parent prion proteins together in amyloid structures and can form fibrils themselves. Kinetic events along the fibrillization pathway influence the types of structures that occur and variations in the sequence affect aggregation kinetics and fibrillar structure. Discontinuous molecular dynamics simulations using the PRIME20 force field are performed on systems containing 48 peptides starting from a random coil configuration. Depending on the sequence, fibrillar structures form spontaneously over a range of temperatures, below which amorphous aggregates form and above which no aggregation occurs. AGAAAAGA forms well organized fibrillar structures whereas VAGAAAAGAV forms less well organized structures that are partially fibrillar and partially amorphous. The degree of order in the fibrillar structure stems in part from the types of kinetic events leading up to its formation, with AGAAAAGA forming less amorphous structures early in the simulation than VAGAAAAGAV. The ability to form fibrils increases as the chain length and the length of the stretch of hydrophobic residues increase. However as the hydrophobicity of the sequence increases, the ability to form well-ordered structures decreases. Thus, longer hydrophobic sequences form slightly disordered aggregates that are partially fibrillar and partially amorphous. Subtle changes in sequence result in slightly different fibril structures. PMID:21557317

Structural basis of toxicity and immunity in contact-dependent growth inhibition (CDI) systems.

PubMed

Morse, Robert P; Nikolakakis, Kiel C; Willett, Julia L E; Gerrick, Elias; Low, David A; Hayes, Christopher S; Goulding, Celia W

2012-12-26

Contact-dependent growth inhibition (CDI) systems encode polymorphic toxin/immunity proteins that mediate competition between neighboring bacterial cells. We present crystal structures of CDI toxin/immunity complexes from Escherichia coli EC869 and Burkholderia pseudomallei 1026b. Despite sharing little sequence identity, the toxin domains are structurally similar and have homology to endonucleases. The EC869 toxin is a Zn(2+)-dependent DNase capable of completely degrading the genomes of target cells, whereas the Bp1026b toxin cleaves the aminoacyl acceptor stems of tRNA molecules. Each immunity protein binds and inactivates its cognate toxin in a unique manner. The EC869 toxin/immunity complex is stabilized through an unusual β-augmentation interaction. In contrast, the Bp1026b immunity protein exploits shape and charge complementarity to occlude the toxin active site. These structures represent the initial glimpse into the CDI toxin/immunity network, illustrating how sequence-diverse toxins adopt convergent folds yet retain distinct binding interactions with cognate immunity proteins. Moreover, we present visual demonstration of CDI toxin delivery into a target cell.

Maximum-Likelihood Detection Of Noncoherent CPM

NASA Technical Reports Server (NTRS)

Divsalar, Dariush; Simon, Marvin K.

1993-01-01

Simplified detectors proposed for use in maximum-likelihood-sequence detection of symbols in alphabet of size M transmitted by uncoded, full-response continuous phase modulation over radio channel with additive white Gaussian noise. Structures of receivers derived from particular interpretation of maximum-likelihood metrics. Receivers include front ends, structures of which depends only on M, analogous to those in receivers of coherent CPM. Parts of receivers following front ends have structures, complexity of which would depend on N.

Structural and functional analyses of Mycobacterium tuberculosis Rv3315c-encoded metal-dependent homotetrameric cytidine deaminase.

PubMed

Sánchez-Quitian, Zilpa A; Schneider, Cristopher Z; Ducati, Rodrigo G; de Azevedo, Walter F; Bloch, Carlos; Basso, Luiz A; Santos, Diógenes S

2010-03-01

The emergence of drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, has exacerbated the treatment and control of this disease. Cytidine deaminase (CDA) is a pyrimidine salvage pathway enzyme that recycles cytidine and 2'-deoxycytidine for uridine and 2'-deoxyuridine synthesis, respectively. A probable M. tuberculosis CDA-coding sequence (cdd, Rv3315c) was cloned, sequenced, expressed in Escherichia coli BL21(DE3), and purified to homogeneity. Mass spectrometry, N-terminal amino acid sequencing, gel filtration chromatography, and metal analysis of M. tuberculosis CDA (MtCDA) were carried out. These results and multiple sequence alignment demonstrate that MtCDA is a homotetrameric Zn(2+)-dependent metalloenzyme. Steady-state kinetic measurements yielded the following parameters: K(m)=1004 microM and k(cat)=4.8s(-1) for cytidine, and K(m)=1059 microM and k(cat)=3.5s(-1) for 2'-deoxycytidine. The pH dependence of k(cat) and k(cat)/K(M) for cytidine indicate that protonation of a single ionizable group with apparent pK(a) value of 4.3 abolishes activity, and protonation of a group with pK(a) value of 4.7 reduces binding. MtCDA was crystallized and crystal diffracted at 2.0 A resolution. Analysis of the crystallographic structure indicated the presence of a Zn(2+) coordinated by three conserved cysteines and the structure exhibits the canonical cytidine deaminase fold. (c) 2009 Elsevier Inc. All rights reserved.

Recombination-dependent replication and gene conversion homogenize repeat sequences and diversify plastid genome structure.

PubMed

Ruhlman, Tracey A; Zhang, Jin; Blazier, John C; Sabir, Jamal S M; Jansen, Robert K

2017-04-01

There is a misinterpretation in the literature regarding the variable orientation of the small single copy region of plastid genomes (plastomes). The common phenomenon of small and large single copy inversion, hypothesized to occur through intramolecular recombination between inverted repeats (IR) in a circular, single unit-genome, in fact, more likely occurs through recombination-dependent replication (RDR) of linear plastome templates. If RDR can be primed through both intra- and intermolecular recombination, then this mechanism could not only create inversion isomers of so-called single copy regions, but also an array of alternative sequence arrangements. We used Illumina paired-end and PacBio single-molecule real-time (SMRT) sequences to characterize repeat structure in the plastome of Monsonia emarginata (Geraniaceae). We used OrgConv and inspected nucleotide alignments to infer ancestral nucleotides and identify gene conversion among repeats and mapped long (>1 kb) SMRT reads against the unit-genome assembly to identify alternative sequence arrangements. Although M. emarginata lacks the canonical IR, we found that large repeats (>1 kilobase; kb) represent ∼22% of the plastome nucleotide content. Among the largest repeats (>2 kb), we identified GC-biased gene conversion and mapping filtered, long SMRT reads to the M. emarginata unit-genome assembly revealed alternative, substoichiometric sequence arrangements. We offer a model based on RDR and gene conversion between long repeated sequences in the M. emarginata plastome and provide support that both intra-and intermolecular recombination between large repeats, particularly in repeat-rich plastomes, varies unit-genome structure while homogenizing the nucleotide sequence of repeats. © 2017 Botanical Society of America.

Cascading failures in interdependent systems under a flow redistribution model

NASA Astrophysics Data System (ADS)

Zhang, Yingrui; Arenas, Alex; Yaǧan, Osman

2018-02-01

Robustness and cascading failures in interdependent systems has been an active research field in the past decade. However, most existing works use percolation-based models where only the largest component of each network remains functional throughout the cascade. Although suitable for communication networks, this assumption fails to capture the dependencies in systems carrying a flow (e.g., power systems, road transportation networks), where cascading failures are often triggered by redistribution of flows leading to overloading of lines. Here, we consider a model consisting of systems A and B with initial line loads and capacities given by {LA,i,CA ,i} i =1 n and {LB,i,CB ,i} i =1 n, respectively. When a line fails in system A , a fraction of its load is redistributed to alive lines in B , while remaining (1 -a ) fraction is redistributed equally among all functional lines in A ; a line failure in B is treated similarly with b giving the fraction to be redistributed to A . We give a thorough analysis of cascading failures of this model initiated by a random attack targeting p1 fraction of lines in A and p2 fraction in B . We show that (i) the model captures the real-world phenomenon of unexpected large scale cascades and exhibits interesting transition behavior: the final collapse is always first order, but it can be preceded by a sequence of first- and second-order transitions; (ii) network robustness tightly depends on the coupling coefficients a and b , and robustness is maximized at non-trivial a ,b values in general; (iii) unlike most existing models, interdependence has a multifaceted impact on system robustness in that interdependency can lead to an improved robustness for each individual network.

Cascading failures in interdependent systems under a flow redistribution model.

PubMed

Zhang, Yingrui; Arenas, Alex; Yağan, Osman

2018-02-01

Robustness and cascading failures in interdependent systems has been an active research field in the past decade. However, most existing works use percolation-based models where only the largest component of each network remains functional throughout the cascade. Although suitable for communication networks, this assumption fails to capture the dependencies in systems carrying a flow (e.g., power systems, road transportation networks), where cascading failures are often triggered by redistribution of flows leading to overloading of lines. Here, we consider a model consisting of systems A and B with initial line loads and capacities given by {L_{A,i},C_{A,i}}_{i=1}^{n} and {L_{B,i},C_{B,i}}_{i=1}^{n}, respectively. When a line fails in system A, a fraction of its load is redistributed to alive lines in B, while remaining (1-a) fraction is redistributed equally among all functional lines in A; a line failure in B is treated similarly with b giving the fraction to be redistributed to A. We give a thorough analysis of cascading failures of this model initiated by a random attack targeting p_{1} fraction of lines in A and p_{2} fraction in B. We show that (i) the model captures the real-world phenomenon of unexpected large scale cascades and exhibits interesting transition behavior: the final collapse is always first order, but it can be preceded by a sequence of first- and second-order transitions; (ii) network robustness tightly depends on the coupling coefficients a and b, and robustness is maximized at non-trivial a,b values in general; (iii) unlike most existing models, interdependence has a multifaceted impact on system robustness in that interdependency can lead to an improved robustness for each individual network.

Assessment of compressive failure process of cortical bone materials using damage-based model.

PubMed

Ng, Theng Pin; R Koloor, S S; Djuansjah, J R P; Abdul Kadir, M R

2017-02-01

The main failure factors of cortical bone are aging or osteoporosis, accident and high energy trauma or physiological activities. However, the mechanism of damage evolution coupled with yield criterion is considered as one of the unclear subjects in failure analysis of cortical bone materials. Therefore, this study attempts to assess the structural response and progressive failure process of cortical bone using a brittle damaged plasticity model. For this reason, several compressive tests are performed on cortical bone specimens made of bovine femur, in order to obtain the structural response and mechanical properties of the material. Complementary finite element (FE) model of the sample and test is prepared to simulate the elastic-to-damage behavior of the cortical bone using the brittle damaged plasticity model. The FE model is validated in a comparative method using the predicted and measured structural response as load-compressive displacement through simulation and experiment. FE results indicated that the compressive damage initiated and propagated at central region where maximum equivalent plastic strain is computed, which coincided with the degradation of structural compressive stiffness followed by a vast amount of strain energy dissipation. The parameter of compressive damage rate, which is a function dependent on damage parameter and the plastic strain is examined for different rates. Results show that considering a similar rate to the initial slope of the damage parameter in the experiment would give a better sense for prediction of compressive failure. Copyright © 2016 Elsevier Ltd. All rights reserved.

European external quality control study on the competence of laboratories to recognize rare sequence variants resulting in unusual genotyping results.

PubMed

Márki-Zay, János; Klein, Christoph L; Gancberg, David; Schimmel, Heinz G; Dux, László

2009-04-01

Depending on the method used, rare sequence variants adjacent to the single nucleotide polymorphism (SNP) of interest may cause unusual or erroneous genotyping results. Because such rare variants are known for many genes commonly tested in diagnostic laboratories, we organized a proficiency study to assess their influence on the accuracy of reported laboratory results. Four external quality control materials were processed and sent to 283 laboratories through 3 EQA organizers for analysis of the prothrombin 20210G>A mutation. Two of these quality control materials contained sequence variants introduced by site-directed mutagenesis. One hundred eighty-nine laboratories participated in the study. When samples gave a usual result with the method applied, the error rate was 5.1%. Detailed analysis showed that more than 70% of the failures were reported from only 9 laboratories. Allele-specific amplification-based PCR had a much higher error rate than other methods (18.3% vs 2.9%). The variants 20209C>T and [20175T>G; 20179_20180delAC] resulted in unusual genotyping results in 67 and 85 laboratories, respectively. Eighty-three (54.6%) of these unusual results were not recognized, 32 (21.1%) were attributed to technical issues, and only 37 (24.3%) were recognized as another sequence variant. Our findings revealed that some of the participating laboratories were not able to recognize and correctly interpret unusual genotyping results caused by rare SNPs. Our study indicates that the majority of the failures could be avoided by improved training and careful selection and validation of the methods applied.

Applying Agrep to r-NSA to solve multiple sequences approximate matching.

PubMed

Ni, Bing; Wong, Man-Hon; Lam, Chi-Fai David; Leung, Kwong-Sak

2014-01-01

This paper addresses the approximate matching problem in a database consisting of multiple DNA sequences, where the proposed approach applies Agrep to a new truncated suffix array, r-NSA. The construction time of the structure is linear to the database size, and the computations of indexing a substring in the structure are constant. The number of characters processed in applying Agrep is analysed theoretically, and the theoretical upper-bound can approximate closely the empirical number of characters, which is obtained through enumerating the characters in the actual structure built. Experiments are carried out using (synthetic) random DNA sequences, as well as (real) genome sequences including Hepatitis-B Virus and X-chromosome. Experimental results show that, compared to the straight-forward approach that applies Agrep to multiple sequences individually, the proposed approach solves the matching problem in much shorter time. The speed-up of our approach depends on the sequence patterns, and for highly similar homologous genome sequences, which are the common cases in real-life genomes, it can be up to several orders of magnitude.

User-defined Material Model for Thermo-mechanical Progressive Failure Analysis

NASA Technical Reports Server (NTRS)

Knight, Norman F., Jr.

2008-01-01

Previously a user-defined material model for orthotropic bimodulus materials was developed for linear and nonlinear stress analysis of composite structures using either shell or solid finite elements within a nonlinear finite element analysis tool. Extensions of this user-defined material model to thermo-mechanical progressive failure analysis are described, and the required input data are documented. The extensions include providing for temperature-dependent material properties, archival of the elastic strains, and a thermal strain calculation for materials exhibiting a stress-free temperature.

Sequence Dependent Interactions Between DNA and Single-Walled Carbon Nanotubes

NASA Astrophysics Data System (ADS)

Roxbury, Daniel

It is known that single-stranded DNA adopts a helical wrap around a single-walled carbon nanotube (SWCNT), forming a water-dispersible hybrid molecule. The ability to sort mixtures of SWCNTs based on chirality (electronic species) has recently been demonstrated using special short DNA sequences that recognize certain matching SWCNTs of specific chirality. This thesis investigates the intricacies of DNA-SWCNT sequence-specific interactions through both experimental and molecular simulation studies. The DNA-SWCNT binding strengths were experimentally quantified by studying the kinetics of DNA replacement by a surfactant on the surface of particular SWCNTs. Recognition ability was found to correlate strongly with measured binding strength, e.g. DNA sequence (TAT)4 was found to bind 20 times stronger to the (6,5)-SWCNT than sequence (TAT)4T. Next, using replica exchange molecular dynamics (REMD) simulations, equilibrium structures formed by (a) single-strands and (b) multiple-strands of 12-mer oligonucleotides adsorbed on various SWCNTs were explored. A number of structural motifs were discovered in which the DNA strand wraps around the SWCNT and 'stitches' to itself via hydrogen bonding. Great variability among equilibrium structures was observed and shown to be directly influenced by DNA sequence and SWCNT type. For example, the (6,5)-SWCNT DNA recognition sequence, (TAT)4, was found to wrap in a tight single-stranded right-handed helical conformation. In contrast, DNA sequence T12 forms a beta-barrel left-handed structure on the same SWCNT. These are the first theoretical indications that DNA-based SWCNT selectivity can arise on a molecular level. In a biomedical collaboration with the Mayo Clinic, pathways for DNA-SWCNT internalization into healthy human endothelial cells were explored. Through absorbance spectroscopy, TEM imaging, and confocal fluorescence microscopy, we showed that intracellular concentrations of SWCNTs far exceeded those of the incubation solution, which suggested an energy-dependent pathway. Additionally, by means of pharmacological inhibition and vector-induced gene knockout studies, the DNA-SWCNTs were shown to enter the cells via Rac1-mediated macropinocytosis.

RNA-dependent RNA polymerase of hepatitis C virus binds to its coding region RNA stem-loop structure, 5BSL3.2, and its negative strand.

PubMed

Kanamori, Hiroshi; Yuhashi, Kazuhito; Ohnishi, Shin; Koike, Kazuhiko; Kodama, Tatsuhiko

2010-05-01

The hepatitis C virus NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme involved in viral replication. Interaction between NS5B RdRp and the viral RNA sequence is likely to be an important step in viral RNA replication. The C-terminal half of the NS5B-coding sequence, which contains the important cis-acting replication element, has been identified as an NS5B-binding sequence. In the present study, we confirm the specific binding of NS5B to one of the RNA stem-loop structures in the region, 5BSL3.2. In addition, we show that NS5B binds to the complementary strand of 5BSL3.2 (5BSL3.2N). The bulge structure of 5BSL3.2N was shown to be indispensable for tight binding to NS5B. In vitro RdRp activity was inhibited by 5BSL3.2N, indicating the importance of the RNA element in the polymerization by RdRp. These results suggest the involvement of the RNA stem-loop structure of the negative strand in the replication process.

Developmental expression of a regulatory gene is programmed at the level of splicing.

PubMed Central

Chou, T B; Zachar, Z; Bingham, P M

1987-01-01

We report sequence and transcript structures for a 6191-base chromosomal segment containing the presumptive regulatory gene from Drosophila, suppressor-of-white-apricot [su(wa)]. Our results indicate that su(wa) expression is controlled by regulating occurrence of specific splices. Seven introns are removed from the su(wa) primary transcript during precellular blastoderm development. The sequence of this mature RNA indicates that it is a conventional messenger RNA. In contrast, after cellular blastoderm the first two of these introns cease to be efficiently removed. The mature RNAs resulting from this failure to remove the first two introns have structures quite unexpected of mRNAs. We propose that postcellular blastoderm su(wa) expression is repressed by preventing splices necessary to produce a functional mRNA. Implications and mechanisms are discussed. Images Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:2832151

An unbiased adaptive sampling algorithm for the exploration of RNA mutational landscapes under evolutionary pressure.

PubMed

Waldispühl, Jérôme; Ponty, Yann

2011-11-01

The analysis of the relationship between sequences and structures (i.e., how mutations affect structures and reciprocally how structures influence mutations) is essential to decipher the principles driving molecular evolution, to infer the origins of genetic diseases, and to develop bioengineering applications such as the design of artificial molecules. Because their structures can be predicted from the sequence data only, RNA molecules provide a good framework to study this sequence-structure relationship. We recently introduced a suite of algorithms called RNAmutants which allows a complete exploration of RNA sequence-structure maps in polynomial time and space. Formally, RNAmutants takes an input sequence (or seed) to compute the Boltzmann-weighted ensembles of mutants with exactly k mutations, and sample mutations from these ensembles. However, this approach suffers from major limitations. Indeed, since the Boltzmann probabilities of the mutations depend of the free energy of the structures, RNAmutants has difficulties to sample mutant sequences with low G+C-contents. In this article, we introduce an unbiased adaptive sampling algorithm that enables RNAmutants to sample regions of the mutational landscape poorly covered by classical algorithms. We applied these methods to sample mutations with low G+C-contents. These adaptive sampling techniques can be easily adapted to explore other regions of the sequence and structural landscapes which are difficult to sample. Importantly, these algorithms come at a minimal computational cost. We demonstrate the insights offered by these techniques on studies of complete RNA sequence structures maps of sizes up to 40 nucleotides. Our results indicate that the G+C-content has a strong influence on the size and shape of the evolutionary accessible sequence and structural spaces. In particular, we show that low G+C-contents favor the apparition of internal loops and thus possibly the synthesis of tertiary structure motifs. On the other hand, high G+C-contents significantly reduce the size of the evolutionary accessible mutational landscapes.

Evolutionary profiles from the QR factorization of multiple sequence alignments

PubMed Central

Sethi, Anurag; O'Donoghue, Patrick; Luthey-Schulten, Zaida

2005-01-01

We present an algorithm to generate complete evolutionary profiles that represent the topology of the molecular phylogenetic tree of the homologous group. The method, based on the multidimensional QR factorization of numerically encoded multiple sequence alignments, removes redundancy from the alignments and orders the protein sequences by increasing linear dependence, resulting in the identification of a minimal basis set of sequences that spans the evolutionary space of the homologous group of proteins. We observe a general trend that these smaller, more evolutionarily balanced profiles have comparable and, in many cases, better performance in database searches than conventional profiles containing hundreds of sequences, constructed in an iterative and computationally intensive procedure. For more diverse families or superfamilies, with sequence identity <30%, structural alignments, based purely on the geometry of the protein structures, provide better alignments than pure sequence-based methods. Merging the structure and sequence information allows the construction of accurate profiles for distantly related groups. These structure-based profiles outperformed other sequence-based methods for finding distant homologs and were used to identify a putative class II cysteinyl-tRNA synthetase (CysRS) in several archaea that eluded previous annotation studies. Phylogenetic analysis showed the putative class II CysRSs to be a monophyletic group and homology modeling revealed a constellation of active site residues similar to that in the known class I CysRS. PMID:15741270

Robustness analysis of complex networks with power decentralization strategy via flow-sensitive centrality against cascading failures

NASA Astrophysics Data System (ADS)

Guo, Wenzhang; Wang, Hao; Wu, Zhengping

2018-03-01

Most existing cascading failure mitigation strategy of power grids based on complex network ignores the impact of electrical characteristics on dynamic performance. In this paper, the robustness of the power grid under a power decentralization strategy is analysed through cascading failure simulation based on AC flow theory. The flow-sensitive (FS) centrality is introduced by integrating topological features and electrical properties to help determine the siting of the generation nodes. The simulation results of the IEEE-bus systems show that the flow-sensitive centrality method is a more stable and accurate approach and can enhance the robustness of the network remarkably. Through the study of the optimal flow-sensitive centrality selection for different networks, we find that the robustness of the network with obvious small-world effect depends more on contribution of the generation nodes detected by community structure, otherwise, contribution of the generation nodes with important influence on power flow is more critical. In addition, community structure plays a significant role in balancing the power flow distribution and further slowing the propagation of failures. These results are useful in power grid planning and cascading failure prevention.

Cost-Effective Sequencing of Full-Length cDNA Clones Powered by a De Novo-Reference Hybrid Assembly

PubMed Central

Sugano, Sumio; Morishita, Shinichi; Suzuki, Yutaka

2010-01-01

Background Sequencing full-length cDNA clones is important to determine gene structures including alternative splice forms, and provides valuable resources for experimental analyses to reveal the biological functions of coded proteins. However, previous approaches for sequencing cDNA clones were expensive or time-consuming, and therefore, a fast and efficient sequencing approach was demanded. Methodology We developed a program, MuSICA 2, that assembles millions of short (36-nucleotide) reads collected from a single flow cell lane of Illumina Genome Analyzer to shotgun-sequence ∼800 human full-length cDNA clones. MuSICA 2 performs a hybrid assembly in which an external de novo assembler is run first and the result is then improved by reference alignment of shotgun reads. We compared the MuSICA 2 assembly with 200 pooled full-length cDNA clones finished independently by the conventional primer-walking using Sanger sequencers. The exon-intron structure of the coding sequence was correct for more than 95% of the clones with coding sequence annotation when we excluded cDNA clones insufficiently represented in the shotgun library due to PCR failure (42 out of 200 clones excluded), and the nucleotide-level accuracy of coding sequences of those correct clones was over 99.99%. We also applied MuSICA 2 to full-length cDNA clones from Toxoplasma gondii, to confirm that its ability was competent even for non-human species. Conclusions The entire sequencing and shotgun assembly takes less than 1 week and the consumables cost only ∼US$3 per clone, demonstrating a significant advantage over previous approaches. PMID:20479877

Thrombin-like enzymes from snake venom: Structural characterization and mechanism of action.

PubMed

Ullah, Anwar; Masood, Rehana; Ali, Ijaz; Ullah, Kifayat; Ali, Hamid; Akbar, Haji; Betzel, Christian

2018-07-15

Snake venom thrombin-like enzymes (SVTLEs) constitute the major portion (10-24%) of snake venom and these are the second most abundant enzymes present in the crude venom. During envenomation, these enzymes had shown prominently the various pathological effects, such as disturbance in hemostatic system, fibrinogenolysis, fibrinolysis, platelet aggregation, thrombosis, neurologic disorders, activation of coagulation factors, coagulant, procoagulant etc. These enzymes also been used as a therapeutic agent for the treatment of various diseases such as congestive heart failure, ischemic stroke, thrombotic disorders etc. Although the crystal structures of five SVTLEs are available in the Protein Data Bank (PDB), there is no single article present in the literature that has described all of them. The current work describes the structural aspects, structure-based mechanism of action, processing and inhibition of these enzymes. The sequence analysis indicates that these enzymes show a high sequence identity (57-85%) with each other and low sequence identity with trypsin (36-43%), human alpha-thrombin (29-36%) and other snake venom serine proteinases (57-85%). Three-dimensional structural analysis indicates that the loops surrounding the active site are variable both in amino acids composition and length that may convey variable substrate specificity to these enzymes. The surface charge distributions also vary in these enzymes. Docking analysis with suramin shows that this inhibitor preferably binds to the C-terminal region of these enzymes and causes the destabilization of their three-dimensional structure. Copyright © 2018 Elsevier B.V. All rights reserved.

Arthroscopic rotator cuff repair in the weight-bearing shoulder.

PubMed

Kerr, Jacek; Borbas, Paul; Meyer, Dominik C; Gerber, Christian; Buitrago Téllez, Carlos; Wieser, Karl

2015-12-01

In wheelchair-dependent individuals, pain often develops because of rotator cuff tendon failure and/or osteoarthritis of the glenohumeral joint. The purposes of this study were to investigate (1) specific rotator cuff tear patterns, (2) structural healing, and (3) clinical outcomes after arthroscopic rotator cuff repair in a cohort of wheelchair-dependent patients. Forty-six shoulders with a mean follow-up of 46 months (range, 24-82 months; SD, 13 months) from a consecutive series of 61 shoulders in 56 patients (46 men and 10 women) undergoing arthroscopic rotator cuff repair were available for analysis. Clinical outcome analysis was performed using the Constant-Murley score, the Subjective Shoulder Value, and the American Shoulder and Elbow Surgeons score. The integrity of the repair was analyzed by ultrasound. Of the shoulders, 87% had supraspinatus involvement, 70% had subscapularis involvement, and 57% had an anterosuperior lesion involving both the supraspinatus and subscapularis. Despite an overall structural failure rate of 33%, the patients showed improvements in the Constant-Murley score from 50 points (range, 22-86 points; SD, 16 points) preoperatively to 80 points (range, 40-98 points; SD, 12 points) postoperatively and in the American Shoulder and Elbow Surgeons score from 56 points (range, 20-92 points; SD, 20 points) preoperatively to 92 points (range, 53-100 points; SD, 10 points) postoperatively, with a mean postoperative Subjective Shoulder Value of 84% (range, 25%-100%; SD, 17%). Failure of the rotator cuff in weight-bearing shoulders occurs primarily anterosuperiorly. Arthroscopic rotator cuff repair leads to a structural failure rate of 33% but satisfactory functional results with high patient satisfaction at midterm follow-up. Copyright © 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Fault Tree Based Diagnosis with Optimal Test Sequencing for Field Service Engineers

NASA Technical Reports Server (NTRS)

Iverson, David L.; George, Laurence L.; Patterson-Hine, F. A.; Lum, Henry, Jr. (Technical Monitor)

1994-01-01

When field service engineers go to customer sites to service equipment, they want to diagnose and repair failures quickly and cost effectively. Symptoms exhibited by failed equipment frequently suggest several possible causes which require different approaches to diagnosis. This can lead the engineer to follow several fruitless paths in the diagnostic process before they find the actual failure. To assist in this situation, we have developed the Fault Tree Diagnosis and Optimal Test Sequence (FTDOTS) software system that performs automated diagnosis and ranks diagnostic hypotheses based on failure probability and the time or cost required to isolate and repair each failure. FTDOTS first finds a set of possible failures that explain exhibited symptoms by using a fault tree reliability model as a diagnostic knowledge to rank the hypothesized failures based on how likely they are and how long it would take or how much it would cost to isolate and repair them. This ordering suggests an optimal sequence for the field service engineer to investigate the hypothesized failures in order to minimize the time or cost required to accomplish the repair task. Previously, field service personnel would arrive at the customer site and choose which components to investigate based on past experience and service manuals. Using FTDOTS running on a portable computer, they can now enter a set of symptoms and get a list of possible failures ordered in an optimal test sequence to help them in their decisions. If facilities are available, the field engineer can connect the portable computer to the malfunctioning device for automated data gathering. FTDOTS is currently being applied to field service of medical test equipment. The techniques are flexible enough to use for many different types of devices. If a fault tree model of the equipment and information about component failure probabilities and isolation times or costs are available, a diagnostic knowledge base for that device can be developed easily.

Design and Manufacturing of a Novel Shear Thickening Fluid Composite (STFC) with Enhanced out-of-Plane Properties and Damage Suppression

NASA Astrophysics Data System (ADS)

Pinto, F.; Meo, M.

2017-06-01

The ability to absorb a large amount of energy during an impact event without generating critical damages represents a key feature of new generation composite systems. Indeed, the intrinsic layered nature of composite materials allows the embodiment of specific hybrid plies within the stacking sequence that can be exploited to increase impact resistance and damping of the entire structure without dramatic weight increase. This work is based on the development of an impact-resistant hybrid composite obtained by including a thin layer of Non-Newtonian silica based fluid in a carbon fibres reinforced polymer (CFRP) laminate. This hybrid phase is able to respond to an external solicitation by activating an order-disorder transition that thickens the fluid increasing its viscosity, hence dissipating the energy impact without any critical failure. Several Shear Thickening Fluids (STFs) were manufactured by changing the dimensions of the particles that constitute the disperse phase and their concentrations into the continuous phase. The dynamic viscosity of the different STFs was evaluated via rheometric tests, observing both shear thinning and shear thickening effects depending on the concentration of silica particles. The solutions were then embedded as an active layer within the stacking sequence to manufacture the hybrid CFRP laminates with different embedded STFs. Free vibration tests were carried out in order to assess the damping properties of the different laminates, while low velocity impact tests were used to evaluate their impact properties. Results indicate that the presence of the non-Newtonian fluid is able to absorb up to 45 % of the energy during an impact event for impacts at 2.5 m/s depending on the different concentrations and particles dimensions. These results were confirmed via C-Scan analyses to assess the extent of the internal delamination.

Computational Simulation of Composite Structural Fatigue

NASA Technical Reports Server (NTRS)

Minnetyan, Levon; Chamis, Christos C. (Technical Monitor)

2005-01-01

Progressive damage and fracture of composite structures subjected to monotonically increasing static, tension-tension cyclic, pressurization, and flexural cyclic loading are evaluated via computational simulation. Constituent material properties, stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for composites. Damage initiation, growth, accumulation, and propagation to fracture due to monotonically increasing static and cyclic loads are included in the simulations. Results show the number of cycles to failure at different temperatures and the damage progression sequence during different degradation stages. A procedure is outlined for use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of results with insight for design decisions.

Computational Simulation of Composite Structural Fatigue

NASA Technical Reports Server (NTRS)

Minnetyan, Levon

2004-01-01

Progressive damage and fracture of composite structures subjected to monotonically increasing static, tension-tension cyclic, pressurization, and flexural cyclic loading are evaluated via computational simulation. Constituent material properties, stress and strain limits are scaled up to the structure level to evaluate the overall damage and fracture propagation for composites. Damage initiation, growth, accumulation, and propagation to fracture due to monotonically increasing static and cyclic loads are included in the simulations. Results show the number of cycles to failure at different temperatures and the damage progression sequence during different degradation stages. A procedure is outlined for use of computational simulation data in the assessment of damage tolerance, determination of sensitive parameters affecting fracture, and interpretation of results with insight for design decisions.

How behavioral economics can help to avoid 'The last mile problem' in whole genome sequencing.

PubMed

Blumenthal-Barby, Jennifer S; McGuire, Amy L; Green, Robert C; Ubel, Peter A

2015-01-01

Failure to consider lessons from behavioral economics in the case of whole genome sequencing may cause us to run into the 'last mile problem' - the failure to integrate newly developed technology, on which billions of dollars have been invested, into society in a way that improves human behavior and decision-making.

Structure of homeodomain-leucine zipper/DNA complexes studied using hydroxyl radical cleavage of DNA and methylation interference.

PubMed

Tron, Adriana E; Comelli, Raúl N; Gonzalez, Daniel H

2005-12-27

Homeodomain-leucine zipper (HD-Zip) proteins, unlike most homeodomain proteins, bind a pseudopalindromic DNA sequence as dimers. We have investigated the structure of the DNA complexes formed by two HD-Zip proteins with different nucleotide preferences at the central position of the binding site using footprinting and interference methods. The results indicate that the respective complexes are not symmetric, with the strand bearing a central purine (top strand) showing higher protection around the central region and the bottom strand protected toward the 3' end. Binding to a sequence with a nonpreferred central base pair produces a decrease in protection in either the top or the bottom strand, depending upon the protein. Modeling studies derived from the complex formed by the monomeric Antennapedia homeodomain with DNA indicate that in the HD-Zip/DNA complex the recognition helix of one of the monomers is displaced within the major groove respective to the other one. This monomer seems to lose contacts with a part of the recognition sequence upon binding to the nonpreferred site. The results show that the structure of the complex formed by HD-Zip proteins with DNA is dependent upon both protein intrinsic characteristics and the nucleotides present at the central position of the recognition sequence.

Comprehensive analysis of RNA-protein interactions by high-throughput sequencing-RNA affinity profiling.

PubMed

Tome, Jacob M; Ozer, Abdullah; Pagano, John M; Gheba, Dan; Schroth, Gary P; Lis, John T

2014-06-01

RNA-protein interactions play critical roles in gene regulation, but methods to quantitatively analyze these interactions at a large scale are lacking. We have developed a high-throughput sequencing-RNA affinity profiling (HiTS-RAP) assay by adapting a high-throughput DNA sequencer to quantify the binding of fluorescently labeled protein to millions of RNAs anchored to sequenced cDNA templates. Using HiTS-RAP, we measured the affinity of mutagenized libraries of GFP-binding and NELF-E-binding aptamers to their respective targets and identified critical regions of interaction. Mutations additively affected the affinity of the NELF-E-binding aptamer, whose interaction depended mainly on a single-stranded RNA motif, but not that of the GFP aptamer, whose interaction depended primarily on secondary structure.

Probabilistic sizing of laminates with uncertainties

NASA Technical Reports Server (NTRS)

Shah, A. R.; Liaw, D. G.; Chamis, C. C.

1993-01-01

A reliability based design methodology for laminate sizing and configuration for a special case of composite structures is described. The methodology combines probabilistic composite mechanics with probabilistic structural analysis. The uncertainties of constituent materials (fiber and matrix) to predict macroscopic behavior are simulated using probabilistic theory. Uncertainties in the degradation of composite material properties are included in this design methodology. A multi-factor interaction equation is used to evaluate load and environment dependent degradation of the composite material properties at the micromechanics level. The methodology is integrated into a computer code IPACS (Integrated Probabilistic Assessment of Composite Structures). Versatility of this design approach is demonstrated by performing a multi-level probabilistic analysis to size the laminates for design structural reliability of random type structures. The results show that laminate configurations can be selected to improve the structural reliability from three failures in 1000, to no failures in one million. Results also show that the laminates with the highest reliability are the least sensitive to the loading conditions.

The effects of pressure dependent constitutive model to simulate concrete structures failure under impact loads

NASA Astrophysics Data System (ADS)

Mokhatar, S. N.; Sonoda, Y.; Kamarudin, A. F.; Noh, M. S. Md; Tokumaru, S.

2018-04-01

The main objective of this paper is to explore the effect of confining pressure in the compression and tension zone by simulating the behaviour of reinforced concrete/mortar structures subjected to the impact load. The analysis comprises the numerical simulation of the influences of high mass low speed impact weight dropping on concrete structures, where the analyses are incorporated with meshless method namely as Smoothed Particle Hydrodynamics (SPH) method. The derivation of the plastic stiffness matrix of Drucker-Prager (DP) that extended from Von-Mises (VM) yield criteria to simulate the concrete behaviour were presented in this paper. In which, the displacements for concrete/mortar structures are assumed to be infinitesimal. Furthermore, the influence of the different material model of DP and VM that used numerically for concrete and mortar structures are also discussed. Validation upon existing experimental test results is carried out to investigate the effect of confining pressure, it is found that VM criterion causes unreal impact failure (flexural cracking) of concrete structures.

Evaluating the accuracy of SHAPE-directed RNA secondary structure predictions

PubMed Central

Sükösd, Zsuzsanna; Swenson, M. Shel; Kjems, Jørgen; Heitsch, Christine E.

2013-01-01

Recent advances in RNA structure determination include using data from high-throughput probing experiments to improve thermodynamic prediction accuracy. We evaluate the extent and nature of improvements in data-directed predictions for a diverse set of 16S/18S ribosomal sequences using a stochastic model of experimental SHAPE data. The average accuracy for 1000 data-directed predictions always improves over the original minimum free energy (MFE) structure. However, the amount of improvement varies with the sequence, exhibiting a correlation with MFE accuracy. Further analysis of this correlation shows that accurate MFE base pairs are typically preserved in a data-directed prediction, whereas inaccurate ones are not. Thus, the positive predictive value of common base pairs is consistently higher than the directed prediction accuracy. Finally, we confirm sequence dependencies in the directability of thermodynamic predictions and investigate the potential for greater accuracy improvements in the worst performing test sequence. PMID:23325843

Postmylonitic deformation in the Raft River metamorphic core complex, northwestern Utah: Evidence of a rolling hinge

NASA Astrophysics Data System (ADS)

Manning, Andrew H.; Bartley, John M.

1994-06-01

Much of the recent debate over low-angle normal faults exposed in metamorphic core complexes has centered on the rolling hinge model. The model predicts tilting of seismogenic high-angle normal faults to lower dips by footwall deformation in response to isostatic forces caused by footwall exhumation. This shallow brittle deformation should visibly overprint the mylonitic fabric in the footwall of a metamorphic core complex. The predicted style and magnitude of rolling hinge strain depends upon the macroscopic mechanism by which the footwall deforms. Two end-members have been proposed: subvertical simple shear and flexural failure. Each mechanism should generate a distinctive pattern of structures that strike perpendicular to the regional extension direction. Subvertical simple shear (SVSS) should generate subvertical faults and kink bands with a shear sense antithetic to the detachment. For an SVSS hinge, the hinge-related strain magnitude should depend only on initial fault dip; rolling hinge structures should shorten the mylonitic foliation by >13% for an initial fault dip of >30°. In flexural failure the footwall behaves as a flexed elastic beam that partially fails in response to bending stresses. Resulting structures include conjugate faults and kink bands that both extend and contract the mylonitic foliation. Extensional sets could predominate as a result of superposition of far-field and flexural stresses. Strain magnitudes do not depend on fault dip but depend on the thickness and radius of curvature of the flexed footwall beam and vary with location within that beam. Postmylonitic structures were examined in the footwall of the Raft River metamorphic core complex in northwestern Utah to test these predictions. Observed structures strike perpendicular to the regional extension direction and include joints, normal faults, tension-gash arrays, and both extensional and contractional kink bands. Aside from the subvertical joints, the extensional structures dip moderately to steeply and are mainly either synthetic to the detachment or form conjugate sets. Range-wide, the extensional structures accomplish about 4% elongation of the mylonitic foliation. Contractional structures dip steeply, mainly record shear antithetic to the detachment, and accomplish <1% contraction of the foliation. These observations are consistent with the presence of a rolling hinge in the Raft River Mountains, but a rolling hinge that reoriented a high-angle normal fault by SVSS is excluded. The pattern and magnitudes of strain favor hinge-related deformation mainly by flexural failure with a subordinate component of SVSS.

Management of Arrhythmias in Heart Failure

PubMed Central

Masarone, Daniele; Limongelli, Giuseppe; Rubino, Marta; Valente, Fabio; Vastarella, Rossella; Ammendola, Ernesto; Gravino, Rita; Verrengia, Marina; Salerno, Gemma; Pacileo, Giuseppe

2017-01-01

Heart failure patients are predisposed to develop arrhythmias. Supraventricular arrhythmias can exacerbate the heart failure symptoms by decreasing the effective cardiac output and their control require pharmacological, electrical, or catheter-based intervention. In the setting of atrial flutter or atrial fibrillation, anticoagulation becomes paramount to prevent systemic or cerebral embolism. Patients with heart failure are also prone to develop ventricular arrhythmias that can present a challenge to the managing clinician. The management strategy depends on the type of arrhythmia, the underlying structural heart disease, the severity of heart failure, and the range from optimization of heart failure therapy to catheter ablation. Patients with heart failure, irrespective of ejection fraction are at high risk for developing sudden cardiac death, however risk stratification is a clinical challenge and requires a multiparametric evaluation for identification of patients who should undergo implantation of a cardioverter defibrillator. Finally, patients with heart failure can also develop symptomatic bradycardia, caused by sinus node dysfunction or atrio-ventricular block. The treatment of bradycardia in these patients with pacing is usually straightforward but needs some specific issue. PMID:29367535

Failure and recovery in dynamical networks.

PubMed

Böttcher, L; Luković, M; Nagler, J; Havlin, S; Herrmann, H J

2017-02-03

Failure, damage spread and recovery crucially underlie many spatially embedded networked systems ranging from transportation structures to the human body. Here we study the interplay between spontaneous damage, induced failure and recovery in both embedded and non-embedded networks. In our model the network's components follow three realistic processes that capture these features: (i) spontaneous failure of a component independent of the neighborhood (internal failure), (ii) failure induced by failed neighboring nodes (external failure) and (iii) spontaneous recovery of a component. We identify a metastable domain in the global network phase diagram spanned by the model's control parameters where dramatic hysteresis effects and random switching between two coexisting states are observed. This dynamics depends on the characteristic link length of the embedded system. For the Euclidean lattice in particular, hysteresis and switching only occur in an extremely narrow region of the parameter space compared to random networks. We develop a unifying theory which links the dynamics of our model to contact processes. Our unifying framework may help to better understand controllability in spatially embedded and random networks where spontaneous recovery of components can mitigate spontaneous failure and damage spread in dynamical networks.

cgDNA: a software package for the prediction of sequence-dependent coarse-grain free energies of B-form DNA.

PubMed

Petkevičiūtė, D; Pasi, M; Gonzalez, O; Maddocks, J H

2014-11-10

cgDNA is a package for the prediction of sequence-dependent configuration-space free energies for B-form DNA at the coarse-grain level of rigid bases. For a fragment of any given length and sequence, cgDNA calculates the configuration of the associated free energy minimizer, i.e. the relative positions and orientations of each base, along with a stiffness matrix, which together govern differences in free energies. The model predicts non-local (i.e. beyond base-pair step) sequence dependence of the free energy minimizer. Configurations can be input or output in either the Curves+ definition of the usual helical DNA structural variables, or as a PDB file of coordinates of base atoms. We illustrate the cgDNA package by comparing predictions of free energy minimizers from (a) the cgDNA model, (b) time-averaged atomistic molecular dynamics (or MD) simulations, and (c) NMR or X-ray experimental observation, for (i) the Dickerson-Drew dodecamer and (ii) three oligomers containing A-tracts. The cgDNA predictions are rather close to those of the MD simulations, but many orders of magnitude faster to compute. Both the cgDNA and MD predictions are in reasonable agreement with the available experimental data. Our conclusion is that cgDNA can serve as a highly efficient tool for studying structural variations in B-form DNA over a wide range of sequences. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Controls on size and occurrence of the largest sub-aerial landslide on Earth: Seymareh (Saidmarreh) landslide, Zagros fold-thrust belt, Iran

NASA Astrophysics Data System (ADS)

Roberts, N. J.; Evans, S. G.

2009-12-01

Gigantic (> 1 Gm3) landslides are high-magnitude, low-frequency extremes of mass movements. They are important factors in topographic evolution and hazard in mountain regions due to their magnitude. However, few examples exist for study because of their infrequency. Consequently, controls on the location and size gigantic landslides remain poorly understood. Re-examination of the Seymareh (Saidmarreh) rock avalanche, Zagros fold-thrust belt, shows it to be the largest sub-aerial landslide on Earth (initial failure volume 38 Gm3), thus representing the upper magnitude limit for terrestrial landslides. Detailed examination of the source area (including orbital remote sensing, geotechnical investigation and structural mapping) provides new insights into controls on the size and mobility of gigantic landslides. The gigantic Early Holocene rockslide initiated on the northeast limb of Kabir Kuh, the largest anticline in the Zagros fold-thrust belt, and involved the simultaneous failure of a rock mass measuring 15 km along strike. The rockslide transformed into a rock avalanche that ran-out 19.0 km, filling two adjacent valleys and overtopping an intervening low mountain ridge. The failure involved 220 m of competent jointed limestone (Asmari Formation) underlain by 580 m of weaker mudrock-dominated units. Geologic structure, geomechanical strength and topography of the source slope strongly controlled failure initiation. Extreme landslide dimensions resulted in part from extensive uniform pre-failure stability, produced by structural and topographic features related to the large scale of the Kabir Kuh anticline. High continuity bedding planes determined the large lateral extent along strike. Bedding normal joints, the breached nature of the anticline and fluvial undercutting at the slope toe accommodated expansive lateral, headscarp and toe release, respectively, necessary for extensive failure. Geomechanically weak units at depth aided the penetration of the failure surface into the source slope while low bedding dip (ca. 19°) allowed kinematic freedom of a particularly thick sequence to move downslope. Prevention of gradual rockmass removal by smaller-magnitude, more frequent denudation ensured its preservation for later simultaneous failure. The overall failure surface (11°) cut across weaker beds and finally breached the Asmari carapace by break-out at the base of the source slope. Relative relief of the source slope on Kabir Kuh was modest (1350 m on average) indicating that uniform structural and topographic conditions along strike, shallow bedding dips, and the geomechnical properties of the source rock mass were more important in determining the magnitude of the landslide that forms the upper magnitude limit for subaerial landslides.

Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils

DOE PAGES

Wang, Shih-Ting; Lin, Yiyang; Spencer, Ryan K.; ...

2017-08-03

Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serinemore » with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. Lastly, we anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development of structure-specific imaging agents and aggregation inhibitors.« less

Variation in multiring basic structures as a function of impact angle

NASA Technical Reports Server (NTRS)

Wichman, R. W.; Schultz, P. H.

1992-01-01

Previous studies have demonstrated that the impact process in the laboratory varies as a function of impact angle. This variation is attributed to changes in energy partitioning and projectile failure during the impact and, in simple craters, produces a sequence of progressively smaller and more asymmetric crater forms as impact angle decreases from approximately 20 degrees. Variations in impact angle can produce differences in the appearance of multiring impact basins. Comparisons of Orientale to the more oblique impact structure at Crisium also suggests that these differences primarily reflect the degree of cavity collapse. The relative changes in massif ring topography, basin scarp relief, and the distribution of peripheral mare units are consistent with a reduction in degree of cavity collapse with decreasing impact angle. The prominent uprange basin scarps and the restriction of tectonically derived peripheral mare units along uprange ring structures also may indicate an uprange enhancement of failure during cavity collapse. Finally, although basin ring faults appear to be preferred pathways for mare volcanism, fault-controlled peripheral mare volcanism occurs most readily uprange of an oblique impact; elsewhere such volcanism apparently requires superposition of an impact structure on the ring fault.

Two new mutations in the MT-TW gene leading to the disruption of the secondary structure of the tRNA(Trp) in patients with Leigh syndrome.

PubMed

Mkaouar-Rebai, Emna; Chamkha, Imen; Kammoun, Fatma; Kammoun, Thouraya; Aloulou, Hajer; Hachicha, Mongia; Triki, Chahnez; Fakhfakh, Faiza

2009-07-01

Leigh syndrome is a progressive neurodegenerative disorder occurring in infancy and childhood characterized in most cases by a psychomotor retardation, optic atrophy, ataxia, dystonia, failure to thrive, seizures and respiratory failure. In this study, we performed a systematic sequence analysis of mitochondrial genes associated with LS in Tunisian patients. We sequenced the encoded complex I units: ND2, ND3, ND4, ND5 and ND6 genes and the mitochondrial ATPase 6, tRNA(Val), tRNA(Leu(UUR)), tRNA(Trp) and tRNA(Lys) genes in 10 unrelated patients with Leigh syndrome. We revealed the presence of 34 reported polymorphisms, nine novel nucleotide variants and two new mutations (T5523G and A5559G) in the tested patients. These two mutations were localized in two conserved regions of the tRNA(Trp) and affect, respectively, the D-stem and the T-stem of the mitochondrial tRNA leading to a disruption of the secondary structure of this tRNA. SSP-PCR analysis showed that the T5523G and A5559G mutations were present with respective heteroplasmic rates of 66% and 43 %. We report here the first mutational screening of mitochondrial mutations in Tunisian patients with Leigh syndrome which described two novel mutations associated with this disorder.

A reduced amino acid alphabet for understanding and designing protein adaptation to mutation.

PubMed

Etchebest, C; Benros, C; Bornot, A; Camproux, A-C; de Brevern, A G

2007-11-01

Protein sequence world is considerably larger than structure world. In consequence, numerous non-related sequences may adopt similar 3D folds and different kinds of amino acids may thus be found in similar 3D structures. By grouping together the 20 amino acids into a smaller number of representative residues with similar features, sequence world simplification may be achieved. This clustering hence defines a reduced amino acid alphabet (reduced AAA). Numerous works have shown that protein 3D structures are composed of a limited number of building blocks, defining a structural alphabet. We previously identified such an alphabet composed of 16 representative structural motifs (5-residues length) called Protein Blocks (PBs). This alphabet permits to translate the structure (3D) in sequence of PBs (1D). Based on these two concepts, reduced AAA and PBs, we analyzed the distributions of the different kinds of amino acids and their equivalences in the structural context. Different reduced sets were considered. Recurrent amino acid associations were found in all the local structures while other were specific of some local structures (PBs) (e.g Cysteine, Histidine, Threonine and Serine for the alpha-helix Ncap). Some similar associations are found in other reduced AAAs, e.g Ile with Val, or hydrophobic aromatic residues Trp with Phe and Tyr. We put into evidence interesting alternative associations. This highlights the dependence on the information considered (sequence or structure). This approach, equivalent to a substitution matrix, could be useful for designing protein sequence with different features (for instance adaptation to environment) while preserving mainly the 3D fold.

Does TATA matter? A structural exploration of the selectivity determinants in its complexes with TATA box-binding protein.

PubMed Central

Pastor, N; Pardo, L; Weinstein, H

1997-01-01

The binding of the TATA box-binding protein (TBP) to a TATA sequence in DNA is essential for eukaryotic basal transcription. TBP binds in the minor groove of DNA, causing a large distortion of the DNA helix. Given the apparent stereochemical equivalence of AT and TA basepairs in the minor groove, DNA deformability must play a significant role in binding site selection, because not all AT-rich sequences are bound effectively by TBP. To gain insight into the precise role that the properties of the TATA sequence have in determining the specificity of the DNA substrates of TBP, the solution structure and dynamics of seven DNA dodecamers have been studied by using molecular dynamics simulations. The analysis of the structural properties of basepair steps in these TATA sequences suggests a reason for the preference for alternating pyrimidine-purine (YR) sequences, but indicates that these properties cannot be the sole determinant of the sequence specificity of TBP. Rather, recognition depends on the interplay between the inherent deformability of the DNA and steric complementarity at the molecular interface. Images FIGURE 2 PMID:9251783

THE FAILURE OF STRUCTURAL METALS SUBJECTED TO STRAIN-CYCLING CONDITIONS

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

Swindeman, R.W.; Douglas, D.A.

1958-11-01

Data showing the isothermal strain-cycling capacity of three metals, inconel, Hastelloy "B," and beryllium, are presented. It is noted that at frequencies of 0.5 cycles per minute the data satisfied am equation of the form N/ sup alpha / epsilon /sub p/ = K, where N is the number of cycles to failure, epsilon /sub p/ is the plastic strain per cycle, and alpha and K are constants whose values depend on the structure and test conditions. Data on Ihconel are given to establish the effect of grain size, specimen geometry, temperature, and frequency. It is found that at temperaturesmore » above 1300 F, grain sine amd frequency exert a pronounced effect on the rupture life. Fine-gralned metal survives more cycles before failure than coarsegrained material. Lomg time cycles shorten the number of cycles to failure when the strain per cycle is low. Thermal strain cycling dain for ihconel are compared to strain cycling data at the same mean temperature. Good correlation is found to exist between the two types of data. (auth)« less

CircularLogo: A lightweight web application to visualize intra-motif dependencies.

PubMed

Ye, Zhenqing; Ma, Tao; Kalmbach, Michael T; Dasari, Surendra; Kocher, Jean-Pierre A; Wang, Liguo

2017-05-22

The sequence logo has been widely used to represent DNA or RNA motifs for more than three decades. Despite its intelligibility and intuitiveness, the traditional sequence logo is unable to display the intra-motif dependencies and therefore is insufficient to fully characterize nucleotide motifs. Many methods have been developed to quantify the intra-motif dependencies, but fewer tools are available for visualization. We developed CircularLogo, a web-based interactive application, which is able to not only visualize the position-specific nucleotide consensus and diversity but also display the intra-motif dependencies. Applying CircularLogo to HNF6 binding sites and tRNA sequences demonstrated its ability to show intra-motif dependencies and intuitively reveal biomolecular structure. CircularLogo is implemented in JavaScript and Python based on the Django web framework. The program's source code and user's manual are freely available at http://circularlogo.sourceforge.net . CircularLogo web server can be accessed from http://bioinformaticstools.mayo.edu/circularlogo/index.html . CircularLogo is an innovative web application that is specifically designed to visualize and interactively explore intra-motif dependencies.

Downregulation of viral RNA translation by hepatitis C virus non-structural protein NS5A requires the poly(U/UC) sequence in the 3' UTR.

PubMed

Hoffman, Brett; Li, Zhubing; Liu, Qiang

2015-08-01

Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is essential for viral replication; however, its effect on HCV RNA translation remains controversial partially due to the use of reporters lacking the 3' UTR, where NS5A binds to the poly(U/UC) sequence. We investigated the role of NS5A in HCV translation using a monocistronic RNA containing a Renilla luciferase gene flanked by the HCV UTRs. We found that NS5A downregulated viral RNA translation in a dose-dependent manner. This downregulation required both the 5' and 3' UTRs of HCV because substitution of either sequence with the 5' and 3' UTRs of enterovirus 71 or a cap structure at the 5' end eliminated the effects of NS5A on translation. Translation of the HCV genomic RNA was also downregulated by NS5A. The inhibition of HCV translation by NS5A required the poly(U/UC) sequence in the 3' UTR as NS5A did not affect translation when it was deleted. In addition, we showed that, whilst the amphipathic α-helix of NS5A has no effect on viral translation, the three domains of NS5A can inhibit translation independently, also dependent on the presence of the poly(U/UC) sequence in the 3' UTR. These results suggested that NS5A downregulated HCV RNA translation through a mechanism involving the poly(U/UC) sequence in the 3' UTR.

On the Impact of Widening Vector Registers on Sequence Alignment

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

Daily, Jeffrey A.; Kalyanaraman, Anantharaman; Krishnamoorthy, Sriram

2016-09-22

Vector extensions, such as SSE, have been part of the x86 since the 1990s, with applications in graphics, signal processing, and scientific applications. Although many algorithms and applications can naturally benefit from automatic vectorization techniques, there are still many that are difficult to vectorize due to their dependence on irregular data structures, dense branch operations, or data dependencies. Sequence alignment, one of the most widely used operations in bioinformatics workflows, has a computational footprint that features complex data dependencies. In this paper, we demonstrate that the trend of widening vector registers adversely affects the state-of-the-art sequence alignment algorithm based onmore » striped data layouts. We present a practically efficient SIMD implementation of a parallel scan based sequence alignment algorithm that can better exploit wider SIMD units. We conduct comprehensive workload and use case analyses to characterize the relative behavior of the striped and scan approaches and identify the best choice of algorithm based on input length and SIMD width.« less

Functional maturation of motor nerve terminals in the avian iris: ultrastructure, transmitter metabolism and synaptic reliability

PubMed Central

Pilar, Guillermo; Tuttle, Jeremy; Vaca, Ken

1981-01-01

1. The transformation of easily fatigued embryonic neuromuscular junctions into highly reliable mature terminals was examined by studying functional and morphological changes during development of the avian iris. The mature ability to follow repetitive electrical nerve stimulation was correlated with the rate of acetylcholine (ACh) synthesis and choline uptake, and with the fine structure of the nerve terminals and the post-synaptic elements. 2. The terminals of the ciliary nerve of the chick initially form functional synaptic contacts with the iris muscle at embryonic St. 34-40. At the onset of this period, no Na+-dependent high affinity choline uptake can be demonstrated, and the low level of ACh synthesis present is sensitive to Na+ removal. At St. 36 [3H]ACh synthesis begins to increase, the increment being Na+-dependent. 3. ACh synthesis in the embryonic iris was insensitive to a conditioning [K+]o depolarization even as late as St. 43. Just before hatching, depolarization elicits some augmentation in synthesis, but by 2 days ex ovo this release-induced response has increased by an order of magnitude. 4. Concurrently with the acquisition of the ability to respond to depolarization with accelerated synthesis, neuromuscular transmission in the iris becomes reliable and secure during stimulation at 20 Hz. Embryonic junctions rapidly block during such stimulation, and the failure is shown to be presynaptic in origin, resulting most probably from failure to sustain adequate levels of transmitter release. 5. Ultrastructural examination of the developing ciliary terminals revealed few synaptic vesicles at early stages, and a dearth of other specializations. The sequence of development from these small structurally undistinguished endings to large en plaque junctions completely filled with vesicles was reconstructed and compared to other neuromuscular junctions. Morphological maturation appears progressive with little evidence of discontinuity signalling functional status, but it is only after the terminals enlarge and become closely packed with vesicles that mature synaptic reliability is found. 6. The temporal correlation between responsiveness of transmitter synthesis to depolarization and reliable neuromuscular transmission suggests that modulation of neurotransmitter metabolism in response to demand signals the achievement of junctional maturity. ImagesABPlate 2Plate 3Plate 4 PMID:6279822

Tidal dissipation in rotating low-mass stars and implications for the orbital evolution of close-in planets. I. From the PMS to the RGB at solar metallicity

NASA Astrophysics Data System (ADS)

Gallet, F.; Bolmont, E.; Mathis, S.; Charbonnel, C.; Amard, L.

2017-08-01

Context. Star-planet interactions must be taken into account in stellar models to understand the dynamical evolution of close-in planets. The dependence of the tidal interactions on the structural and rotational evolution of the star is of particular importance and should be correctly treated. Aims: We quantify how tidal dissipation in the convective envelope of rotating low-mass stars evolves from the pre-main sequence up to the red-giant branch depending on the initial stellar mass. We investigate the consequences of this evolution on planetary orbital evolution. Methods: We couple the tidal dissipation formalism previously described to the stellar evolution code STAREVOL and apply this coupling to rotating stars with masses between 0.3 and 1.4 M⊙. As a first step, this formalism assumes a simplified bi-layer stellar structure with corresponding averaged densities for the radiative core and the convective envelope. We use a frequency-averaged treatment of the dissipation of tidal inertial waves in the convection zone (but neglect the dissipation of tidal gravity waves in the radiation zone). In addition, we generalize a recent work by following the orbital evolution of close-in planets using the new tidal dissipation predictions for advanced phases of stellar evolution. Results: On the pre-main sequence the evolution of tidal dissipation is controlled by the evolution of the internal structure of the contracting star. On the main sequence it is strongly driven by the variation of surface rotation that is impacted by magnetized stellar winds braking. The main effect of taking into account the rotational evolution of the stars is to lower the tidal dissipation strength by about four orders of magnitude on the main sequence, compared to a normalized dissipation rate that only takes into account structural changes. Conclusions: The evolution of the dissipation strongly depends on the evolution of the internal structure and rotation of the star. From the pre-main sequence up to the tip of the red-giant branch, it varies by several orders of magnitude, with strong consequences for the orbital evolution of close-in massive planets. These effects are the strongest during the pre-main sequence, implying that the planets are mainly sensitive to the star's early history.

Integrated Design Software Predicts the Creep Life of Monolithic Ceramic Components

NASA Technical Reports Server (NTRS)

1996-01-01

Significant improvements in propulsion and power generation for the next century will require revolutionary advances in high-temperature materials and structural design. Advanced ceramics are candidate materials for these elevated-temperature applications. As design protocols emerge for these material systems, designers must be aware of several innate features, including the degrading ability of ceramics to carry sustained load. Usually, time-dependent failure in ceramics occurs because of two different, delayedfailure mechanisms: slow crack growth and creep rupture. Slow crack growth initiates at a preexisting flaw and continues until a critical crack length is reached, causing catastrophic failure. Creep rupture, on the other hand, occurs because of bulk damage in the material: void nucleation and coalescence that eventually leads to macrocracks which then propagate to failure. Successful application of advanced ceramics depends on proper characterization of material behavior and the use of an appropriate design methodology. The life of a ceramic component can be predicted with the NASA Lewis Research Center's Ceramics Analysis and Reliability Evaluation of Structures (CARES) integrated design programs. CARES/CREEP determines the expected life of a component under creep conditions, and CARES/LIFE predicts the component life due to fast fracture and subcritical crack growth. The previously developed CARES/LIFE program has been used in numerous industrial and Government applications.

The Conservation of Structure and Mechanism of Catalytic Action in a Family of Thiamin Pyrophosphate (TPP)-dependent Enzymes

NASA Technical Reports Server (NTRS)

Dominiak, P.; Ciszak, Ewa

2004-01-01

Thiamin pyrophosphate (TPP)-dependent enzymes are a divergent family of TPP and metal ion binding proteins that perform a wide range of functions with the common decarboxylation steps of a -(O=)C-C(OH)- fragment of alpha-ketoacids and alpha- hydroxyaldehydes. To determine how structure and catalytic action are conserved in the context of large sequence differences existing within this family of enzymes, we have carried out an analysis of TPP-dependent enzymes of known structures. The common structure of TPP-dependent enzymes is formed at the interface of four alpha/beta domains from at least two subunits, which provide for two metal and TPP-binding sites. Residues around these catalytic sites are conserved for functional purpose, while those further away from TPP are conserved for structural reasons. Together they provide a network of contacts required for flip-flop catalytic action within TPP-dependent enzymes. Thus our analysis defines a TPP-action motif that is proposed for annotating TPP-dependent enzymes for advancing functional proteomics.

The Study of the Relationship between Probabilistic Design and Axiomatic Design Methodology. Volume 2

NASA Technical Reports Server (NTRS)

Onwubiko, Chin-Yere; Onyebueke, Landon

1996-01-01

The structural design, or the design of machine elements, has been traditionally based on deterministic design methodology. The deterministic method considers all design parameters to be known with certainty. This methodology is, therefore, inadequate to design complex structures that are subjected to a variety of complex, severe loading conditions. A nonlinear behavior that is dependent on stress, stress rate, temperature, number of load cycles, and time is observed on all components subjected to complex conditions. These complex conditions introduce uncertainties; hence, the actual factor of safety margin remains unknown. In the deterministic methodology, the contingency of failure is discounted; hence, there is a use of a high factor of safety. It may be most useful in situations where the design structures are simple. The probabilistic method is concerned with the probability of non-failure performance of structures or machine elements. It is much more useful in situations where the design is characterized by complex geometry, possibility of catastrophic failure, sensitive loads and material properties. Also included: Comparative Study of the use of AGMA Geometry Factors and Probabilistic Design Methodology in the Design of Compact Spur Gear Set.

Molecular dynamics simulations showing 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) membrane mechanoporation damage under different strain paths.

PubMed

Murphy, M A; Mun, Sungkwang; Horstemeyer, M F; Baskes, M I; Bakhtiary, A; LaPlaca, Michelle C; Gwaltney, Steven R; Williams, Lakiesha N; Prabhu, R K

2018-04-09

Continuum finite element material models used for traumatic brain injury lack local injury parameters necessitating nanoscale mechanical injury mechanisms be incorporated. One such mechanism is membrane mechanoporation, which can occur during physical insults and can be devastating to cells, depending on the level of disruption. The current study investigates the strain state dependence of phospholipid bilayer mechanoporation and failure. Using molecular dynamics, a simplified membrane, consisting of 72 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) phospholipids, was subjected to equibiaxial, 2:1 non-equibiaxial, 4:1 non-equibiaxial, strip biaxial, and uniaxial tensile deformations at a von Mises strain rate of 5.45 × 10 8 s -1 , resulting in velocities in the range of 1 to 4.6 m·s -1 . A water bridge forming through both phospholipid bilayer leaflets was used to determine structural failure. The stress magnitude, failure strain, headgroup clustering, and damage responses were found to be strain state-dependent. The strain state order of detrimentality in descending order was equibiaxial, 2:1 non-equibiaxial, 4:1 non-equibiaxial, strip biaxial, and uniaxial. The phospholipid bilayer failed at von Mises strains of .46, .47, .53, .77, and 1.67 during these respective strain path simulations. Additionally, a Membrane Failure Limit Diagram (MFLD) was created using the pore nucleation, growth, and failure strains to demonstrate safe and unsafe membrane deformation regions. This MFLD allowed representative equations to be derived to predict membrane failure from in-plane strains. These results provide the basis to implement a more accurate mechano-physiological internal state variable continuum model that captures lower length scale damage and will aid in developing higher fidelity injury models.

Structural health monitoring of wind turbine blades : SE 265 Final Project.

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

Barkley, W. C.; Jacobs, Laura D.; Rutherford, A. C.

2006-03-23

ACME Wind Turbine Corporation has contacted our dynamic analysis firm regarding structural health monitoring of their wind turbine blades. ACME has had several failures in previous years. Examples are shown in Figure 1. These failures have resulted in economic loss for the company due to down time of the turbines (lost revenue) and repair costs. Blade failures can occur in several modes, which may depend on the type of construction and load history. Cracking and delamination are some typical modes of blade failure. ACME warranties its turbines and wishes to decrease the number of blade failures they have to repairmore » and replace. The company wishes to implement a real time structural health monitoring system in order to better understand when blade replacement is necessary. Because of warranty costs incurred to date, ACME is interested in either changing the warranty period for the blades in question or predicting imminent failure before it occurs. ACME's current practice is to increase the number of physical inspections when blades are approaching the end of their fatigue lives. Implementation of an in situ monitoring system would eliminate or greatly reduce the need for such physical inspections. Another benefit of such a monitoring system is that the life of any given component could be extended since real conditions would be monitored. The SHM system designed for ACME must be able to operate while the wind turbine is in service. This means that wireless communication options will likely be implemented. Because blade failures occur due to cyclic stresses in the blade material, the sensing system will focus on monitoring strain at various points.« less

Failure of cement hydrates: freeze-thaw and fracture

NASA Astrophysics Data System (ADS)

Ioannidou, Katerina; Del Gado, Emanuela; Ulm, Franz-Josef; Pellenq, Roland

Mechanical and viscoelastic behavior of concrete crucially depends on cement hydrates, the ``glue'' of cement. Even more than the atomistic structure, the mesoscale amorphous texture of cement hydrates over hundreds of nanometers plays a crucial role for material properties. We use simulations that combine information of the nano-scale building units of cement hydrates and on their effective interactions, obtained from atomistic simulations and experiments, into a statistical physics framework for aggregating nanoparticles.Our mesoscale model was able to reconcile different experimental results ranging from small-angle neutron scattering, SEM, adsorption/desorption of N2, and water to nanoindentation and gain the new fundamental insights into the microscopic origin of the properties measured. Our results suggest that heterogeneities developed during the early stages of hydration persist in the structure of C-S-H, impacting the rheological and mechanical performance of the hardened cement paste. In this talk I discuss recent investigation on failure mechanism at the mesoscale of hardened cement paste such as freeze-thaw and fracture. Using correlations between local volume fractions and local stress we provide a link between structural and mechanical heterogeneities during the failure mechanisms.

Impact-initiated damage thresholds in composites

NASA Technical Reports Server (NTRS)

Sharma, A. V.

1980-01-01

An experimental investigation was conducted to study the effect of low velocity projectile impact on the sandwich-type structural components. The materials used in the fabrication of the impact surface were graphite-, Kevlar-, and boron-fibers with appropriate epoxy matrices. The testing of the specimens was performed at moderately low- and high-temperatures as well as at room temperature to assess the impact-initiated strength degradation of the laminates. Eleven laminates with different stacking sequences, orientations, and thicknesses were tested. The low energy projectile impact is considered to simulate the damage caused by runway debris, dropping of the hand tools during servicing, etc., on the secondary aircraft structures fabricated with the composite materials. The results show the preload and the impact energy combinations necessary to cause catastrophic failures in the laminates tested. A set of faired curves indicating the failure thresholds is shown separately for the tension- and compression-loaded laminates. The specific-strengths and -moduli for the various laminates tested are also given.

Robustness of spatial micronetworks

NASA Astrophysics Data System (ADS)

McAndrew, Thomas C.; Danforth, Christopher M.; Bagrow, James P.

2015-04-01

Power lines, roadways, pipelines, and other physical infrastructure are critical to modern society. These structures may be viewed as spatial networks where geographic distances play a role in the functionality and construction cost of links. Traditionally, studies of network robustness have primarily considered the connectedness of large, random networks. Yet for spatial infrastructure, physical distances must also play a role in network robustness. Understanding the robustness of small spatial networks is particularly important with the increasing interest in microgrids, i.e., small-area distributed power grids that are well suited to using renewable energy resources. We study the random failures of links in small networks where functionality depends on both spatial distance and topological connectedness. By introducing a percolation model where the failure of each link is proportional to its spatial length, we find that when failures depend on spatial distances, networks are more fragile than expected. Accounting for spatial effects in both construction and robustness is important for designing efficient microgrids and other network infrastructure.

Failure Atlas for Rolling Bearings in Wind Turbines

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

Tallian, T. E.

2006-01-01

This Atlas is structured as a supplement to the book: T.E. Tallian: Failure Atlas for Hertz Contact Machine Elements, 2nd edition, ASME Press New York, (1999). The content of the atlas comprises plate pages from the book that contain bearing failure images, application data, and descriptions of failure mode, image, and suspected failure causes. Rolling bearings are a critical component of the mainshaft system, gearbox and generator in the rapidly developing technology of power generating wind turbines. The demands for long service life are stringent; the design load, speed and temperature regimes are demanding and the environmental conditions including weather,more » contamination, impediments to monitoring and maintenance are often unfavorable. As a result, experience has shown that the rolling bearings are prone to a variety of failure modes that may prevent achievement of design lives. Morphological failure diagnosis is extensively used in the failure analysis and improvement of bearing operation. Accumulated experience shows that the failure appearance and mode of failure causation in wind turbine bearings has many distinguishing features. The present Atlas is a first effort to collect an interpreted database of specifically wind turbine related rolling bearing failures and make it widely available. This Atlas is structured as a supplement to the book: T. E. Tallian: Failure Atlas for Hertz Contact Machine Elements, 2d edition, ASME Press New York, (1999). The main body of that book is a comprehensive collection of self-contained pages called Plates, containing failure images, bearing and application data, and three descriptions: failure mode, image and suspected failure causes. The Plates are sorted by main failure mode into chapters. Each chapter is preceded by a general technical discussion of the failure mode, its appearance and causes. The Plates part is supplemented by an introductory part, describing the appearance classification and failure classification systems used, and by several indexes. The present Atlas is intended as a supplement to the book. It has the same structure but contains only Plate pages, arranged in chapters, each with a chapter heading page giving a short definition of the failure mode illustrated. Each Plate page is self contained, with images, bearing and application data, and descriptions of the failure mode, the images and the suspected causes. Images are provided in two resolutions: The text page includes 6 by 9 cm images. In addition, high resolution image files are attached, to be retrieved by clicking on their 'push pin' icon. While the material in the present Atlas is self-contained, it is nonetheless a supplement to the book and the complete interpretation of the terse image descriptions and of the system underlying the failure code presupposes familiarity with the book. Since this Atlas is a supplement to the book, its chapter numbering follows that of the book. Not all failure modes covered in the book have been found among the observed wind turbines. For that reason, and because of the omission of introductory matter, the chapter numbers in this Atlas are not a continuous sequence.« less

14 CFR § 1216.203 - Definition of key terms.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section § 1216.203 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION ENVIRONMENTAL..., and their contents to protect against structural failure, to keep water out or to reduce the effects... practicable depends upon the situation and includes consideration of the pertinent factors, such as...

Double-stranded RNA interferes in a sequence-specific manner with the infection of representative members of the two viroid families

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

Carbonell, Alberto; Martinez de Alba, Angel-Emilio; Flores, Ricardo

2008-02-05

Infection by viroids, non-protein-coding circular RNAs, occurs with the accumulation of 21-24 nt viroid-derived small RNAs (vd-sRNAs) with characteristic properties of small interfering RNAs (siRNAs) associated to RNA silencing. The vd-sRNAs most likely derive from dicer-like (DCL) enzymes acting on viroid-specific dsRNA, the key elicitor of RNA silencing, or on the highly structured genomic RNA. Previously, viral dsRNAs delivered mechanically or agroinoculated have been shown to interfere with virus infection in a sequence-specific manner. Here, we report similar results with members of the two families of nuclear- and chloroplast-replicating viroids. Moreover, homologous vd-sRNAs co-delivered mechanically also interfered with one ofmore » the viroids examined. The interference was sequence-specific, temperature-dependent and, in some cases, also dependent on the dose of the co-inoculated dsRNA or vd-sRNAs. The sequence-specific nature of these effects suggests the involvement of the RNA induced silencing complex (RISC), which provides sequence specificity to RNA silencing machinery. Therefore, viroid titer in natural infections might be regulated by the concerted action of DCL and RISC. Viroids could have evolved their secondary structure as a compromise between resistance to DCL and RISC, which act preferentially against RNAs with compact and relaxed secondary structures, respectively. In addition, compartmentation, association with proteins or active replication might also help viroids to elude their host RNA silencing machinery.« less

The role of molecular structure of sugar-phosphate backbone and nucleic acid bases in the formation of single-stranded and double-stranded DNA structures.

PubMed

Poltev, Valeri; Anisimov, Victor M; Danilov, Victor I; Garcia, Dolores; Sanchez, Carolina; Deriabina, Alexandra; Gonzalez, Eduardo; Rivas, Francisco; Polteva, Nina

2014-06-01

Our previous DFT computations of deoxydinucleoside monophosphate complexes with Na(+)-ions (dDMPs) have demonstrated that the main characteristics of Watson-Crick (WC) right-handed duplex families are predefined in the local energy minima of dDMPs. In this work, we study the mechanisms of contribution of chemically monotonous sugar-phosphate backbone and the bases into the double helix irregularity. Geometry optimization of sugar-phosphate backbone produces energy minima matching the WC DNA conformations. Studying the conformational variability of dDMPs in response to sequence permutation, we found that simple replacement of bases in the previously fully optimized dDMPs, e.g. by constructing Pyr-Pur from Pur-Pyr, and Pur-Pyr from Pyr-Pur sequences, while retaining the backbone geometry, automatically produces the mutual base position characteristic of the target sequence. Based on that, we infer that the directionality and the preferable regions of the sugar-phosphate torsions, combined with the difference of purines from pyrimidines in ring shape, determines the sequence dependence of the structure of WC DNA. No such sequence dependence exists in dDMPs corresponding to other DNA conformations (e.g., Z-family and Hoogsteen duplexes). Unlike other duplexes, WC helix is unique by its ability to match the local energy minima of the free single strand to the preferable conformations of the duplex. Copyright © 2013 Wiley Periodicals, Inc.

Early pregnancy assessment in multiple pregnancies.

PubMed

D'Antonio, Francesco; Bhide, Amar

2014-02-01

Early ultrasound assessment and accurate determination of chorionicity is crucial so that appropriate care of multiple pregnancy can be provided. It is best achieved in the first trimester of pregnancy using the Lambda 'λ' and 'T' signs. Accurate labelling of the twins is needed to ensure that the same individual fetus is measured through the pregnancy so that the longitudinal growth pattern can be correctly assessed. Discrepancy in crown-rump length indicates a possibility for future development of selective intrauterine growth restriction. Careful early ultrasound assessment is needed to identify structural and chromosomal anomalies, as twin pregnancies are at increased risk. Twin-to-twin transfusion syndrome, selective intrauterine growth restriction and congenital abnormalities represent the major determinants of perinatal loss in monochorionic pregnancies, and diagnosis and prognosis are discussed in detail. Treatment of twin reverse arterial perfusion sequence is more effective in early pregnancy, so early identification is needed. Outcome of conjoined twins is guarded, and is dependent on the extent of fusion, degree of sharing of organs, associated anomalies, and presence of cardiac failure in utero. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of low-speed impact damage and damage location on behavior of composite panels

NASA Technical Reports Server (NTRS)

Jegley, Dawn C.

1992-01-01

The effect of low speed impact damage on the compression and tension strength of thin and moderately thick composite specimens was investigated. Impact speed ranged from 50 to 550 ft./sec., with corresponding impact energies from 0.25 to 30.7 ft. x lb. Impact locations were near the center of the specimen or near a lateral unloaded edge. In this study, thin specimens with only 90 degree and + or - 45 degree plies that were impacted away from the unloaded edge suffered less reduction in load carrying capability because of impact damage than of the same specimens impacted near the unloaded edge. Failure loads of thicker compression loaded specimens with a similar stacking sequence were independent of impact location. Failure loads of thin tension loaded specimens with 0 degree plies was independent of impact location, whereas failure loads of thicker compression loaded specimens with 0 degree plies were dependent upon impact location. A finite element analysis indicated that high axial strains occurred near the unloaded edges of the postbuckled panels. Thus, impacts near the unloaded edge would significantly affect the behavior of the postbuckled panel.

Graphical workstation capability for reliability modeling

NASA Technical Reports Server (NTRS)

Bavuso, Salvatore J.; Koppen, Sandra V.; Haley, Pamela J.

1992-01-01

In addition to computational capabilities, software tools for estimating the reliability of fault-tolerant digital computer systems must also provide a means of interfacing with the user. Described here is the new graphical interface capability of the hybrid automated reliability predictor (HARP), a software package that implements advanced reliability modeling techniques. The graphics oriented (GO) module provides the user with a graphical language for modeling system failure modes through the selection of various fault-tree gates, including sequence-dependency gates, or by a Markov chain. By using this graphical input language, a fault tree becomes a convenient notation for describing a system. In accounting for any sequence dependencies, HARP converts the fault-tree notation to a complex stochastic process that is reduced to a Markov chain, which it can then solve for system reliability. The graphics capability is available for use on an IBM-compatible PC, a Sun, and a VAX workstation. The GO module is written in the C programming language and uses the graphical kernal system (GKS) standard for graphics implementation. The PC, VAX, and Sun versions of the HARP GO module are currently in beta-testing stages.

Piezosurgery an Asset in Treatment of Pierre Robin Sequence.

PubMed

Singh, Divya; Gadre, Pushkar; Gadre, Kiran; Ramanojam, Shandilya

2017-03-01

Pierre Robin sequence (formerly a syndrome) is named after the French stomatologist who, in 1923 and 1934, described the problems associated with micrognathia in newborn. It comprises mandibular micrognathia, U-shaped cleft palate, and glossoptosis. The typical symptoms are hypoxaemia, noisy breathing, snoring, stridor, cyanosis, bradycardia, feeding difficulties, and failure to thrive. Distraction osteogenesis has recently been considered as a surgical option for early intervention to lengthen the mandible and relieve respiratory problems. Piezosurgery offers a modality to make precise bone cuts preserving vital structures, minimizing the invasiveness of the surgical procedure, and offering bloodless field. We present case of 1-year-old male malnourished child with Pierre Robin sequence and tracheostomy in situ since day 11 of his birth. The staged treatment plan involving mandibular lengthening in which mandibular osteotomies were performed with the piezoelectric scalpel followed by decannulation of tracheostomy, which has been described in detail in this article.

Percolation in random-Sierpiński carpets: A real space renormalization group approach

NASA Astrophysics Data System (ADS)

Perreau, Michel; Peiro, Joaquina; Berthier, Serge

1996-11-01

The site percolation transition in random Sierpiński carpets is investigated by real space renormalization. The fixed point is not unique like in regular translationally invariant lattices, but depends on the number k of segmentation steps of the generation process of the fractal. It is shown that, for each scale invariance ratio n, the sequence of fixed points pn,k is increasing with k, and converges when k-->∞ toward a limit pn strictly less than 1. Moreover, in such scale invariant structures, the percolation threshold does not depend only on the scale invariance ratio n, but also on the scale. The sequence pn,k and pn are calculated for n=4, 8, 16, 32, and 64, and for k=1 to k=11, and k=∞. The corresponding thermal exponent sequence νn,k is calculated for n=8 and 16, and for k=1 to k=5, and k=∞. Suggestions are made for an experimental test in physical self-similar structures.

An analysis by metabolic labelling of the encephalomyocarditis virus ribosomal frameshifting efficiency and stimulators.

PubMed

Ling, Roger; Firth, Andrew E

2017-08-01

Programmed -1 ribosomal frameshifting is a mechanism of gene expression whereby specific signals within messenger RNAs direct a proportion of ribosomes to shift -1 nt and continue translating in the new reading frame. Such frameshifting normally depends on an RNA structure stimulator 3'-adjacent to a 'slippery' heptanucleotide shift site sequence. Recently we identified an unusual frameshifting mechanism in encephalomyocarditis virus, where the stimulator involves a trans-acting virus protein. Thus, in contrast to other examples of -1 frameshifting, the efficiency of frameshifting in encephalomyocarditis virus is best studied in the context of virus infection. Here we use metabolic labelling to analyse the frameshifting efficiency of wild-type and mutant viruses. Confirming previous results, frameshifting depends on a G_GUU_UUU shift site sequence and a 3'-adjacent stem-loop structure, but is not appreciably affected by the 'StopGo' sequence present ~30 nt upstream. At late timepoints, frameshifting was estimated to be 46-76 % efficient.

Comparison of illumina and 454 deep sequencing in participants failing raltegravir-based antiretroviral therapy.

PubMed

Li, Jonathan Z; Chapman, Brad; Charlebois, Patrick; Hofmann, Oliver; Weiner, Brian; Porter, Alyssa J; Samuel, Reshmi; Vardhanabhuti, Saran; Zheng, Lu; Eron, Joseph; Taiwo, Babafemi; Zody, Michael C; Henn, Matthew R; Kuritzkes, Daniel R; Hide, Winston; Wilson, Cara C; Berzins, Baiba I; Acosta, Edward P; Bastow, Barbara; Kim, Peter S; Read, Sarah W; Janik, Jennifer; Meres, Debra S; Lederman, Michael M; Mong-Kryspin, Lori; Shaw, Karl E; Zimmerman, Louis G; Leavitt, Randi; De La Rosa, Guy; Jennings, Amy

2014-01-01

The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.

Improving the realism of white matter numerical phantoms: a step towards a better understanding of the influence of structural disorders in diffusion MRI

NASA Astrophysics Data System (ADS)

Ginsburger, Kévin; Poupon, Fabrice; Beaujoin, Justine; Estournet, Delphine; Matuschke, Felix; Mangin, Jean-François; Axer, Markus; Poupon, Cyril

2018-02-01

White matter is composed of irregularly packed axons leading to a structural disorder in the extra-axonal space. Diffusion MRI experiments using oscillating gradient spin echo sequences have shown that the diffusivity transverse to axons in this extra-axonal space is dependent on the frequency of the employed sequence. In this study, we observe the same frequency-dependence using 3D simulations of the diffusion process in disordered media. We design a novel white matter numerical phantom generation algorithm which constructs biomimicking geometric configurations with few design parameters, and enables to control the level of disorder of the generated phantoms. The influence of various geometrical parameters present in white matter, such as global angular dispersion, tortuosity, presence of Ranvier nodes, beading, on the extra-cellular perpendicular diffusivity frequency dependence was investigated by simulating the diffusion process in numerical phantoms of increasing complexity and fitting the resulting simulated diffusion MR signal attenuation with an adequate analytical model designed for trapezoidal OGSE sequences. This work suggests that angular dispersion and especially beading have non-negligible effects on this extracellular diffusion metrics that may be measured using standard OGSE DW-MRI clinical protocols.

Environmental protection in Italy: the emerging concept of a right to a healthful environment

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

Patti, S.

1984-07-01

Italy's concepts of private law limit the possibilities for environmental protection. The failure to use available public law effectively and the failure of other governments to solve the problem with constitutional changes, emphasizes the need to establish an effective legal means within the existing constitutional structure. A recent approach draws on the right of the individual to a healthful environment, but whether this succeeds in protecting the environment depends, to a large degree, on the ability of Italians to overcome a system characterized by economic individualism. 40 references.

Distribution and Features of the Six Classes of Peroxiredoxins

PubMed Central

Poole, Leslie B.; Nelson, Kimberly J.

2016-01-01

Peroxiredoxins are cysteine-dependent peroxide reductases that group into 6 different, structurally discernable classes. In 2011, our research team reported the application of a bioinformatic approach called active site profiling to extract active site-proximal sequence segments from the 29 distinct, structurally-characterized peroxiredoxins available at the time. These extracted sequences were then used to create unique profiles for the six groups which were subsequently used to search GenBank(nr), allowing identification of ∼3500 peroxiredoxin sequences and their respective subgroups. Summarized in this minireview are the features and phylogenetic distributions of each of these peroxiredoxin subgroups; an example is also provided illustrating the use of the web accessible, searchable database known as PREX to identify subfamily-specific peroxiredoxin sequences for the organism Vitis vinifera (grape). PMID:26810075

[Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein].

PubMed

Kubota, Takeo

2013-01-01

Epigenome is defined as DNA and histone modification-dependent gene regulation system. Abnormalities in this system are known to cause various neuro-developmental diseases. We recently reported that neurological symptoms of Rett syndrome, which is an autistic disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2), was associated with failure of epigenomic gene regulation in neuronal cells, and that clinical differences in the identical twins with Rett syndrome in the differences in DNA methylation in neuronal genes, but not caused by DNA sequence differences. Since central nervus system requires precise gene regulation, neurological diseases including Alzheimer and Parkinson diseases may be caused by acquired DNA modification (epigenomic) changes that results in aberrant gene regulation as well as DNA sequence changes congenitally occurred (mutation).

Structural hot spots for the solubility of globular proteins

PubMed Central

Ganesan, Ashok; Siekierska, Aleksandra; Beerten, Jacinte; Brams, Marijke; Van Durme, Joost; De Baets, Greet; Van der Kant, Rob; Gallardo, Rodrigo; Ramakers, Meine; Langenberg, Tobias; Wilkinson, Hannah; De Smet, Frederik; Ulens, Chris; Rousseau, Frederic; Schymkowitz, Joost

2016-01-01

Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human α-galactosidase and protective antigen of Bacillus anthracis through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function. PMID:26905391

Combined mechanical loading of composite tubes

NASA Technical Reports Server (NTRS)

Derstine, Mark S.; Pindera, Marek-Jerzy; Bowles, David E.

1988-01-01

An analytical/experimental investigation was performed to study the effect of material nonlinearities on the response of composite tubes subjected to combined axial and torsional loading. The effect of residual stresses on subsequent mechanical response was included in the investigation. Experiments were performed on P75/934 graphite-epoxy tubes with a stacking sequence of (15/0/ + or - 10/0/ -15), using pure torsion and combined axial/torsional loading. In the presence of residual stresses, the analytical model predicted a reduction in the initial shear modulus. Experimentally, coupling between axial loading and shear strain was observed in laminated tubes under combined loading. The phenomenon was predicted by the nonlinear analytical model. The experimentally observed linear limit of the global shear response was found to correspond to the analytically predicted first ply failure. Further, the failure of the tubes was found to be path dependent above a critical load level.

Robust Feature Matching in Terrestrial Image Sequences

NASA Astrophysics Data System (ADS)

Abbas, A.; Ghuffar, S.

2018-04-01

From the last decade, the feature detection, description and matching techniques are most commonly exploited in various photogrammetric and computer vision applications, which includes: 3D reconstruction of scenes, image stitching for panoramic creation, image classification, or object recognition etc. However, in terrestrial imagery of urban scenes contains various issues, which include duplicate and identical structures (i.e. repeated windows and doors) that cause the problem in feature matching phase and ultimately lead to failure of results specially in case of camera pose and scene structure estimation. In this paper, we will address the issue related to ambiguous feature matching in urban environment due to repeating patterns.

Benchmarking Inverse Statistical Approaches for Protein Structure and Design with Exactly Solvable Models.

PubMed

Jacquin, Hugo; Gilson, Amy; Shakhnovich, Eugene; Cocco, Simona; Monasson, Rémi

2016-05-01

Inverse statistical approaches to determine protein structure and function from Multiple Sequence Alignments (MSA) are emerging as powerful tools in computational biology. However the underlying assumptions of the relationship between the inferred effective Potts Hamiltonian and real protein structure and energetics remain untested so far. Here we use lattice protein model (LP) to benchmark those inverse statistical approaches. We build MSA of highly stable sequences in target LP structures, and infer the effective pairwise Potts Hamiltonians from those MSA. We find that inferred Potts Hamiltonians reproduce many important aspects of 'true' LP structures and energetics. Careful analysis reveals that effective pairwise couplings in inferred Potts Hamiltonians depend not only on the energetics of the native structure but also on competing folds; in particular, the coupling values reflect both positive design (stabilization of native conformation) and negative design (destabilization of competing folds). In addition to providing detailed structural information, the inferred Potts models used as protein Hamiltonian for design of new sequences are able to generate with high probability completely new sequences with the desired folds, which is not possible using independent-site models. Those are remarkable results as the effective LP Hamiltonians used to generate MSA are not simple pairwise models due to the competition between the folds. Our findings elucidate the reasons for the success of inverse approaches to the modelling of proteins from sequence data, and their limitations.

Deriving high-resolution protein backbone structure propensities from all crystal data using the information maximization device.

PubMed

Solis, Armando D

2014-01-01

The most informative probability distribution functions (PDFs) describing the Ramachandran phi-psi dihedral angle pair, a fundamental descriptor of backbone conformation of protein molecules, are derived from high-resolution X-ray crystal structures using an information-theoretic approach. The Information Maximization Device (IMD) is established, based on fundamental information-theoretic concepts, and then applied specifically to derive highly resolved phi-psi maps for all 20 single amino acid and all 8000 triplet sequences at an optimal resolution determined by the volume of current data. The paper shows that utilizing the latent information contained in all viable high-resolution crystal structures found in the Protein Data Bank (PDB), totaling more than 77,000 chains, permits the derivation of a large number of optimized sequence-dependent PDFs. This work demonstrates the effectiveness of the IMD and the superiority of the resulting PDFs by extensive fold recognition experiments and rigorous comparisons with previously published triplet PDFs. Because it automatically optimizes PDFs, IMD results in improved performance of knowledge-based potentials, which rely on such PDFs. Furthermore, it provides an easy computational recipe for empirically deriving other kinds of sequence-dependent structural PDFs with greater detail and precision. The high-resolution phi-psi maps derived in this work are available for download.

High Speed Dynamics in Brittle Materials

NASA Astrophysics Data System (ADS)

Hiermaier, Stefan

2015-06-01

Brittle Materials under High Speed and Shock loading provide a continuous challenge in experimental physics, analysis and numerical modelling, and consequently for engineering design. The dependence of damage and fracture processes on material-inherent length and time scales, the influence of defects, rate-dependent material properties and inertia effects on different scales make their understanding a true multi-scale problem. In addition, it is not uncommon that materials show a transition from ductile to brittle behavior when the loading rate is increased. A particular case is spallation, a brittle tensile failure induced by the interaction of stress waves leading to a sudden change from compressive to tensile loading states that can be invoked in various materials. This contribution highlights typical phenomena occurring when brittle materials are exposed to high loading rates in applications such as blast and impact on protective structures, or meteorite impact on geological materials. A short review on experimental methods that are used for dynamic characterization of brittle materials will be given. A close interaction of experimental analysis and numerical simulation has turned out to be very helpful in analyzing experimental results. For this purpose, adequate numerical methods are required. Cohesive zone models are one possible method for the analysis of brittle failure as long as some degree of tension is present. Their recent successful application for meso-mechanical simulations of concrete in Hopkinson-type spallation tests provides new insight into the dynamic failure process. Failure under compressive loading is a particular challenge for numerical simulations as it involves crushing of material which in turn influences stress states in other parts of a structure. On a continuum scale, it can be modeled using more or less complex plasticity models combined with failure surfaces, as will be demonstrated for ceramics. Models which take microstructural cracking directly into account may provide a more physics-based approach for compressive failure in the future.

The ion-induced folding of the hammerhead ribozyme: core sequence changes that perturb folding into the active conformation.

PubMed Central

Bassi, G S; Murchie, A I; Lilley, D M

1996-01-01

The hammerhead ribozyme undergoes an ion-dependent folding process into the active conformation. We find that the folding can be blocked at specific stages by changes of sequence or functionality within the core. In the the absence of added metal ions, the global structure of the hammerhead is extended, with a large angle subtended between stems I and II. No core sequence changes appear to alter this geometry, consistent with an unstructured core under these conditions. Upon addition of low concentrations of magnesium ions, the hammerhead folds by an association of stems II and III, to include a large angle between them. This stage is inhibited or altered by mutations within the oligopurine sequence lying between stems II and III, and folding is completely prevented by an A14G mutation. Further increase in magnesium ion concentration brings about a second stage of folding in the natural sequence hammerhead, involving a reorientation of stem I, which rotates around into the same direction of stem II. Because this transition occurs over the same range of magnesium ion concentration over which the hammerhead ribozyme becomes active, it is likely that the final conformation is most closely related to the active form of the structure. Magnesium ion-dependent folding into this conformation is prevented by changes at G5, notably removal of the 2'-hydroxyl group and replacement of the base by cytidine. The ability to dissect the folding process by means of sequence changes suggests that two separate ion-dependent stages are involved in the folding of the hammerhead ribozyme into the active conformation. PMID:8752086

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring

PubMed Central

2012-01-01

Background Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. Results The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Conclusions Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family. PMID:22793672

Statistical discovery of site inter-dependencies in sub-molecular hierarchical protein structuring.

PubMed

Durston, Kirk K; Chiu, David Ky; Wong, Andrew Kc; Li, Gary Cl

2012-07-13

Much progress has been made in understanding the 3D structure of proteins using methods such as NMR and X-ray crystallography. The resulting 3D structures are extremely informative, but do not always reveal which sites and residues within the structure are of special importance. Recently, there are indications that multiple-residue, sub-domain structural relationships within the larger 3D consensus structure of a protein can be inferred from the analysis of the multiple sequence alignment data of a protein family. These intra-dependent clusters of associated sites are used to indicate hierarchical inter-residue relationships within the 3D structure. To reveal the patterns of associations among individual amino acids or sub-domain components within the structure, we apply a k-modes attribute (aligned site) clustering algorithm to the ubiquitin and transthyretin families in order to discover associations among groups of sites within the multiple sequence alignment. We then observe what these associations imply within the 3D structure of these two protein families. The k-modes site clustering algorithm we developed maximizes the intra-group interdependencies based on a normalized mutual information measure. The clusters formed correspond to sub-structural components or binding and interface locations. Applying this data-directed method to the ubiquitin and transthyretin protein family multiple sequence alignments as a test bed, we located numerous interesting associations of interdependent sites. These clusters were then arranged into cluster tree diagrams which revealed four structural sub-domains within the single domain structure of ubiquitin and a single large sub-domain within transthyretin associated with the interface among transthyretin monomers. In addition, several clusters of mutually interdependent sites were discovered for each protein family, each of which appear to play an important role in the molecular structure and/or function. Our results demonstrate that the method we present here using a k-modes site clustering algorithm based on interdependency evaluation among sites obtained from a sequence alignment of homologous proteins can provide significant insights into the complex, hierarchical inter-residue structural relationships within the 3D structure of a protein family.

Femtosecond laser-induced periodic surface structures on silicon upon polarization controlled two-color double-pulse irradiation.

PubMed

Höhm, Sandra; Herzlieb, Marcel; Rosenfeld, Arkadi; Krüger, Jörg; Bonse, Jörn

2015-01-12

Two-color double-fs-pulse experiments were performed on silicon wafers to study the temporally distributed energy deposition in the formation of laser-induced periodic surface structures (LIPSS). A Mach-Zehnder interferometer generated parallel or cross-polarized double-pulse sequences at 400 and 800 nm wavelength, with inter-pulse delays up to a few picoseconds between the sub-ablation 50-fs-pulses. Multiple two-color double-pulse sequences were collinearly focused by a spherical mirror to the sample. The resulting LIPSS characteristics (periods, areas) were analyzed by scanning electron microscopy. A wavelength-dependent plasmonic mechanism is proposed to explain the delay-dependence of the LIPSS. These two-color experiments extend previous single-color studies and prove the importance of the ultrafast energy deposition for LIPSS formation.

DEPEND - A design environment for prediction and evaluation of system dependability

NASA Technical Reports Server (NTRS)

Goswami, Kumar K.; Iyer, Ravishankar K.

1990-01-01

The development of DEPEND, an integrated simulation environment for the design and dependability analysis of fault-tolerant systems, is described. DEPEND models both hardware and software components at a functional level, and allows automatic failure injection to assess system performance and reliability. It relieves the user of the work needed to inject failures, maintain statistics, and output reports. The automatic failure injection scheme is geared toward evaluating a system under high stress (workload) conditions. The failures that are injected can affect both hardware and software components. To illustrate the capability of the simulator, a distributed system which employs a prediction-based, dynamic load-balancing heuristic is evaluated. Experiments were conducted to determine the impact of failures on system performance and to identify the failures to which the system is especially susceptible.

Rupture directivity of microseismic events recorded during hydraulic fracture stimulations.

NASA Astrophysics Data System (ADS)

Urbancic, T.; Smith-Boughner, L.; Baig, A.; Viegas, G.

2016-12-01

We model the dynamics of a complex rupture sequence with four sub-events. These events were recorded during hydraulic fracture stimulations in a gas-bearing shale formation. With force-balance accelerometers, 4.5Hz and 15Hz instruments recording the failure history, we study the directivity of the entire rupture sequence and each sub-event. Two models are considered: unilateral and bi-lateral failures of penny shaped cracks. From the seismic moment tensors of these sub-events, we consider different potential failure planes and rupture directions. Using numerical wave-propagation codes, we generate synthetic rupture sequences with both unilateral and bi-lateral ruptures. These are compared to the four sub-events to determine the directionality of the observed failures and the sensitivity of our recording bandwidth and geometry to distinguishing between different rupture processes. The frequency of unilateral and bilateral rupture processes throughout the fracture stimulation is estimated by comparing the directivity characteristics of the modeled sub-events to other high-quality microseismic events recorded during the same stimulation program. Understanding the failure processes of these microseismic events can provide great insight into the changes in the rock mass responsible for these complex rupture processes.

A folded viral noncoding RNA blocks host cell exoribonucleases through a conformationally dynamic RNA structure.

PubMed

Steckelberg, Anna-Lena; Akiyama, Benjamin M; Costantino, David A; Sit, Tim L; Nix, Jay C; Kieft, Jeffrey S

2018-06-19

Folded RNA elements that block processive 5' → 3' cellular exoribonucleases (xrRNAs) to produce biologically active viral noncoding RNAs have been discovered in flaviviruses, potentially revealing a new mode of RNA maturation. However, whether this RNA structure-dependent mechanism exists elsewhere and, if so, whether a singular RNA fold is required, have been unclear. Here we demonstrate the existence of authentic RNA structure-dependent xrRNAs in dianthoviruses, plant-infecting viruses unrelated to animal-infecting flaviviruses. These xrRNAs have no sequence similarity to known xrRNAs; thus, we used a combination of biochemistry and virology to characterize their sequence requirements and mechanism of stopping exoribonucleases. By solving the structure of a dianthovirus xrRNA by X-ray crystallography, we reveal a complex fold that is very different from that of the flavivirus xrRNAs. However, both versions of xrRNAs contain a unique topological feature, a pseudoknot that creates a protective ring around the 5' end of the RNA structure; this may be a defining structural feature of xrRNAs. Single-molecule FRET experiments reveal that the dianthovirus xrRNAs undergo conformational changes and can use "codegradational remodeling," exploiting the exoribonucleases' degradation-linked helicase activity to help form their resistant structure; such a mechanism has not previously been reported. Convergent evolution has created RNA structure-dependent exoribonuclease resistance in different contexts, which establishes it as a general RNA maturation mechanism and defines xrRNAs as an authentic functional class of RNAs.

Protein Phosphatase 2A (PP2A)-specific Ubiquitin Ligase MID1 Is a Sequence-dependent Regulator of Translation Efficiency Controlling 3-Phosphoinositide-dependent Protein Kinase-1 (PDPK-1)*

PubMed Central

Aranda-Orgillés, Beatriz; Rutschow, Désirée; Zeller, Raphael; Karagiannidis, Antonios I.; Köhler, Andrea; Chen, Changwei; Wilson, Timothy; Krause, Sven; Roepcke, Stefan; Lilley, David; Schneider, Rainer; Schweiger, Susann

2011-01-01

We have shown previously that the ubiquitin ligase MID1, mutations of which cause the midline malformation Opitz BBB/G syndrome (OS), serves as scaffold for a microtubule-associated protein complex that regulates protein phosphatase 2A (PP2A) activity in a ubiquitin-dependent manner. Here, we show that the MID1 protein complex associates with mRNAs via a purine-rich sequence motif called MIDAS (MID1 association sequence) and thereby increases stability and translational efficiency of these mRNAs. Strikingly, inclusion of multiple copies of the MIDAS motif into mammalian mRNAs increases production of the encoded proteins up to 20-fold. Mutated MID1, as found in OS patients, loses its influence on MIDAS-containing mRNAs, suggesting that the malformations in OS patients could be caused by failures in the regulation of cytoskeleton-bound protein translation. This is supported by the observation that the majority of mRNAs that carry MIDAS motifs is involved in developmental processes and/or energy homeostasis. Further analysis of one of the proteins encoded by a MIDAS-containing mRNA, namely PDPK-1 (3-phosphoinositide dependent protein kinase-1), which is an important regulator of mammalian target of rapamycin/PP2A signaling, showed that PDPK-1 protein synthesis is significantly reduced in cells from an OS patient compared with an age-matched control and can be rescued by functional MID1. Together, our data uncover a novel messenger ribonucleoprotein complex that regulates microtubule-associated protein translation. They suggest a novel mechanism underlying OS and point at an enormous potential of the MIDAS motif to increase the efficiency of biotechnological protein production in mammalian cells. PMID:21930711

T box riboswitches in Actinobacteria: Translational regulation via novel tRNA interactions

PubMed Central

Sherwood, Anna V.; Grundy, Frank J.; Henkin, Tina M.

2015-01-01

The T box riboswitch regulates many amino acid-related genes in Gram-positive bacteria. T box riboswitch-mediated gene regulation was shown previously to occur at the level of transcription attenuation via structural rearrangements in the 5′ untranslated (leader) region of the mRNA in response to binding of a specific uncharged tRNA. In this study, a novel group of isoleucyl-tRNA synthetase gene (ileS) T box leader sequences found in organisms of the phylum Actinobacteria was investigated. The Stem I domains of these RNAs lack several highly conserved elements that are essential for interaction with the tRNA ligand in other T box RNAs. Many of these RNAs were predicted to regulate gene expression at the level of translation initiation through tRNA-dependent stabilization of a helix that sequesters a sequence complementary to the Shine–Dalgarno (SD) sequence, thus freeing the SD sequence for ribosome binding and translation initiation. We demonstrated specific binding to the cognate tRNAIle and tRNAIle-dependent structural rearrangements consistent with regulation at the level of translation initiation, providing the first biochemical demonstration, to our knowledge, of translational regulation in a T box riboswitch. PMID:25583497

Crystal structure and sequence-dependent conformation of the A.G mispaired oligonucleotide d(CGCAAGCTGGCG).

PubMed Central

Webster, G D; Sanderson, M R; Skelly, J V; Neidle, S; Swann, P F; Li, B F; Tickle, I J

1990-01-01

The crystal structure of the dodecanucleotide d(CGCAAGCTGGCG) has been determined to a resolution of 2.5 A and refined to an R factor of 19.3% for 1710 reflections. The sequence crystallizes as a B-type double helix, with two G(anti).A(syn) base pairs. These are stabilized by three-center hydrogen bonds to pyrimidines that induce perturbations in base-pair geometry. The central AGCT region of the helix has a wide (greater than 6 A) minor groove. PMID:2395870

Congenital Heart Disease: Causes, Diagnosis, Symptoms, and Treatments.

PubMed

Sun, RongRong; Liu, Min; Lu, Lei; Zheng, Yi; Zhang, Peiying

2015-07-01

The congenital heart disease includes abnormalities in heart structure that occur before birth. Such defects occur in the fetus while it is developing in the uterus during pregnancy. About 500,000 adults have congenital heart disease in USA (WebMD, Congenital heart defects medications, www.WebMD.com/heart-disease/tc/congenital-heart-defects-medications , 2014). 1 in every 100 children has defects in their heart due to genetic or chromosomal abnormalities, such as Down syndrome. The excessive alcohol consumption during pregnancy and use of medications, maternal viral infection, such as Rubella virus, measles (German), in the first trimester of pregnancy, all these are risk factors for congenital heart disease in children, and the risk increases if parent or sibling has a congenital heart defect. These are heart valves defects, atrial and ventricular septa defects, stenosis, the heart muscle abnormalities, and a hole inside wall of the heart which causes defect in blood circulation, heart failure, and eventual death. There are no particular symptoms of congenital heart disease, but shortness of breath and limited ability to do exercise, fatigue, abnormal sound of heart as heart murmur, which is diagnosed by a physician while listening to the heart beats. The echocardiogram or transesophageal echocardiogram, electrocardiogram, chest X-ray, cardiac catheterization, and MRI methods are used to detect congenital heart disease. Several medications are given depending on the severity of this disease, and catheter method and surgery are required for serious cases to repair heart valves or heart transplantation as in endocarditis. For genetic study, first DNA is extracted from blood followed by DNA sequence analysis and any defect in nucleotide sequence of DNA is determined. For congenital heart disease, genes in chromosome 1 show some defects in nucleotide sequence. In this review the causes, diagnosis, symptoms, and treatments of congenital heart disease are described.

Full-length genome characterization and genetic relatedness analysis of hepatitis A virus outbreak strains associated with acute liver failure among children.

PubMed

Vaughan, Gilberto; Forbi, Joseph C; Xia, Guo-Liang; Fonseca-Ford, Maureen; Vazquez, Roberto; Khudyakov, Yury E; Montiel, Sonia; Waterman, Steve; Alpuche, Celia; Gonçalves Rossi, Livia Maria; Luna, Norma

2014-02-01

Clinical infection by hepatitis A virus (HAV) is generally self-limited but in some cases can progress to liver failure. Here, an HAV outbreak investigation among children with acute liver failure in a highly endemic country is presented. In addition, a sensitive method for HAV whole genome amplification and sequencing suitable for analysis of clinical samples is described. In this setting, two fatal cases attributed to acute liver failure and two asymptomatic cases living in the same household were identified. In a second household, one HAV case was observed with jaundice which resolved spontaneously. Partial molecular characterization showed that both households were infected by HAV subtype IA; however, the infecting strains in the two households were different. The HAV outbreak strains recovered from all cases grouped together within cluster IA1, which contains closely related HAV strains from the United States commonly associated with international travelers. Full-genome HAV sequences obtained from the household with the acute liver failure cases were related (genetic distances ranging from 0.01% to 0.04%), indicating a common-source infection. Interestingly, the strain recovered from the asymptomatic household contact was nearly identical to the strain causing acute liver failure. The whole genome sequence from the case in the second household was distinctly different from the strains associated with acute liver failure. Thus, infection with almost identical HAV strains resulted in drastically different clinical outcomes. © 2013 Wiley Periodicals, Inc.

Inhibition of the ATPase from Halobacterium Saccharovorum by Thiol Inhibitors: Evidence for the Presence of More Than One Essential Cysteinyl Residue

NASA Technical Reports Server (NTRS)

Hochstein, Lawrence I.; Emrich, Errol; Stan-Lotter, Helga; DeVincenzi, Donald L. (Technical Monitor)

1995-01-01

The vacuolar-like ATPase from Halobacterium saccha vorum is inhibited by N-ethylmaleimide and p-chloromercudphenylsulfonate. The failure of adenine nucleotides to protect against p-chloromercuriphenyisulfonate inhibition, of p-chloromercuriphenylsulfonate to protect against N-ethylmaleimide inhibition, and the difference in the temperature dependence of inactivation infers that the enzyme contains at least two thiols that are essential for enzyme activity. CNBr cleavage of C-14-N-ethylmaleimide labeled subunit results in two radioactive peptides that locates the N-ethylmaleimide-reactive cysteinyl residue as cysteine-262 in the H. salinarium sequence.

Reliability assessment of slender concrete columns at the stability failure

NASA Astrophysics Data System (ADS)

Valašík, Adrián; Benko, Vladimír; Strauss, Alfred; Täubling, Benjamin

2018-01-01

The European Standard for designing concrete columns within the use of non-linear methods shows deficiencies in terms of global reliability, in case that the concrete columns fail by the loss of stability. The buckling failure is a brittle failure which occurs without warning and the probability of its formation depends on the columns slenderness. Experiments with slender concrete columns were carried out in cooperation with STRABAG Bratislava LTD in Central Laboratory of Faculty of Civil Engineering SUT in Bratislava. The following article aims to compare the global reliability of slender concrete columns with slenderness of 90 and higher. The columns were designed according to methods offered by EN 1992-1-1 [1]. The mentioned experiments were used as basis for deterministic nonlinear modelling of the columns and subsequent the probabilistic evaluation of structural response variability. Final results may be utilized as thresholds for loading of produced structural elements and they aim to present probabilistic design as less conservative compared to classic partial safety factor based design and alternative ECOV method.

Influences of the molecular fuel structure on combustion reactions towards soot precursors in selected alkane and alkene flames.

PubMed

Ruwe, Lena; Moshammer, Kai; Hansen, Nils; Kohse-Höinghaus, Katharina

2018-04-25

In this study, we experimentally investigate the high-temperature oxidation kinetics of n-pentane, 1-pentene and 2-methyl-2-butene (2M2B) in a combustion environment using flame-sampling molecular beam mass spectrometry. The selected C5 fuels are prototypes for linear and branched, saturated and unsaturated fuel components, featuring different C-C and C-H bond structures. It is shown that the formation tendency of species, such as polycyclic aromatic hydrocarbons (PAHs), yielded through mass growth reactions increases drastically in the sequence n-pentane < 1-pentene < 2M2B. This comparative study enables valuable insights into fuel-dependent reaction sequences of the gas-phase combustion mechanism that provide explanations for the observed difference in the PAH formation tendency. First, we investigate the fuel-structure-dependent formation of small hydrocarbon species that are yielded as intermediate species during the fuel decomposition, because these species are at the origin of the subsequent mass growth reaction pathways. Second, we review typical PAH formation reactions inspecting repetitive growth sequences in dependence of the molecular fuel structure. Third, we discuss how differences in the intermediate species pool influence the formation reactions of key aromatic ring species that are important for the PAH growth process underlying soot formation. As a main result it was found that for the fuels featuring a C[double bond, length as m-dash]C double bond, the chemistry of their allylic fuel radicals and their decomposition products strongly influences the combination reactions to the initially formed aromatic ring species and as a consequence, the PAH formation tendency.

Effect of vacancies on the mechanical properties of phosphorene nanotubes.

PubMed

Sorkin, V; Zhang, Y W

2018-06-08

Using density functional tight-binding method, we studied the mechanical properties, deformation and failure of armchair (AC) and zigzag (ZZ) phosphorene nanotubes (PNTs) with monovacancies and divacancies subjected to uniaxial tensile strain. We found that divacancies in AC PNTs and monovacancies in ZZ PNTs possess the lowest vacancy formation energy, which decreases with the tube diameter in AC PNTs and increases in ZZ PNTs. The Young's modulus is reduced, while the radial and thickness Poisson's ratios are increased by hosted vacancies. In defective AC PNTs, deformation involves fracture of the intra-pucker bonds and formation of the new inter-pucker bonds at a critical strain, and the most stretched bonds around the vacancy rupture first, triggering a sequence of the structural transformations terminated by the ultimate failure. The critical strain of AC PNTs is reduced significantly by hosted vacancies, whereas their effect on the critical stress is relatively weaker. Defective ZZ PNTs fail in a brittle-like manner once the most stretched bonds around a vacancy rupture, and vacancies are able to significantly reduce the failure strain but only moderately reduce the failure stress of ZZ PNTs. The understandings revealed here on the mechanical properties and the deformation and failure mechanisms of PNTs provide useful guidelines for their design and fabrication as building blocks in nanodevices.

Effect of vacancies on the mechanical properties of phosphorene nanotubes

NASA Astrophysics Data System (ADS)

Sorkin, V.; Zhang, Y. W.

2018-06-01

Using density functional tight-binding method, we studied the mechanical properties, deformation and failure of armchair (AC) and zigzag (ZZ) phosphorene nanotubes (PNTs) with monovacancies and divacancies subjected to uniaxial tensile strain. We found that divacancies in AC PNTs and monovacancies in ZZ PNTs possess the lowest vacancy formation energy, which decreases with the tube diameter in AC PNTs and increases in ZZ PNTs. The Young’s modulus is reduced, while the radial and thickness Poisson’s ratios are increased by hosted vacancies. In defective AC PNTs, deformation involves fracture of the intra-pucker bonds and formation of the new inter-pucker bonds at a critical strain, and the most stretched bonds around the vacancy rupture first, triggering a sequence of the structural transformations terminated by the ultimate failure. The critical strain of AC PNTs is reduced significantly by hosted vacancies, whereas their effect on the critical stress is relatively weaker. Defective ZZ PNTs fail in a brittle-like manner once the most stretched bonds around a vacancy rupture, and vacancies are able to significantly reduce the failure strain but only moderately reduce the failure stress of ZZ PNTs. The understandings revealed here on the mechanical properties and the deformation and failure mechanisms of PNTs provide useful guidelines for their design and fabrication as building blocks in nanodevices.

Protein family clustering for structural genomics.

PubMed

Yan, Yongpan; Moult, John

2005-10-28

A major goal of structural genomics is the provision of a structural template for a large fraction of protein domains. The magnitude of this task depends on the number and nature of protein sequence families. With a large number of bacterial genomes now fully sequenced, it is possible to obtain improved estimates of the number and diversity of families in that kingdom. We have used an automated clustering procedure to group all sequences in a set of genomes into protein families. Bench-marking shows the clustering method is sensitive at detecting remote family members, and has a low level of false positives. This comprehensive protein family set has been used to address the following questions. (1) What is the structure coverage for currently known families? (2) How will the number of known apparent families grow as more genomes are sequenced? (3) What is a practical strategy for maximizing structure coverage in future? Our study indicates that approximately 20% of known families with three or more members currently have a representative structure. The study indicates also that the number of apparent protein families will be considerably larger than previously thought: We estimate that, by the criteria of this work, there will be about 250,000 protein families when 1000 microbial genomes have been sequenced. However, the vast majority of these families will be small, and it will be possible to obtain structural templates for 70-80% of protein domains with an achievable number of representative structures, by systematically sampling the larger families.

The computational linguistics of biological sequences

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

Searls, D.

1995-12-31

This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. Protein sequences are analogous in many respects, particularly their folding behavior. Proteins have a much richer variety of interactions, but in theory the same linguistic principles could come to bear in describing dependencies between distant residues that arise by virtue of three-dimensional structure. This tutorial will concentrate on nucleic acid sequences.

A parallel implementation of the Wuchty algorithm with additional experimental filters to more thoroughly explore RNA conformational space.

PubMed

Stone, Jonathan W; Bleckley, Samuel; Lavelle, Sean; Schroeder, Susan J

2015-01-01

We present new modifications to the Wuchty algorithm in order to better define and explore possible conformations for an RNA sequence. The new features, including parallelization, energy-independent lonely pair constraints, context-dependent chemical probing constraints, helix filters, and optional multibranch loops, provide useful tools for exploring the landscape of RNA folding. Chemical probing alone may not necessarily define a single unique structure. The helix filters and optional multibranch loops are global constraints on RNA structure that are an especially useful tool for generating models of encapsidated viral RNA for which cryoelectron microscopy or crystallography data may be available. The computations generate a combinatorially complete set of structures near a free energy minimum and thus provide data on the density and diversity of structures near the bottom of a folding funnel for an RNA sequence. The conformational landscapes for some RNA sequences may resemble a low, wide basin rather than a steep funnel that converges to a single structure.

Categorizing accident sequences in the external radiotherapy for risk analysis

PubMed Central

2013-01-01

Purpose This study identifies accident sequences from the past accidents in order to help the risk analysis application to the external radiotherapy. Materials and Methods This study reviews 59 accidental cases in two retrospective safety analyses that have collected the incidents in the external radiotherapy extensively. Two accident analysis reports that accumulated past incidents are investigated to identify accident sequences including initiating events, failure of safety measures, and consequences. This study classifies the accidents by the treatments stages and sources of errors for initiating events, types of failures in the safety measures, and types of undesirable consequences and the number of affected patients. Then, the accident sequences are grouped into several categories on the basis of similarity of progression. As a result, these cases can be categorized into 14 groups of accident sequence. Results The result indicates that risk analysis needs to pay attention to not only the planning stage, but also the calibration stage that is committed prior to the main treatment process. It also shows that human error is the largest contributor to initiating events as well as to the failure of safety measures. This study also illustrates an event tree analysis for an accident sequence initiated in the calibration. Conclusion This study is expected to provide sights into the accident sequences for the prospective risk analysis through the review of experiences. PMID:23865005

Cloning and characterization of a Prevotella melaninogenica hemolysin.

PubMed Central

Allison, H E; Hillman, J D

1997-01-01

Hemolysins have been proven to be important virulence factors in many medically relevant pathogenic organisms. Their production has also been implicated in the etiology of periodontal disease. Hemolytic strain 361B of Prevotella melaninogenica, a putative etiologic agent of periodontal disease, was used in this study. The cloning, sequencing, and characterization of phyA, the structural gene for a P. melaninogenica hemolysin, is described. No extensive sequence homology could be identified between phyA and any reported sequence at either the nucleotide or amino acid level. As predicted from sequence analysis, this gene produces a 39-kDa protein which has hemolytic activity as measured by zymogram analysis. Unlike many Ca2+-dependent bacterial hemolysins, both the cloned and native PhyA proteins were enhanced by the presence of EDTA in a dose-dependent fashion with 40 mM EDTA allowing maximum activity. Ca2+ and Mg2+ were found to be inhibitory. The hemolytic activity also was found to have a dose-dependent endpoint. Through recovery of hemolytic activity from a spent reaction, this endpoint was shown to be the result of end product inhibition. This is the first report describing the cloning and sequencing of a gene from P. melaninogenica. PMID:9199448

Cloning and characterization of a Prevotella melaninogenica hemolysin.

PubMed

Allison, H E; Hillman, J D

1997-07-01

Hemolysins have been proven to be important virulence factors in many medically relevant pathogenic organisms. Their production has also been implicated in the etiology of periodontal disease. Hemolytic strain 361B of Prevotella melaninogenica, a putative etiologic agent of periodontal disease, was used in this study. The cloning, sequencing, and characterization of phyA, the structural gene for a P. melaninogenica hemolysin, is described. No extensive sequence homology could be identified between phyA and any reported sequence at either the nucleotide or amino acid level. As predicted from sequence analysis, this gene produces a 39-kDa protein which has hemolytic activity as measured by zymogram analysis. Unlike many Ca2+-dependent bacterial hemolysins, both the cloned and native PhyA proteins were enhanced by the presence of EDTA in a dose-dependent fashion with 40 mM EDTA allowing maximum activity. Ca2+ and Mg2+ were found to be inhibitory. The hemolytic activity also was found to have a dose-dependent endpoint. Through recovery of hemolytic activity from a spent reaction, this endpoint was shown to be the result of end product inhibition. This is the first report describing the cloning and sequencing of a gene from P. melaninogenica.

Vibrations of beams and rods carrying a moving mass

NASA Astrophysics Data System (ADS)

Zhao, X. W.; van der Heijden, G. H. M.; Hu, Z. D.

2016-05-01

We study the vibration of slender one-dimensional elastic structures (beams, cables, wires, rods) under the effect of a moving mass or load. We first consider the classical small- deflection (Euler-Bernoulli) beam case, where we look at tip vibrations of a cantilever as a model for a barreled launch system. Then we develop a theory for large deformations based on Cosserat rod theory. We illustrate the effect of moving loads on large-deformation structures with a few cable and arch problems. Large deformations are found to have a resonance detuning effect on the cable. For the arch we find different failure modes depending on its depth: a shallow arch fails by in-plane collapse, while a deep arch fails by sideways flopping. In both cases the speed of the traversing load is found to have a stabilising effect on the structure, with failure suppressed entirely at sufficiently high speed.

Analysis of Accelerometer Data from a Woven Inflatable Creep Burst Test

NASA Technical Reports Server (NTRS)

James, George H.; Grygier, Michael; Selig, Molly M.

2015-01-01

Accelerometers were used to montor an inflatable test article during a creep test to failure. The test article experienced impulse events that were classified based on the response of the sensors and their time-dependent manifestation. These impulse events required specialized techniques to process the structural dynamics data. However, certain phenomena were defined as worthy of additional study. An assessment of one phenomena (a frequency near 1000Hz) showed a time dependent frequency and an amplitude that increased significantly near the end of the test. Hence, these observations are expected to drive future understanding of and utility in inflatable space structures.

PredPPCrys: accurate prediction of sequence cloning, protein production, purification and crystallization propensity from protein sequences using multi-step heterogeneous feature fusion and selection.

PubMed

Wang, Huilin; Wang, Mingjun; Tan, Hao; Li, Yuan; Zhang, Ziding; Song, Jiangning

2014-01-01

X-ray crystallography is the primary approach to solve the three-dimensional structure of a protein. However, a major bottleneck of this method is the failure of multi-step experimental procedures to yield diffraction-quality crystals, including sequence cloning, protein material production, purification, crystallization and ultimately, structural determination. Accordingly, prediction of the propensity of a protein to successfully undergo these experimental procedures based on the protein sequence may help narrow down laborious experimental efforts and facilitate target selection. A number of bioinformatics methods based on protein sequence information have been developed for this purpose. However, our knowledge on the important determinants of propensity for a protein sequence to produce high diffraction-quality crystals remains largely incomplete. In practice, most of the existing methods display poorer performance when evaluated on larger and updated datasets. To address this problem, we constructed an up-to-date dataset as the benchmark, and subsequently developed a new approach termed 'PredPPCrys' using the support vector machine (SVM). Using a comprehensive set of multifaceted sequence-derived features in combination with a novel multi-step feature selection strategy, we identified and characterized the relative importance and contribution of each feature type to the prediction performance of five individual experimental steps required for successful crystallization. The resulting optimal candidate features were used as inputs to build the first-level SVM predictor (PredPPCrys I). Next, prediction outputs of PredPPCrys I were used as the input to build second-level SVM classifiers (PredPPCrys II), which led to significantly enhanced prediction performance. Benchmarking experiments indicated that our PredPPCrys method outperforms most existing procedures on both up-to-date and previous datasets. In addition, the predicted crystallization targets of currently non-crystallizable proteins were provided as compendium data, which are anticipated to facilitate target selection and design for the worldwide structural genomics consortium. PredPPCrys is freely available at http://www.structbioinfor.org/PredPPCrys.

Treatment carryover impacts on effectiveness of intraocular pressure lowering agents, estimated by a discrete event simulation model.

PubMed

Denis, P; Le Pen, C; Umuhire, D; Berdeaux, G

2008-01-01

To compare the effectiveness of two treatment sequences, latanoprost-latanoprost timolol fixed combination (L-LT) versus travoprost-travoprost timolol fixed combination (T-TT), in the treatment of open-angle glaucoma (OAG) or ocular hypertension (OHT). A discrete event simulation (DES) model was constructed. Patients with either OAG or OHT were treated first-line with a prostaglandin, either latanoprost or travoprost. In case of treatment failure, patients were switched to the specific prostaglandin-timolol sequence LT or TT. Failure was defined as intraocular pressure higher than or equal to 18 mmHg at two visits. Time to failure was estimated from two randomized clinical trials. Log-rank tests were computed. Linear functions after log-log transformation were used to model time to failure. The time horizon of the model was 60 months. Outcomes included treatment failure and disease progression. Sensitivity analyses were performed. Latanoprost treatment resulted in more treatment failures than travoprost (p<0.01), and LT more than TT (p<0.01). At 60 months, the probability of starting a third treatment line was 39.2% with L-LT versus 29.9% with T-TT. On average, L-LT patients developed 0.55 new visual field defects versus 0.48 for T-TT patients. The probability of no disease progression at 60 months was 61.4% with L-LT and 65.5% with T-TT. Based on randomized clinical trial results and using a DES model, the T-TT sequence was more effective at avoiding starting a third line treatment than the L-LT sequence. T-TT treated patients developed less glaucoma progression.

Inherited metabolic disorders presenting as acute liver failure in newborns and young children: King's College Hospital experience.

PubMed

Hegarty, Robert; Hadzic, Nedim; Gissen, Paul; Dhawan, Anil

2015-10-01

Acute liver failure (ALF) in children is a rare condition that is often fatal without liver transplantation. The diagnostic work-up is complex, and the etiology is unidentified in up to half of patients, making decisions like therapeutic transplantation extremely difficult. We collected clinical, laboratory, and outcome data on all patients under 5 years of age who were admitted between January 2001 and December 2011 to King's College Hospital with ALF secondary to an inherited metabolic disease (IMD), a common cause of pediatric acute liver failure. Thirty-six of 127 children with ALF had a metabolic etiology: galactosemia (17); mitochondrial respiratory chain disorder (MRCD, 7); ornithine transcarbamylase (OTC) deficiency (4); tyrosinemia type 1 (4); Niemann-Pick disease type C (NPC, 3); and congenital disorder of glycosylation type 1b (1). Seven children died: MRCD (4) and NPC (3). Four children were transplanted: OTC deficiency (1) and MRCD (3). Fifteen of 25 children followed up showed evidence of developmental delay. IMD is the most common group of disorders in this age group; indeterminate cases may yet include undiagnosed metabolic disorders; the overall survival rate is good but largely depends on diagnosis, while developmental outcome of the surviving patients is less favorable. • Up to half of children with ALF may be undiagnosed. • IMD is a common cause of pediatric acute liver failure. What is New: • Initial diagnostic clues may be gathered from the child's age and laboratory parameters. • Survival of children with IMD-related ALF is good, but developmental outcome is less favorable. • In the future, novel sequencing methods will aid in the diagnosis of disorders in which therapeutic decisions depend upon.

The Murine Norovirus Core Subgenomic RNA Promoter Consists of a Stable Stem-Loop That Can Direct Accurate Initiation of RNA Synthesis

PubMed Central

Yunus, Muhammad Amir; Lin, Xiaoyan; Bailey, Dalan; Karakasiliotis, Ioannis; Chaudhry, Yasmin; Vashist, Surender; Zhang, Guo; Thorne, Lucy; Kao, C. Cheng

2014-01-01

ABSTRACT All members of the Caliciviridae family of viruses produce a subgenomic RNA during infection. The subgenomic RNA typically encodes only the major and minor capsid proteins, but in murine norovirus (MNV), the subgenomic RNA also encodes the VF1 protein, which functions to suppress host innate immune responses. To date, the mechanism of norovirus subgenomic RNA synthesis has not been characterized. We have previously described the presence of an evolutionarily conserved RNA stem-loop structure on the negative-sense RNA, the complementary sequence of which codes for the viral RNA-dependent RNA polymerase (NS7). The conserved stem-loop is positioned 6 nucleotides 3′ of the start site of the subgenomic RNA in all caliciviruses. We demonstrate that the conserved stem-loop is essential for MNV viability. Mutant MNV RNAs with substitutions in the stem-loop replicated poorly until they accumulated mutations that revert to restore the stem-loop sequence and/or structure. The stem-loop sequence functions in a noncoding context, as it was possible to restore the replication of an MNV mutant by introducing an additional copy of the stem-loop between the NS7- and VP1-coding regions. Finally, in vitro biochemical data suggest that the stem-loop sequence is sufficient for the initiation of viral RNA synthesis by the recombinant MNV RNA-dependent RNA polymerase, confirming that the stem-loop forms the core of the norovirus subgenomic promoter. IMPORTANCE Noroviruses are a significant cause of viral gastroenteritis, and it is important to understand the mechanism of norovirus RNA synthesis. Here we describe the identification of an RNA stem-loop structure that functions as the core of the norovirus subgenomic RNA promoter in cells and in vitro. This work provides new insights into the molecular mechanisms of norovirus RNA synthesis and the sequences that determine the recognition of viral RNA by the RNA-dependent RNA polymerase. PMID:25392209

The murine norovirus core subgenomic RNA promoter consists of a stable stem-loop that can direct accurate initiation of RNA synthesis.

PubMed

Yunus, Muhammad Amir; Lin, Xiaoyan; Bailey, Dalan; Karakasiliotis, Ioannis; Chaudhry, Yasmin; Vashist, Surender; Zhang, Guo; Thorne, Lucy; Kao, C Cheng; Goodfellow, Ian

2015-01-15

All members of the Caliciviridae family of viruses produce a subgenomic RNA during infection. The subgenomic RNA typically encodes only the major and minor capsid proteins, but in murine norovirus (MNV), the subgenomic RNA also encodes the VF1 protein, which functions to suppress host innate immune responses. To date, the mechanism of norovirus subgenomic RNA synthesis has not been characterized. We have previously described the presence of an evolutionarily conserved RNA stem-loop structure on the negative-sense RNA, the complementary sequence of which codes for the viral RNA-dependent RNA polymerase (NS7). The conserved stem-loop is positioned 6 nucleotides 3' of the start site of the subgenomic RNA in all caliciviruses. We demonstrate that the conserved stem-loop is essential for MNV viability. Mutant MNV RNAs with substitutions in the stem-loop replicated poorly until they accumulated mutations that revert to restore the stem-loop sequence and/or structure. The stem-loop sequence functions in a noncoding context, as it was possible to restore the replication of an MNV mutant by introducing an additional copy of the stem-loop between the NS7- and VP1-coding regions. Finally, in vitro biochemical data suggest that the stem-loop sequence is sufficient for the initiation of viral RNA synthesis by the recombinant MNV RNA-dependent RNA polymerase, confirming that the stem-loop forms the core of the norovirus subgenomic promoter. Noroviruses are a significant cause of viral gastroenteritis, and it is important to understand the mechanism of norovirus RNA synthesis. Here we describe the identification of an RNA stem-loop structure that functions as the core of the norovirus subgenomic RNA promoter in cells and in vitro. This work provides new insights into the molecular mechanisms of norovirus RNA synthesis and the sequences that determine the recognition of viral RNA by the RNA-dependent RNA polymerase. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Sequence dependence of electron-induced DNA strand breakage revealed by DNA nanoarrays

PubMed Central

Keller, Adrian; Rackwitz, Jenny; Cauët, Emilie; Liévin, Jacques; Körzdörfer, Thomas; Rotaru, Alexandru; Gothelf, Kurt V.; Besenbacher, Flemming; Bald, Ilko

2014-01-01

The electronic structure of DNA is determined by its nucleotide sequence, which is for instance exploited in molecular electronics. Here we demonstrate that also the DNA strand breakage induced by low-energy electrons (18 eV) depends on the nucleotide sequence. To determine the absolute cross sections for electron induced single strand breaks in specific 13 mer oligonucleotides we used atomic force microscopy analysis of DNA origami based DNA nanoarrays. We investigated the DNA sequences 5′-TT(XYX)3TT with X = A, G, C and Y = T, BrU 5-bromouracil and found absolute strand break cross sections between 2.66 · 10−14 cm2 and 7.06 · 10−14 cm2. The highest cross section was found for 5′-TT(ATA)3TT and 5′-TT(ABrUA)3TT, respectively. BrU is a radiosensitizer, which was discussed to be used in cancer radiation therapy. The replacement of T by BrU into the investigated DNA sequences leads to a slight increase of the absolute strand break cross sections resulting in sequence-dependent enhancement factors between 1.14 and 1.66. Nevertheless, the variation of strand break cross sections due to the specific nucleotide sequence is considerably higher. Thus, the present results suggest the development of targeted radiosensitizers for cancer radiation therapy. PMID:25487346

Epigenetic Instability due to Defective Replication of Structured DNA

PubMed Central

Sarkies, Peter; Reams, Charlie; Simpson, Laura J.; Sale, Julian E.

2010-01-01

Summary The accurate propagation of histone marks during chromosomal replication is proposed to rely on the tight coupling of replication with the recycling of parental histones to the daughter strands. Here, we show in the avian cell line DT40 that REV1, a key regulator of DNA translesion synthesis at the replication fork, is required for the maintenance of repressive chromatin marks and gene silencing in the vicinity of DNA capable of forming G-quadruplex (G4) structures. We demonstrate a previously unappreciated requirement for REV1 in replication of G4 forming sequences and show that transplanting a G4 forming sequence into a silent locus leads to its derepression in REV1-deficient cells. Together, our observations support a model in which failure to maintain processive DNA replication at G4 DNA in REV1-deficient cells leads to uncoupling of DNA synthesis from histone recycling, resulting in localized loss of repressive chromatin through biased incorporation of newly synthesized histones. PMID:21145480

Modeling joint restoration strategies for interdependent infrastructure systems.

PubMed

Zhang, Chao; Kong, Jingjing; Simonovic, Slobodan P

2018-01-01

Life in the modern world depends on multiple critical services provided by infrastructure systems which are interdependent at multiple levels. To effectively respond to infrastructure failures, this paper proposes a model for developing optimal joint restoration strategy for interdependent infrastructure systems following a disruptive event. First, models for (i) describing structure of interdependent infrastructure system and (ii) their interaction process, are presented. Both models are considering the failure types, infrastructure operating rules and interdependencies among systems. Second, an optimization model for determining an optimal joint restoration strategy at infrastructure component level by minimizing the economic loss from the infrastructure failures, is proposed. The utility of the model is illustrated using a case study of electric-water systems. Results show that a small number of failed infrastructure components can trigger high level failures in interdependent systems; the optimal joint restoration strategy varies with failure occurrence time. The proposed models can help decision makers to understand the mechanisms of infrastructure interactions and search for optimal joint restoration strategy, which can significantly enhance safety of infrastructure systems.

SVM-based tree-type neural networks as a critic in adaptive critic designs for control.

PubMed

Deb, Alok Kanti; Jayadeva; Gopal, Madan; Chandra, Suresh

2007-07-01

In this paper, we use the approach of adaptive critic design (ACD) for control, specifically, the action-dependent heuristic dynamic programming (ADHDP) method. A least squares support vector machine (SVM) regressor has been used for generating the control actions, while an SVM-based tree-type neural network (NN) is used as the critic. After a failure occurs, the critic and action are retrained in tandem using the failure data. Failure data is binary classification data, where the number of failure states are very few as compared to the number of no-failure states. The difficulty of conventional multilayer feedforward NNs in learning this type of classification data has been overcome by using the SVM-based tree-type NN, which due to its feature to add neurons to learn misclassified data, has the capability to learn any binary classification data without a priori choice of the number of neurons or the structure of the network. The capability of the trained controller to handle unforeseen situations is demonstrated.

Effect of temperature on terahertz photonic and omnidirectional band gaps in one-dimensional quasi-periodic photonic crystals composed of semiconductor InSb.

PubMed

Singh, Bipin K; Pandey, Praveen C

2016-07-20

Engineering of thermally tunable terahertz photonic and omnidirectional bandgaps has been demonstrated theoretically in one-dimensional quasi-periodic photonic crystals (PCs) containing semiconductor and dielectric materials. The considered quasi-periodic structures are taken in the form of Fibonacci, Thue-Morse, and double periodic sequences. We have shown that the photonic and omnidirectional bandgaps in the quasi-periodic structures with semiconductor constituents are strongly depend on the temperature, thickness of the constituted semiconductor and dielectric material layers, and generations of the quasi-periodic sequences. It has been found that the number of photonic bandgaps increases with layer thickness and generation of the quasi-periodic sequences. Omnidirectional bandgaps in the structures have also been obtained. Results show that the bandwidths of photonic and omnidirectional bandgaps are tunable by changing the temperature and lattice parameters of the structures. The generation of quasi-periodic sequences can also change the properties of photonic and omnidirectional bandgaps remarkably. The frequency range of the photonic and omnidirectional bandgaps can be tuned by the change of temperature and layer thickness of the considered quasi-periodic structures. This work will be useful to design tunable terahertz PC devices.

Dolichol phosphate mannose synthase: a Glycosyltransferase with Unity in molecular diversities.

PubMed

Banerjee, Dipak K; Zhang, Zhenbo; Baksi, Krishna; Serrano-Negrón, Jesús E

2017-08-01

N-glycans provide structural and functional stability to asparagine-linked (N-linked) glycoproteins, and add flexibility. Glycan biosynthesis is elaborative, multi-compartmental and involves many glycosyltransferases. Failure to assemble N-glycans leads to phenotypic changes developing infection, cancer, congenital disorders of glycosylation (CDGs) among others. Biosynthesis of N-glycans begins at the endoplasmic reticulum (ER) with the assembly of dolichol-linked tetra-decasaccharide (Glc 3 Man 9 GlcNAc 2 -PP-Dol) where dolichol phosphate mannose synthase (DPMS) plays a central role. DPMS is also essential for GPI anchor biosynthesis as well as for O- and C-mannosylation of proteins in yeast and in mammalian cells. DPMS has been purified from several sources and its gene has been cloned from 39 species (e.g., from protozoan parasite to human). It is an inverting GT-A folded enzyme and classified as GT2 by CAZy (carbohydrate active enZyme; http://www.cazy.org ). The sequence alignment detects the presence of a metal binding DAD signature in DPMS from all 39 species but finds cAMP-dependent protein phosphorylation motif (PKA motif) in only 38 species. DPMS also has hydrophobic region(s). Hydropathy analysis of amino acid sequences from bovine, human, S. crevisiae and A. thaliana DPMS show PKA motif is present between the hydrophobic domains. The location of PKA motif as well as the hydrophobic domain(s) in the DPMS sequence vary from species to species. For example, the domain(s) could be located at the center or more towards the C-terminus. Irrespective of their catalytic similarity, the DNA sequence, the amino acid identity, and the lack of a stretch of hydrophobic amino acid residues at the C-terminus, DPMS is still classified as Type I and Type II enzyme. Because of an apparent bio-sensing ability, extracellular signaling and microenvironment regulate DPMS catalytic activity. In this review, we highlight some important features and the molecular diversities of DPMS.

DNA interactions with a Methylene Blue redox indicator depend on the DNA length and are sequence specific.

PubMed

Farjami, Elaheh; Clima, Lilia; Gothelf, Kurt V; Ferapontova, Elena E

2010-06-01

A DNA molecular beacon approach was used for the analysis of interactions between DNA and Methylene Blue (MB) as a redox indicator of a hybridization event. DNA hairpin structures of different length and guanine (G) content were immobilized onto gold electrodes in their folded states through the alkanethiol linker at the 5'-end. Binding of MB to the folded hairpin DNA was electrochemically studied and compared with binding to the duplex structure formed by hybridization of the hairpin DNA to a complementary DNA strand. Variation of the electrochemical signal from the DNA-MB complex was shown to depend primarily on the DNA length and sequence used: the G-C base pairs were the preferential sites of MB binding in the duplex. For short 20 nts long DNA sequences, the increased electrochemical response from MB bound to the duplex structure was consistent with the increased amount of bound and electrochemically readable MB molecules (i.e. MB molecules that are available for the electron transfer (ET) reaction with the electrode). With longer DNA sequences, the balance between the amounts of the electrochemically readable MB molecules bound to the hairpin DNA and to the hybrid was opposite: a part of the MB molecules bound to the long-sequence DNA duplex seem to be electrochemically mute due to long ET distance. The increasing electrochemical response from MB bound to the short-length DNA hybrid contrasts with the decreasing signal from MB bound to the long-length DNA hybrid and allows an "off"-"on" genosensor development.

Ayame/PAM-D apogee kick motor nozzle failure analysis

NASA Technical Reports Server (NTRS)

1981-01-01

The failure of two communication satellites during firing sequence were examined. The correlation/comparison of the circumstances of the Ayame incidents and the failure of the STAR 48 (DM-2) motor are reviewed. The massive nozzle failure of the AKM to determine the impact on spacecraft performance is examined. It is recommended that a closer watch is kept on systems techniques,

Neonatal Hypoxia, Hippocampal Atrophy, and Memory Impairment: Evidence of a Causal Sequence

PubMed Central

Cooper, Janine M.; Gadian, David G.; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W. Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

2015-01-01

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. PMID:24343890

Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence.

PubMed

Cooper, Janine M; Gadian, David G; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

2015-06-01

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. © The Author 2013. Published by Oxford University Press.

Estimation of the lower and upper bounds on the probability of failure using subset simulation and random set theory

NASA Astrophysics Data System (ADS)

Alvarez, Diego A.; Uribe, Felipe; Hurtado, Jorge E.

2018-02-01

Random set theory is a general framework which comprises uncertainty in the form of probability boxes, possibility distributions, cumulative distribution functions, Dempster-Shafer structures or intervals; in addition, the dependence between the input variables can be expressed using copulas. In this paper, the lower and upper bounds on the probability of failure are calculated by means of random set theory. In order to accelerate the calculation, a well-known and efficient probability-based reliability method known as subset simulation is employed. This method is especially useful for finding small failure probabilities in both low- and high-dimensional spaces, disjoint failure domains and nonlinear limit state functions. The proposed methodology represents a drastic reduction of the computational labor implied by plain Monte Carlo simulation for problems defined with a mixture of representations for the input variables, while delivering similar results. Numerical examples illustrate the efficiency of the proposed approach.

Complex Failure Forewarning System - DHS Conference Proceedings

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

Abercrombie, Robert K; Hively, Lee M; Prowell, Stacy J

2011-01-01

As the critical infrastructures of the United States have become more and more dependent on public and private networks, the potential for widespread national impact resulting from disruption or failure of these networks has also increased. Securing the nation s critical infrastructures requires protecting not only their physical systems but, just as important, the cyber portions of the systems on which they rely. A failure is inclusive of random events, design flaws, and instabilities caused by cyber (and/or physical) attack. One such domain, aging bridges, is used to explain the Complex Structure Failure Forewarning System. We discuss the workings ofmore » such a system in the context of the necessary sensors, command and control and data collection as well as the cyber security efforts that would support this system. Their application and the implications of this computing architecture are also discussed, with respect to our nation s aging infrastructure.« less

Conservation of Fold and Topology of Functional Elements in Thiamin Pyrophosphate Enzymes

NASA Technical Reports Server (NTRS)

Dominiak, P.; Ciszak, E. M.

2005-01-01

Thiamin pyrophosphate (TPP)-dependent enzymes are a highly divergent family of proteins binding both TPP and metal ions. They perform decarboxylation-hydroxyaldehydes. Prior -ketoacids and of a common - (O=)C-C(OH)- fragment of to knowledge of three-dimensional structures of these enzmes, the GDGY25-30NN sequence was used to identify these enzymes. Subsequently, a number of structural studies on those enzymes revealed multi-subunit organization and the features of the two duplicate cofactor binding sites. Analyzing the structures of 44 structurally known enzymes, we found that the common structure of these enzymes is reduced to 180-220 amino acid long fragments of two PP and two PYR domains that form the [PP:PYR]2 binding center of two cofactor molecules. The structures of PP and PYR are arranged in a similar fold-sheet with triplets of helices on both sides.Dconsisting of a six-stranded Residues surrounding the cofactors are not strictly conserved, but they provide the same interatomic contacts required for the catalytic functions that these enzymes perform while maintaining interactive structural integrity. These structural and functional amino acids are topological counterparts located in the same positions of the conserved fold of sets of PP and PYR domains. Additional parallels include short fragments of sequences that link these amino acids to the fold and function. This report on the structural commonalities amongst TPP dependent enzymes is thought to contribute new approaches to annotation that may assist in advancing the functional proteomics of TPP dependent enzymes, and trace their complexity within evolutionary context.

Structures of Bacterial Biosynthetic Arginine Decarboxylases

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

F Forouhar; S Lew; J Seetharaman

2011-12-31

Biosynthetic arginine decarboxylase (ADC; also known as SpeA) plays an important role in the biosynthesis of polyamines from arginine in bacteria and plants. SpeA is a pyridoxal-5'-phosphate (PLP)-dependent enzyme and shares weak sequence homology with several other PLP-dependent decarboxylases. Here, the crystal structure of PLP-bound SpeA from Campylobacter jejuni is reported at 3.0 {angstrom} resolution and that of Escherichia coli SpeA in complex with a sulfate ion is reported at 3.1 {angstrom} resolution. The structure of the SpeA monomer contains two large domains, an N-terminal TIM-barrel domain followed by a {beta}-sandwich domain, as well as two smaller helical domains. Themore » TIM-barrel and {beta}-sandwich domains share structural homology with several other PLP-dependent decarboxylases, even though the sequence conservation among these enzymes is less than 25%. A similar tetramer is observed for both C. jejuni and E. coli SpeA, composed of two dimers of tightly associated monomers. The active site of SpeA is located at the interface of this dimer and is formed by residues from the TIM-barrel domain of one monomer and a highly conserved loop in the {beta}-sandwich domain of the other monomer. The PLP cofactor is recognized by hydrogen-bonding, {pi}-stacking and van der Waals interactions.« less

Competition between B-Z and B-L transitions in a single DNA molecule: Computational studies

NASA Astrophysics Data System (ADS)

Kwon, Ah-Young; Nam, Gi-Moon; Johner, Albert; Kim, Seyong; Hong, Seok-Cheol; Lee, Nam-Kyung

2016-02-01

Under negative torsion, DNA adopts left-handed helical forms, such as Z-DNA and L-DNA. Using the random copolymer model developed for a wormlike chain, we represent a single DNA molecule with structural heterogeneity as a helical chain consisting of monomers which can be characterized by different helical senses and pitches. By Monte Carlo simulation, where we take into account bending and twist fluctuations explicitly, we study sequence dependence of B-Z transitions under torsional stress and tension focusing on the interaction with B-L transitions. We consider core sequences, (GC) n repeats or (TG) n repeats, which can interconvert between the right-handed B form and the left-handed Z form, imbedded in a random sequence, which can convert to left-handed L form with different (tension dependent) helical pitch. We show that Z-DNA formation from the (GC) n sequence is always supported by unwinding torsional stress but Z-DNA formation from the (TG) n sequence, which are more costly to convert but numerous, can be strongly influenced by the quenched disorder in the surrounding random sequence.

Is there a domain-general cognitive structuring system? Evidence from structural priming across music, math, action descriptions, and language.

PubMed

Van de Cavey, Joris; Hartsuiker, Robert J

2016-01-01

Cognitive processing in many domains (e.g., sentence comprehension, music listening, and math solving) requires sequential information to be organized into an integrational structure. There appears to be some overlap in integrational processing across domains, as shown by cross-domain interference effects when for example linguistic and musical stimuli are jointly presented (Koelsch, Gunter, Wittfoth, & Sammler, 2005; Slevc, Rosenberg, & Patel, 2009). These findings support theories of overlapping resources for integrational processing across domains (cfr. SSIRH Patel, 2003; SWM, Kljajevic, 2010). However, there are some limitations to the studies mentioned above, such as the frequent use of unnaturalistic integrational difficulties. In recent years, the idea has risen that evidence for domain-generality in structural processing might also be yielded though priming paradigms (cfr. Scheepers, 2003). The rationale behind this is that integrational processing across domains regularly requires the processing of dependencies across short or long distances in the sequence, involving respectively less or more syntactic working memory resources (cfr. SWM, Kljajevic, 2010), and such processing decisions might persist over time. However, whereas recent studies have shown suggestive priming of integrational structure between language and arithmetics (though often dependent on arithmetic performance, cfr. Scheepers et al., 2011; Scheepers & Sturt, 2014), it remains to be investigated to what extent we can also find evidence for priming in other domains, such as music and action (cfr. SWM, Kljajevic, 2010). Experiment 1a showed structural priming from the processing of musical sequences onto the position in the sentence structure (early or late) to which a relative clause was attached in subsequent sentence completion. Importantly, Experiment 1b showed that a similar structural manipulation based on non-hierarchically ordered color sequences did not yield any priming effect, suggesting that the priming effect is not based on linear order, but integrational dependency. Finally, Experiment 2 presented primes in four domains (relative clause sentences, music, mathematics, and structured descriptions of actions), and consistently showed priming within and across domains. These findings provide clear evidence for domain-general structural processing mechanisms. Copyright © 2015 Elsevier B.V. All rights reserved.

Detailed observations of California foreshock sequences: Implications for the earthquake initiation process

USGS Publications Warehouse

Dodge, D.A.; Beroza, G.C.; Ellsworth, W.L.

1996-01-01

We find that foreshocks provide clear evidence for an extended nucleation process before some earthquakes. In this study, we examine in detail the evolution of six California foreshock sequences, the 1986 Mount Lewis (ML, = 5.5), the 1986 Chalfant (ML = 6.4), the. 1986 Stone Canyon (ML = 4.7), the 1990 Upland (ML = 5.2), the 1992 Joshua Tree (MW= 6.1), and the 1992 Landers (MW = 7.3) sequence. Typically, uncertainties in hypocentral parameters are too large to establish the geometry of foreshock sequences and hence to understand their evolution. However, the similarity of location and focal mechanisms for the events in these sequences leads to similar foreshock waveforms that we cross correlate to obtain extremely accurate relative locations. We use these results to identify small-scale fault zone structures that could influence nucleation and to determine the stress evolution leading up to the mainshock. In general, these foreshock sequences are not compatible with a cascading failure nucleation model in which the foreshocks all occur on a single fault plane and trigger the mainshock by static stress transfer. Instead, the foreshocks seem to concentrate near structural discontinuities in the fault and may themselves be a product of an aseismic nucleation process. Fault zone heterogeneity may also be important in controlling the number of foreshocks, i.e., the stronger the heterogeneity, the greater the number of foreshocks. The size of the nucleation region, as measured by the extent of the foreshock sequence, appears to scale with mainshock moment in the same manner as determined independently by measurements of the seismic nucleation phase. We also find evidence for slip localization as predicted by some models of earthquake nucleation. Copyright 1996 by the American Geophysical Union.

Transient Reliability of Ceramic Structures For Heat Engine Applications

NASA Technical Reports Server (NTRS)

Nemeth, Noel N.; Jadaan, Osama M.

2002-01-01

The objectives of this report was to develop a methodology to predict the time-dependent reliability (probability of failure) of brittle material components subjected to transient thermomechanical loading, taking into account the change in material response with time. This methodology for computing the transient reliability in ceramic components subjected to fluctuation thermomechanical loading was developed, assuming SCG (Slow Crack Growth) as the delayed mode of failure. It takes into account the effect of varying Weibull modulus and materials with time. It was also coded into a beta version of NASA's CARES/Life code, and an example demonstrating its viability was presented.

Computer-aided operations engineering with integrated models of systems and operations

NASA Technical Reports Server (NTRS)

Malin, Jane T.; Ryan, Dan; Fleming, Land

1994-01-01

CONFIG 3 is a prototype software tool that supports integrated conceptual design evaluation from early in the product life cycle, by supporting isolated or integrated modeling, simulation, and analysis of the function, structure, behavior, failures and operation of system designs. Integration and reuse of models is supported in an object-oriented environment providing capabilities for graph analysis and discrete event simulation. Integration is supported among diverse modeling approaches (component view, configuration or flow path view, and procedure view) and diverse simulation and analysis approaches. Support is provided for integrated engineering in diverse design domains, including mechanical and electro-mechanical systems, distributed computer systems, and chemical processing and transport systems. CONFIG supports abstracted qualitative and symbolic modeling, for early conceptual design. System models are component structure models with operating modes, with embedded time-related behavior models. CONFIG supports failure modeling and modeling of state or configuration changes that result in dynamic changes in dependencies among components. Operations and procedure models are activity structure models that interact with system models. CONFIG is designed to support evaluation of system operability, diagnosability and fault tolerance, and analysis of the development of system effects of problems over time, including faults, failures, and procedural or environmental difficulties.

Optimization of rotamers prior to template minimization improves stability predictions made by computational protein design.

PubMed

Davey, James A; Chica, Roberto A

2015-04-01

Computational protein design (CPD) predictions are highly dependent on the structure of the input template used. However, it is unclear how small differences in template geometry translate to large differences in stability prediction accuracy. Herein, we explored how structural changes to the input template affect the outcome of stability predictions by CPD. To do this, we prepared alternate templates by Rotamer Optimization followed by energy Minimization (ROM) and used them to recapitulate the stability of 84 protein G domain β1 mutant sequences. In the ROM process, side-chain rotamers for wild-type (WT) or mutant sequences are optimized on crystal or nuclear magnetic resonance (NMR) structures prior to template minimization, resulting in alternate structures termed ROM templates. We show that use of ROM templates prepared from sequences known to be stable results predominantly in improved prediction accuracy compared to using the minimized crystal or NMR structures. Conversely, ROM templates prepared from sequences that are less stable than the WT reduce prediction accuracy by increasing the number of false positives. These observed changes in prediction outcomes are attributed to differences in side-chain contacts made by rotamers in ROM templates. Finally, we show that ROM templates prepared from sequences that are unfolded or that adopt a nonnative fold result in the selective enrichment of sequences that are also unfolded or that adopt a nonnative fold, respectively. Our results demonstrate the existence of a rotamer bias caused by the input template that can be harnessed to skew predictions toward sequences displaying desired characteristics. © 2014 The Protein Society.

Exome Sequencing Establishes Diagnosis of Alström Syndrome in an Infant Presenting with Non-Syndromic Dilated Cardiomyopathy

PubMed Central

Long, Pamela A.; Evans, Jared M.; Olson, Timothy M.

2015-01-01

Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care. PMID:25706677

Self-monitoring fiber reinforced polymer strengthening system for civil engineering infrastructures

NASA Astrophysics Data System (ADS)

Jiang, Guoliang; Dawood, Mina; Peters, Kara; Rizkalla, Sami

2008-03-01

Fiber reinforced polymer (FRP) materials are currently used for strengthening civil engineering infrastructures. The strengthening system is dependant on the bond characteristics of the FRP to the external surface of the structure to be effective in resisting the applied loads. This paper presents an innovative self-monitoring FRP strengthening system. The system consists of two components which can be embedded in FRP materials to monitor the global and local behavior of the strengthened structure respectively. The first component of the system is designed to evaluate the applied load acting on a structure based on elongation of the FRP layer along the entire span of the structure. Success of the global system has been demonstrated using a full-scale prestressed concrete bridge girder which was loaded up to failure. The test results indicate that this type of sensor can be used to accurately determine the load prior to failure within 15 percent of the measured value. The second sensor component consists of fiber Bragg grating sensors. The sensors were used to monitor the behavior of steel double-lap shear splices tested under tensile loading up to failure. The measurements were used to identify abnormal structural behavior such as epoxy cracking and FRP debonding. Test results were also compared to numerical values obtained from a three dimensional shear-lag model which was developed to predict the sensor response.

Sequence- and Temperature-Dependent Properties of Unfolded and Disordered Proteins from Atomistic Simulations.

PubMed

Zerze, Gül H; Best, Robert B; Mittal, Jeetain

2015-11-19

We use all-atom molecular simulation with explicit solvent to study the properties of selected intrinsically disordered proteins and unfolded states of foldable proteins, which include chain dimensions and shape, secondary structure propensity, solvent accessible surface area, and contact formation. We find that the qualitative scaling behavior of the chains matches expectations from theory under ambient conditions. In particular, unfolded globular proteins tend to be more collapsed under the same conditions than charged disordered sequences of the same length. However, inclusion of explicit solvent in addition naturally captures temperature-dependent solvation effects, which results in an initial collapse of the chains as temperature is increased, in qualitative agreement with experiment. There is a universal origin to the collapse, revealed in the change of hydration of individual residues as a function of temperature: namely, that the initial collapse is driven by unfavorable solvation free energy of individual residues, which in turn has a strong temperature dependence. We also observe that in unfolded globular proteins, increased temperature also initially favors formation of native-like (rather than non-native-like) structure. Our results help to establish how sequence encodes the degree of intrinsic disorder or order as well as its response to changes in environmental conditions.

Subtelomeric Rearrangements and Copy Number Variations in People with Intellectual Disabilities

ERIC Educational Resources Information Center

Christofolini, D. M.; De Paula Ramos, M. A.; Kulikowski, L. D.; Da Silva Bellucco, F. T.; Belangero, S. I. N.; Brunoni, D.; Melaragno, M. I.

2010-01-01

Background: The most prevalent type of structural variation in the human genome is represented by copy number variations that can affect transcription levels, sequence, structure and function of genes. Method: In the present study, we used the multiplex ligation-dependent probe amplification (MLPA) technique and quantitative PCR for the detection…

Individual patient data meta-analysis of organ failure in acute pancreatitis: protocol of the PANCREA II study.

PubMed

Das, Stephanie L M; Papachristou, George I; De Campos, Tercio; Panek, Jozefa; Poves Prim, Ignasi; Serrablo, Alejandro; Parks, Rowan W; Uomo, Generoso; Windsor, John A; Petrov, Maxim S

2013-09-10

Organ failure is a major determinant of mortality in patients with acute pancreatitis. These patients usually require admission to high dependency or intensive care units and consume considerable health care resources. Given a low incidence rate of organ failure and a lack of large non-interventional studies in the field of acute pancreatitis, the characteristics of organ failure that influence outcomes of patients with acute pancreatitis remain largely unknown. Therefore, the Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA) aims to conduct a meta-analysis of individual patient data from prospective non-interventional studies to determine the influence of timing, duration, sequence, and combination of different organ failures on mortality in patients with acute pancreatitis. Pancreatologists currently active with acute pancreatitis clinical research will be invited to contribute. To be eligible for inclusion patients will have to meet the criteria of acute pancreatitis, develop at least one organ failure during the first week of hospitalization, and not be enrolled into an intervention study. Raw data will then be collated and checked. Individual patient data analysis based on a logistic regression model with adjustment for confounding variables will be done. For all analyses, corresponding 95% confidence intervals and P values will be reported. This collaborative individual patient data meta-analysis will answer important clinical questions regarding patients with acute pancreatitis that develop organ failure. Information derived from this study will be used to optimize routine clinical management and improve care strategies. It can also help validate outcome definitions, allow comparability of results and form a more accurate basis for patient allocation in further clinical studies.

Numerical simulation of damage and progressive failures in composite laminates using the layerwise plate theory

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

Reddy, Y.S.

1992-01-01

The failure behavior of composite laminates is modeled numerically using the Generalized Layerwise Plate Theory (GLPT) of Reddy and a progressive failure algorithm. The Layerwise Theory of Reddy assumes a piecewise continuous displacement field through the thickness of the laminate and therefore has the ability to capture the interlaminar stress fields near the free edges and cut outs more accurately. The progressive failure algorithm is based on the assumption that the material behaves like a stable progressively fracturing solid. A three-dimensional stiffness reduction scheme is developed and implemented to study progressive failures in composite laminates. The effect of various parametersmore » such as out-of-plane material properties, boundary conditions, and stiffness reduction methods on the failure stresses and strains of a quasi-isotropic composite laminate with free edges subjected to tensile loading is studied. The ultimate stresses and strains predicted by the Generalized Layerwise Plate Theory (GLPT) and the more widely used First Order Shear Deformation Theory (FSDT) are compared with experimental results. The predictions of the GLPT are found to be in good agreement with the experimental results both qualitatively and quantitatively, while the predictions of FSDT are found to be different from experimental results both qualitatively and quantitatively. The predictive ability of various phenomenological failure criteria is evaluated with reference to the experimental results available in the literature. The effect of geometry of the test specimen and the displacement boundary conditions at the grips on the ultimate stresses and strains of a composite laminate under compressive loading is studied. The ultimate stresses and strains are found to be quite sensitive to the geometry of the test specimen and the displacement boundary conditions at the grips. The degree of sensitivity is observed to depend strongly on the lamination sequence.« less

Network Analysis of Protein Adaptation: Modeling the Functional Impact of Multiple Mutations

PubMed Central

Beleva Guthrie, Violeta; Masica, David L; Fraser, Andrew; Federico, Joseph; Fan, Yunfan; Camps, Manel; Karchin, Rachel

2018-01-01

Abstract The evolution of new biochemical activities frequently involves complex dependencies between mutations and rapid evolutionary radiation. Mutation co-occurrence and covariation have previously been used to identify compensating mutations that are the result of physical contacts and preserve protein function and fold. Here, we model pairwise functional dependencies and higher order interactions that enable evolution of new protein functions. We use a network model to find complex dependencies between mutations resulting from evolutionary trade-offs and pleiotropic effects. We present a method to construct these networks and to identify functionally interacting mutations in both extant and reconstructed ancestral sequences (Network Analysis of Protein Adaptation). The time ordering of mutations can be incorporated into the networks through phylogenetic reconstruction. We apply NAPA to three distantly homologous β-lactamase protein clusters (TEM, CTX-M-3, and OXA-51), each of which has experienced recent evolutionary radiation under substantially different selective pressures. By analyzing the network properties of each protein cluster, we identify key adaptive mutations, positive pairwise interactions, different adaptive solutions to the same selective pressure, and complex evolutionary trajectories likely to increase protein fitness. We also present evidence that incorporating information from phylogenetic reconstruction and ancestral sequence inference can reduce the number of spurious links in the network, whereas preserving overall network community structure. The analysis does not require structural or biochemical data. In contrast to function-preserving mutation dependencies, which are frequently from structural contacts, gain-of-function mutation dependencies are most commonly between residues distal in protein structure. PMID:29522102

Structure prediction of Fe(II) 2-oxoglutarate dioxygenase from a psychrophilic yeast Glaciozyma antarctica PI12

NASA Astrophysics Data System (ADS)

Yusof, Nik Yusnoraini; Bakar, Farah Diba Abu; Mahadi, Nor Muhammad; Raih, Mohd Firdaus; Murad, Abdul Munir Abdul

2015-09-01

A cDNA encoding Fe(II) 2-oxoglutarate (2OG) dependent dioxygenases was isolated from psychrophilic yeast, Glaciozyma antarctica PI12. We have successfully amplified 1,029 bp cDNA sequence that encodes 342 amino acid with predicted molecular weight 38 kDa. The prediction protein was analysed using various bioinformatics tools to explore the properties of the protein. Based on a BLAST search analysis, the Fe2OX amino acid sequence showed 61% identity to the sequence of oxoglutarate/iron-dependent oxygenase from Rhodosporidium toruloides NP11. SignalP prediction showed that the Fe2OX protein contains no putative signal peptide, which suggests that this enzyme most probably localised intracellularly.The structure of Fe2OX was predicted by homology modelling using MODELLER9v11. The model with the lowest objective function was selected from hundred models generated using MODELLER9v11. Analysis of the structure revealed the longer loop at Fe2OX from G.antarctica that might be responsible for the flexibility of the structure, which contributes to its adaptation to low temperatures. Fe2OX hold a highly conserved Fe(II) binding HXD/E…H triad motif. The binding site for 2-oxoglutarate was found conserved for Arg280 among reported studies, however the Phe268 was found to be different in Fe2OX.

Structure and dynamics of single hydrophobic/ionic heteropolymers at the vapor-liquid interface of water.

PubMed

Vembanur, Srivathsan; Venkateshwaran, Vasudevan; Garde, Shekhar

2014-04-29

We focus on the conformational stability, structure, and dynamics of hydrophobic/charged homopolymers and heteropolymers at the vapor-liquid interface of water using extensive molecular dynamics simulations. Hydrophobic polymers collapse into globular structures in bulk water but unfold and sample a broad range of conformations at the vapor-liquid interface of water. We show that adding a pair of charges to a hydrophobic polymer at the interface can dramatically change its conformations, stabilizing hairpinlike structures, with molecular details depending on the location of the charged pair in the sequence. The translational dynamics of homopolymers and heteropolymers are also different, whereas the homopolymers skate on the interface with low drag, the tendency of charged groups to remain hydrated pulls the heteropolymers toward the liquid side of the interface, thus pinning them, increasing drag, and slowing the translational dynamics. The conformational dynamics of heteropolymers are also slower than that of the homopolymer and depend on the location of the charged groups in the sequence. Conformational dynamics are most restricted for the end-charged heteropolymer and speed up as the charge pair is moved toward the center of the sequence. We rationalize these trends using the fundamental understanding of the effects of the interface on primitive pair-level interactions between two hydrophobic groups and between oppositely charged ions in its vicinity.

Community detection in sequence similarity networks based on attribute clustering

DOE PAGES

Chowdhary, Janamejaya; Loeffler, Frank E.; Smith, Jeremy C.

2017-07-24

Networks are powerful tools for the presentation and analysis of interactions in multi-component systems. A commonly studied mesoscopic feature of networks is their community structure, which arises from grouping together similar nodes into one community and dissimilar nodes into separate communities. Here in this paper, the community structure of protein sequence similarity networks is determined with a new method: Attribute Clustering Dependent Communities (ACDC). Sequence similarity has hitherto typically been quantified by the alignment score or its expectation value. However, pair alignments with the same score or expectation value cannot thus be differentiated. To overcome this deficiency, the method constructs,more » for pair alignments, an extended alignment metric, the link attribute vector, which includes the score and other alignment characteristics. Rescaling components of the attribute vectors qualitatively identifies a systematic variation of sequence similarity within protein superfamilies. The problem of community detection is then mapped to clustering the link attribute vectors, selection of an optimal subset of links and community structure refinement based on the partition density of the network. ACDC-predicted communities are found to be in good agreement with gold standard sequence databases for which the "ground truth" community structures (or families) are known. ACDC is therefore a community detection method for sequence similarity networks based entirely on pair similarity information. A serial implementation of ACDC is available from https://cmb.ornl.gov/resources/developments« less

Community detection in sequence similarity networks based on attribute clustering

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

Chowdhary, Janamejaya; Loeffler, Frank E.; Smith, Jeremy C.

Networks are powerful tools for the presentation and analysis of interactions in multi-component systems. A commonly studied mesoscopic feature of networks is their community structure, which arises from grouping together similar nodes into one community and dissimilar nodes into separate communities. Here in this paper, the community structure of protein sequence similarity networks is determined with a new method: Attribute Clustering Dependent Communities (ACDC). Sequence similarity has hitherto typically been quantified by the alignment score or its expectation value. However, pair alignments with the same score or expectation value cannot thus be differentiated. To overcome this deficiency, the method constructs,more » for pair alignments, an extended alignment metric, the link attribute vector, which includes the score and other alignment characteristics. Rescaling components of the attribute vectors qualitatively identifies a systematic variation of sequence similarity within protein superfamilies. The problem of community detection is then mapped to clustering the link attribute vectors, selection of an optimal subset of links and community structure refinement based on the partition density of the network. ACDC-predicted communities are found to be in good agreement with gold standard sequence databases for which the "ground truth" community structures (or families) are known. ACDC is therefore a community detection method for sequence similarity networks based entirely on pair similarity information. A serial implementation of ACDC is available from https://cmb.ornl.gov/resources/developments« less

Independent Evolution of Six Families of Halogenating Enzymes.

PubMed

Xu, Gangming; Wang, Bin-Gui

2016-01-01

Halogenated natural products are widespread in the environment, and the halogen atoms are typically vital to their bioactivities. Thus far, six families of halogenating enzymes have been identified: cofactor-free haloperoxidases (HPO), vanadium-dependent haloperoxidases (V-HPO), heme iron-dependent haloperoxidases (HI-HPO), non-heme iron-dependent halogenases (NI-HG), flavin-dependent halogenases (F-HG), and S-adenosyl-L-methionine (SAM)-dependent halogenases (S-HG). However, these halogenating enzymes with similar biological functions but distinct structures might have evolved independently. Phylogenetic and structural analyses suggest that the HPO, V-HPO, HI-HPO, NI-HG, F-HG, and S-HG enzyme families may have evolutionary relationships to the α/β hydrolases, acid phosphatases, peroxidases, chemotaxis phosphatases, oxidoreductases, and SAM hydroxide adenosyltransferases, respectively. These halogenating enzymes have established sequence homology, structural conservation, and mechanistic features within each family. Understanding the distinct evolutionary history of these halogenating enzymes will provide further insights into the study of their catalytic mechanisms and halogenation specificity.

An experimental evaluation of software redundancy as a strategy for improving reliability

NASA Technical Reports Server (NTRS)

Eckhardt, Dave E., Jr.; Caglayan, Alper K.; Knight, John C.; Lee, Larry D.; Mcallister, David F.; Vouk, Mladen A.; Kelly, John P. J.

1990-01-01

The strategy of using multiple versions of independently developed software as a means to tolerate residual software design faults is suggested by the success of hardware redundancy for tolerating hardware failures. Although, as generally accepted, the independence of hardware failures resulting from physical wearout can lead to substantial increases in reliability for redundant hardware structures, a similar conclusion is not immediate for software. The degree to which design faults are manifested as independent failures determines the effectiveness of redundancy as a method for improving software reliability. Interest in multi-version software centers on whether it provides an adequate measure of increased reliability to warrant its use in critical applications. The effectiveness of multi-version software is studied by comparing estimates of the failure probabilities of these systems with the failure probabilities of single versions. The estimates are obtained under a model of dependent failures and compared with estimates obtained when failures are assumed to be independent. The experimental results are based on twenty versions of an aerospace application developed and certified by sixty programmers from four universities. Descriptions of the application, development and certification processes, and operational evaluation are given together with an analysis of the twenty versions.

Target Site Recognition by a Diversity-Generating Retroelement

PubMed Central

Guo, Huatao; Tse, Longping V.; Nieh, Angela W.; Czornyj, Elizabeth; Williams, Steven; Oukil, Sabrina; Liu, Vincent B.; Miller, Jeff F.

2011-01-01

Diversity-generating retroelements (DGRs) are in vivo sequence diversification machines that are widely distributed in bacterial, phage, and plasmid genomes. They function to introduce vast amounts of targeted diversity into protein-encoding DNA sequences via mutagenic homing. Adenine residues are converted to random nucleotides in a retrotransposition process from a donor template repeat (TR) to a recipient variable repeat (VR). Using the Bordetella bacteriophage BPP-1 element as a prototype, we have characterized requirements for DGR target site function. Although sequences upstream of VR are dispensable, a 24 bp sequence immediately downstream of VR, which contains short inverted repeats, is required for efficient retrohoming. The inverted repeats form a hairpin or cruciform structure and mutational analysis demonstrated that, while the structure of the stem is important, its sequence can vary. In contrast, the loop has a sequence-dependent function. Structure-specific nuclease digestion confirmed the existence of a DNA hairpin/cruciform, and marker coconversion assays demonstrated that it influences the efficiency, but not the site of cDNA integration. Comparisons with other phage DGRs suggested that similar structures are a conserved feature of target sequences. Using a kanamycin resistance determinant as a reporter, we found that transplantation of the IMH and hairpin/cruciform-forming region was sufficient to target the DGR diversification machinery to a heterologous gene. In addition to furthering our understanding of DGR retrohoming, our results suggest that DGRs may provide unique tools for directed protein evolution via in vivo DNA diversification. PMID:22194701

3D printed, bio-inspired prototypes and analytical models for structured suture interfaces with geometrically-tuned deformation and failure behavior

NASA Astrophysics Data System (ADS)

Lin, Erica; Li, Yaning; Ortiz, Christine; Boyce, Mary C.

2014-12-01

Geometrically structured interfaces in nature possess enhanced, and often surprising, mechanical properties, and provide inspiration for materials design. This paper investigates the mechanics of deformation and failure mechanisms of suture interface designs through analytical models and experiments on 3D printed polymer physical prototypes. Suture waveforms with generalized trapezoidal geometries (trapezoidal, rectangular, anti-trapezoidal, and triangular) are studied and characterized by several important geometric parameters: the presence or absence of a bonded tip region, the tip angle, and the geometry. It is shown that a wide range (in some cases as great as an order of magnitude) in stiffness, strength, and toughness is achievable dependent on tip bonding, tip angle, and geometry. Suture interfaces with a bonded tip region exhibit a higher initial stiffness due to the greater load bearing by the skeletal teeth, a double peak in the stress-strain curve corresponding to the failure of the bonded tip and the failure of the slanted interface region or tooth, respectively, and an additional failure and toughening mechanism due to the failure of the bonded tip. Anti-trapezoidal geometries promote the greatest amplification of properties for suture interfaces with a bonded tip due the large tip interface area. The tip angle and geometry govern the stress distributions in the teeth and the ratio of normal to shear stresses in the interfacial layers, which together determine the failure mechanism of the interface and/or the teeth. Rectangular suture interfaces fail by simple shearing of the interfaces. Trapezoidal and triangular suture interfaces fail by a combination of shear and tensile normal stresses in the interface, leading to plastic deformation, cavitation events, and subsequent stretching of interface ligaments with mostly elastic deformation in the teeth. Anti-trapezoidal suture interfaces with small tip angles have high stress concentrations in the teeth and fail catastrophically by tooth failure, whereas larger tip angles exhibit a shear failure of the interfaces. Therefore, larger tip angles and trapezoidal or triangular geometries promote graceful failure, and smaller tip angles and anti-trapezoidal geometries promote more brittle-like failure. This dependence is reminiscent of biological systems, which exhibit a range of failure behaviors with limited materials and varied geometry. Triangular geometries uniquely exhibit uniform stress distributions in its teeth and promote the greatest amplification of mechanical properties. In both the bonded and unbonded cases, the predictions from the presented analytical models and experimental results on 3D printed prototypes show excellent agreement. This validates the analytical models and allows for the models to be used as a tool for the design of new materials and interfaces with tailored mechanical behavior.

Protein structural failure in mid-IR laser ablation of cornea

NASA Astrophysics Data System (ADS)

Hutson, M. Shane; Xiao, Yaowu; Guo, Mingsheng

2006-05-01

Researchers have previously observed that tissue ablation with a free electron laser tuned to wavelengths between 6-7 μm is accompanied by remarkably little collateral damage. Attempts to explain these observations have invoked a wavelength-dependent loss of protein structural integrity; however, the molecular nature of this structural failure has been heretofore ill-defined. In this report, we evaluate several candidates for the relevant transition by analyzing the non-volatile debris ejected during ablation. Porcine corneas were ablated with a free electron laser tuned to either 2.77 or 6.45 μm - wavelengths that are equally well absorbed by hydrated corneas, but that respectively target water or protein as the primary chromophore. The ejected debris was characterized via gel electrophoresis, as well as FTIR, micro-Raman and 13C-NMR spectroscopy. We find that high-fluence (240 J/cm2) ablation at 6.45 μm, but not at 2.77 μm, leads to protein fragmentation. This fragmentation is accompanied by the accumulation of nitrile and alkyne species. Although these initial experiments did not detect significant protein unfolding, the loss of collagen triple-helix structure was evident using UV and vibrational circular dichroism. The candidate transition most consistent with all these observations is scission of the collagen protein backbone at N-alkylamide bonds. Identifying this transition is a key step towards understanding the observed wavelength-dependence of collateral damage.

Structural changes induced by binding of the high-mobility group I protein to a mouse satellite DNA sequence.

PubMed Central

Slama-Schwok, A; Zakrzewska, K; Léger, G; Leroux, Y; Takahashi, M; Käs, E; Debey, P

2000-01-01

Using spectroscopic methods, we have studied the structural changes induced in both protein and DNA upon binding of the High-Mobility Group I (HMG-I) protein to a 21-bp sequence derived from mouse satellite DNA. We show that these structural changes depend on the stoichiometry of the protein/DNA complexes formed, as determined by Job plots derived from experiments using pyrene-labeled duplexes. Circular dichroism and melting temperature experiments extended in the far ultraviolet range show that while native HMG-I is mainly random coiled in solution, it adopts a beta-turn conformation upon forming a 1:1 complex in which the protein first binds to one of two dA.dT stretches present in the duplex. HMG-I structure in the 1:1 complex is dependent on the sequence of its DNA target. A 3:1 HMG-I/DNA complex can also form and is characterized by a small increase in the DNA natural bend and/or compaction coupled to a change in the protein conformation, as determined from fluorescence resonance energy transfer (FRET) experiments. In addition, a peptide corresponding to an extended DNA-binding domain of HMG-I induces an ordered condensation of DNA duplexes. Based on the constraints derived from pyrene excimer measurements, we present a model of these nucleated structures. Our results illustrate an extreme case of protein structure induced by DNA conformation that may bear on the evolutionary conservation of the DNA-binding motifs of HMG-I. We discuss the functional relevance of the structural flexibility of HMG-I associated with the nature of its DNA targets and the implications of the binding stoichiometry for several aspects of chromatin structure and gene regulation. PMID:10777751

Sequence and structural characterization of Trx-Grx type of monothiol glutaredoxins from Ashbya gossypii.

PubMed

Yadav, Saurabh; Kumari, Pragati; Kushwaha, Hemant Ritturaj

2013-01-01

Glutaredoxins are enzymatic antioxidants which are small, ubiquitous, glutathione dependent and essentially classified under thioredoxin-fold superfamily. Glutaredoxins are classified into two types: dithiol and monothiol. Monothiol glutaredoxins which carry the signature "CGFS" as a redox active motif is known for its role in oxidative stress, inside the cell. In the present analysis, the 138 amino acid long monothiol glutaredoxin, AgGRX1 from Ashbya gossypii was identified and has been used for the analysis. The multiple sequence alignment of the AgGRX1 protein sequence revealed the characteristic motif of typical monothiol glutaredoxin as observed in various other organisms. The proposed structure of the AgGRX1 protein was used to analyze signature folds related to the thioredoxin superfamily. Further, the study highlighted the structural features pertaining to the complex mechanism of glutathione docking and interacting residues.

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.

The dependence of the tunneling characteristic on the electronic energy bands and the carrier’s states of Graphene superlattice

NASA Astrophysics Data System (ADS)

Yang, C. H.; Shen, G. Z.; Ao, Z. M.; Xu, Y. W.

2016-09-01

Using the transfer matrix method, the carrier tunneling properties in graphene superlattice generated by the Thue-Morse sequence and Kolakoski sequence are investigated. The positions and strength of the transmission can be modulated by the barrier structures, the incident energy and angle, the height and width of the potential. These carriers tunneling characteristic can be understood from the energy band structures in the corresponding superlattice systems and the carrier’s states in well/barriers. The transmission peaks above the critical incident angle rely on the carrier’s resonance in the well regions. The structural diversity can modulate the electronic and transport properties, thus expanding its applications.

Spatio-Temporal Structure, Path Characteristics, and Perceptual Grouping in Immediate Serial Spatial Recall

PubMed Central

De Lillo, Carlo; Kirby, Melissa; Poole, Daniel

2016-01-01

Immediate serial spatial recall measures the ability to retain sequences of locations in short-term memory and is considered the spatial equivalent of digit span. It is tested by requiring participants to reproduce sequences of movements performed by an experimenter or displayed on a monitor. Different organizational factors dramatically affect serial spatial recall but they are often confounded or underspecified. Untangling them is crucial for the characterization of working-memory models and for establishing the contribution of structure and memory capacity to spatial span. We report five experiments assessing the relative role and independence of factors that have been reported in the literature. Experiment 1 disentangled the effects of spatial clustering and path-length by manipulating the distance of items displayed on a touchscreen monitor. Long-path sequences segregated by spatial clusters were compared with short-path sequences not segregated by clusters. Recall was more accurate for sequences segregated by clusters independently from path-length. Experiment 2 featured conditions where temporal pauses were introduced between or within cluster boundaries during the presentation of sequences with the same paths. Thus, the temporal structure of the sequences was either consistent or inconsistent with a hierarchical representation based on segmentation by spatial clusters but the effect of structure could not be confounded with effects of path-characteristics. Pauses at cluster boundaries yielded more accurate recall, as predicted by a hierarchical model. In Experiment 3, the systematic manipulation of sequence structure, path-length, and presence of path-crossings of sequences showed that structure explained most of the variance, followed by the presence/absence of path-crossings, and path-length. Experiments 4 and 5 replicated the results of the previous experiments in immersive virtual reality navigation tasks where the viewpoint of the observer changed dynamically during encoding and recall. This suggested that the effects of structure in spatial span are not dependent on perceptual grouping processes induced by the aerial view of the stimulus array typically afforded by spatial recall tasks. These results demonstrate the independence of coding strategies based on structure from effects of path characteristics and perceptual grouping in immediate serial spatial recall. PMID:27891101

Structural polymorphism of a cytosine-rich DNA sequence forming i-motif structure: Exploring pH based biosensors.

PubMed

Ahmed, Saami; Kaushik, Mahima; Chaudhary, Swati; Kukreti, Shrikant

2018-05-01

Sequence recognition and conformational polymorphism enable DNA to emerge out as a substantial tool in fabricating the devices within nano-dimensions. These DNA associated nano devices work on the principle of conformational switches, which can be facilitated by many factors like sequence of DNA/RNA strand, change in pH or temperature, enzyme or ligand interactions etc. Thus, controlling these DNA conformational changes to acquire the desired function is significant for evolving DNA hybridization biosensor, used in genetic screening and molecular diagnosis. For exploring this conformational switching ability of cytosine-rich DNA oligonucleotides as a function of pH for their potential usage as biosensors, this study has been designed. A C-rich stretch of DNA sequence (5'-TCCCCCAATTAATTCCCCCA-3'; SG20c) has been investigated using UV-Thermal denaturation, poly-acrylamide gel electrophoresis and CD spectroscopy. The SG20c sequence is shown to adopt various topologies of i-motif structure at low pH. This pH dependent transition of SG20c from unstructured single strand to unimolecular and bimolecular i-motif structures can further be exploited for its utilization as switching on/off pH-based biosensors. Copyright © 2018. Published by Elsevier B.V.

Sites of instability in the human TCF3 (E2A) gene adopt G-quadruplex DNA structures in vitro

PubMed Central

Williams, Jonathan D.; Fleetwood, Sara; Berroyer, Alexandra; Kim, Nayun; Larson, Erik D.

2015-01-01

The formation of highly stable four-stranded DNA, called G-quadruplex (G4), promotes site-specific genome instability. G4 DNA structures fold from repetitive guanine sequences, and increasing experimental evidence connects G4 sequence motifs with specific gene rearrangements. The human transcription factor 3 (TCF3) gene (also termed E2A) is subject to genetic instability associated with severe disease, most notably a common translocation event t(1;19) associated with acute lymphoblastic leukemia. The sites of instability in TCF3 are not randomly distributed, but focused to certain sequences. We asked if G4 DNA formation could explain why TCF3 is prone to recombination and mutagenesis. Here we demonstrate that sequences surrounding the major t(1;19) break site and a region associated with copy number variations both contain G4 sequence motifs. The motifs identified readily adopt G4 DNA structures that are stable enough to interfere with DNA synthesis in physiological salt conditions in vitro. When introduced into the yeast genome, TCF3 G4 motifs promoted gross chromosomal rearrangements in a transcription-dependent manner. Our results provide a molecular rationale for the site-specific instability of human TCF3, suggesting that G4 DNA structures contribute to oncogenic DNA breaks and recombination. PMID:26029241

Stress-Constrained Structural Topology Optimization with Design-Dependent Loads

NASA Astrophysics Data System (ADS)

Lee, Edmund

Topology optimization is commonly used to distribute a given amount of material to obtain the stiffest structure, with predefined fixed loads. The present work investigates the result of applying stress constraints to topology optimization, for problems with design-depending loading, such as self-weight and pressure. In order to apply pressure loading, a material boundary identification scheme is proposed, iteratively connecting points of equal density. In previous research, design-dependent loading problems have been limited to compliance minimization. The present study employs a more practical approach by minimizing mass subject to failure constraints, and uses a stress relaxation technique to avoid stress constraint singularities. The results show that these design dependent loading problems may converge to a local minimum when stress constraints are enforced. Comparisons between compliance minimization solutions and stress-constrained solutions are also given. The resulting topologies of these two solutions are usually vastly different, demonstrating the need for stress-constrained topology optimization.

Progressive Failure Analysis Methodology for Laminated Composite Structures

NASA Technical Reports Server (NTRS)

Sleight, David W.

1999-01-01

A progressive failure analysis method has been developed for predicting the failure of laminated composite structures under geometrically nonlinear deformations. The progressive failure analysis uses C(exp 1) shell elements based on classical lamination theory to calculate the in-plane stresses. Several failure criteria, including the maximum strain criterion, Hashin's criterion, and Christensen's criterion, are used to predict the failure mechanisms and several options are available to degrade the material properties after failures. The progressive failure analysis method is implemented in the COMET finite element analysis code and can predict the damage and response of laminated composite structures from initial loading to final failure. The different failure criteria and material degradation methods are compared and assessed by performing analyses of several laminated composite structures. Results from the progressive failure method indicate good correlation with the existing test data except in structural applications where interlaminar stresses are important which may cause failure mechanisms such as debonding or delaminations.

Investigating lithium-ion battery materials during overcharge-induced thermal runaway: an operando and multi-scale X-ray CT study.

PubMed

Finegan, Donal P; Scheel, Mario; Robinson, James B; Tjaden, Bernhard; Di Michiel, Marco; Hinds, Gareth; Brett, Dan J L; Shearing, Paul R

2016-11-16

Catastrophic failure of lithium-ion batteries occurs across multiple length scales and over very short time periods. A combination of high-speed operando tomography, thermal imaging and electrochemical measurements is used to probe the degradation mechanisms leading up to overcharge-induced thermal runaway of a LiCoO 2 pouch cell, through its interrelated dynamic structural, thermal and electrical responses. Failure mechanisms across multiple length scales are explored using a post-mortem multi-scale tomography approach, revealing significant morphological and phase changes in the LiCoO 2 electrode microstructure and location dependent degradation. This combined operando and multi-scale X-ray computed tomography (CT) technique is demonstrated as a comprehensive approach to understanding battery degradation and failure.

Mapping RNA Structure In Vitro with SHAPE Chemistry and Next-Generation Sequencing (SHAPE-Seq).

PubMed

Watters, Kyle E; Lucks, Julius B

2016-01-01

Mapping RNA structure with selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemistry has proven to be a versatile method for characterizing RNA structure in a variety of contexts. SHAPE reagents covalently modify RNAs in a structure-dependent manner to create adducts at the 2'-OH group of the ribose backbone at nucleotides that are structurally flexible. The positions of these adducts are detected using reverse transcriptase (RT) primer extension, which stops one nucleotide before the modification, to create a pool of cDNAs whose lengths reflect the location of SHAPE modification. Quantification of the cDNA pools is used to estimate the "reactivity" of each nucleotide in an RNA molecule to the SHAPE reagent. High reactivities indicate nucleotides that are structurally flexible, while low reactivities indicate nucleotides that are inflexible. These SHAPE reactivities can then be used to infer RNA structures by restraining RNA structure prediction algorithms. Here, we provide a state-of-the-art protocol describing how to perform in vitro RNA structure probing with SHAPE chemistry using next-generation sequencing to quantify cDNA pools and estimate reactivities (SHAPE-Seq). The use of next-generation sequencing allows for higher throughput, more consistent data analysis, and multiplexing capabilities. The technique described herein, SHAPE-Seq v2.0, uses a universal reverse transcription priming site that is ligated to the RNA after SHAPE modification. The introduced priming site allows for the structural analysis of an RNA independent of its sequence.

Relative stability of major types of beta-turns as a function of amino acid composition: a study based on Ab initio energetic and natural abundance data.

PubMed

Perczel, András; Jákli, Imre; McAllister, Michael A; Csizmadia, Imre G

2003-06-06

Folding properties of small globular proteins are determined by their amino acid sequence (primary structure). This holds both for local (secondary structure) and for global conformational features of linear polypeptides and proteins composed from natural amino acid derivatives. It thus provides the rational basis of structure prediction algorithms. The shortest secondary structure element, the beta-turn, most typically adopts either a type I or a type II form, depending on the amino acid composition. Herein we investigate the sequence-dependent folding stability of both major types of beta-turns using simple dipeptide models (-Xxx-Yyy-). Gas-phase ab initio properties of 16 carefully selected and suitably protected dipeptide models (for example Val-Ser, Ala-Gly, Ser-Ser) were studied. For each backbone fold most probable side-chain conformers were considered. Fully optimized 321G RHF molecular structures were employed in medium level [B3LYP/6-311++G(d,p)//RHF/3-21G] energy calculations to estimate relative populations of the different backbone conformers. Our results show that the preference for beta-turn forms as calculated by quantum mechanics and observed in Xray determined proteins correlates significantly.

The effects of stacking sequence and thermal cycling on the flexural properties of laminate composites of aluminium-epoxy/basalt-glass fibres

NASA Astrophysics Data System (ADS)

Abdollahi Azghan, Mehdi; Eslami-Farsani, Reza

2018-02-01

The current study aimed at investigating the effects of different stacking sequences and thermal cycling on the flexural properties of fibre metal laminates (FMLs). FMLs were composed of two aluminium alloy 2024-T3 sheets and epoxy polymer-matrix composites that have four layers of basalt and/or glass fibres with five different stacking sequences. For FML samples the thermal cycle time was about 6 min for temperature cycles from 25 °C to 115 °C. Flexural properties of samples evaluated after 55 thermal cycles and compared to non-exposed samples. Surface modification of aluminium performed by electrochemical treatment (anodizing) method and aluminium surfaces have been examined by scanning electron microscopy (SEM). Also, the flexural failure mechanisms investigated by the optical microscope study of fractured surfaces. SEM images indicated that the porosity of the aluminium surface increased after anodizing process. The findings of the present study showed that flexural modulus were maximum for basalt fibres based FML, minimum for glass fibres based FML while basalt/glass fibres based FML lies between them. Due to change in the failure mechanism of basalt/glass fibres based FMLs that have glass fibres at outer layer of the polymer composite, the flexural strength of this FML is lower than glass and basalt fibres based FML. After thermal cycling, due to the good thermal properties of basalt fibres, flexural properties of basalt fibres based FML structures decreased less than other composites.

The primary structure of fatty-acid-binding protein from nurse shark liver. Structural and evolutionary relationship to the mammalian fatty-acid-binding protein family.

PubMed

Medzihradszky, K F; Gibson, B W; Kaur, S; Yu, Z H; Medzihradszky, D; Burlingame, A L; Bass, N M

1992-02-01

The primary structure of a fatty-acid-binding protein (FABP) isolated from the liver of the nurse shark (Ginglymostoma cirratum) was determined by high-performance tandem mass spectrometry (employing multichannel array detection) and Edman degradation. Shark liver FABP consists of 132 amino acids with an acetylated N-terminal valine. The chemical molecular mass of the intact protein determined by electrospray ionization mass spectrometry (Mr = 15124 +/- 2.5) was in good agreement with that calculated from the amino acid sequence (Mr = 15121.3). The amino acid sequence of shark liver FABP displays significantly greater similarity to the FABP expressed in mammalian heart, peripheral nerve myelin and adipose tissue (61-53% sequence similarity) than to the FABP expressed in mammalian liver (22% similarity). Phylogenetic trees derived from the comparison of the shark liver FABP amino acid sequence with the members of the mammalian fatty-acid/retinoid-binding protein gene family indicate the initial divergence of an ancestral gene into two major subfamilies: one comprising the genes for mammalian liver FABP and gastrotropin, the other comprising the genes for mammalian cellular retinol-binding proteins I and II, cellular retinoic-acid-binding protein myelin P2 protein, adipocyte FABP, heart FABP and shark liver FABP, the latter having diverged from the ancestral gene that ultimately gave rise to the present day mammalian heart-FABP, adipocyte FABP and myelin P2 protein sequences. The sequence for intestinal FABP from the rat could be assigned to either subfamily, depending on the approach used for phylogenetic tree construction, but clearly diverged at a relatively early evolutionary time point. Indeed, sequences proximately ancestral or closely related to mammalian intestinal FABP, liver FABP, gastrotropin and the retinoid-binding group of proteins appear to have arisen prior to the divergence of shark liver FABP and should therefore also be present in elasmobranchs. The presence in shark liver of an FABP which differs substantially in primary structure from mammalian liver FABP, while being closely related to the FABP expressed in mammalian heart muscle, peripheral nerve myelin and adipocytes, opens a further dimension regarding the question of the existence of structure-dependent and tissue-specific specialization of FABP function in lipid metabolism.

Failure modes and conditions of a cohesive, spherical body due to YORP spin-up

NASA Astrophysics Data System (ADS)

Hirabayashi, Masatoshi

2015-12-01

This paper presents transition of the failure mode of a cohesive, spherical body due to The Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) spin-up. On the assumption that the distribution of materials in the body is homogeneous, failed regions first appearing in the body at different spin rates are predicted by comparing the yield condition of an elastic stress in the body. It is found that as the spin rate increases, the locations of the failed regions move from the equatorial surface to the central region. To avoid such failure modes, the body should have higher cohesive strength. The results by this model are consistent with those by a plastic finite element model. Then, this model and a two-layered-cohesive model first proposed by Hirabayashi et al. are used to classify possible evolution and disruption of a spherical body. There are three possible pathways to disruption. First, because of a strong structure, failure of the central region is dominant and eventually leads to a breakup into multiple components. Secondly, a weak surface and a weak interior make the body oblate. Thirdly, a strong internal core prevents the body from failing and only allows surface shedding. This implies that observed failure modes may highly depend on the internal structure of an asteroid, which could provide crucial information for giving constraints on the physical properties.

Geno2pheno[HCV] – A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents

PubMed Central

Kalaghatgi, Prabhav; Sikorski, Anna Maria; Knops, Elena; Rupp, Daniel; Sierra, Saleta; Heger, Eva; Neumann-Fraune, Maria; Beggel, Bastian; Walker, Andreas; Timm, Jörg; Walter, Hauke; Obermeier, Martin; Kaiser, Rolf; Bartenschlager, Ralf; Lengauer, Thomas

2016-01-01

The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno[HCV] (g2p[HCV]) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p[HCV] aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p[HCV] offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients’ virus variants. PMID:27196673

A 3D sequence-independent representation of the protein data bank.

PubMed

Fischer, D; Tsai, C J; Nussinov, R; Wolfson, H

1995-10-01

Here we address the following questions. How many structurally different entries are there in the Protein Data Bank (PDB)? How do the proteins populate the structural universe? To investigate these questions a structurally non-redundant set of representative entries was selected from the PDB. Construction of such a dataset is not trivial: (i) the considerable size of the PDB requires a large number of comparisons (there were more than 3250 structures of protein chains available in May 1994); (ii) the PDB is highly redundant, containing many structurally similar entries, not necessarily with significant sequence homology, and (iii) there is no clear-cut definition of structural similarity. The latter depend on the criteria and methods used. Here, we analyze structural similarity ignoring protein topology. To date, representative sets have been selected either by hand, by sequence comparison techniques which ignore the three-dimensional (3D) structures of the proteins or by using sequence comparisons followed by linear structural comparison (i.e. the topology, or the sequential order of the chains, is enforced in the structural comparison). Here we describe a 3D sequence-independent automated and efficient method to obtain a representative set of protein molecules from the PDB which contains all unique structures and which is structurally non-redundant. The method has two novel features. The first is the use of strictly structural criteria in the selection process without taking into account the sequence information. To this end we employ a fast structural comparison algorithm which requires on average approximately 2 s per pairwise comparison on a workstation. The second novel feature is the iterative application of a heuristic clustering algorithm that greatly reduces the number of comparisons required. We obtain a representative set of 220 chains with resolution better than 3.0 A, or 268 chains including lower resolution entries, NMR entries and models. The resulting set can serve as a basis for extensive structural classification and studies of 3D recurring motifs and of sequence-structure relationships. The clustering algorithm succeeds in classifying into the same structural family chains with no significant sequence homology, e.g. all the globins in one single group, all the trypsin-like serine proteases in another or all the immunoglobulin-like folds into a third. In addition, unexpected structural similarities of interest have been automatically detected between pairs of chains. A cluster analysis of the representative structures demonstrates the way the "structural universe' is populated.

Evolution of sparsity and modularity in a model of protein allostery

NASA Astrophysics Data System (ADS)

Hemery, Mathieu; Rivoire, Olivier

2015-04-01

The sequence of a protein is not only constrained by its physical and biochemical properties under current selection, but also by features of its past evolutionary history. Understanding the extent and the form that these evolutionary constraints may take is important to interpret the information in protein sequences. To study this problem, we introduce a simple but physical model of protein evolution where selection targets allostery, the functional coupling of distal sites on protein surfaces. This model shows how the geometrical organization of couplings between amino acids within a protein structure can depend crucially on its evolutionary history. In particular, two scenarios are found to generate a spatial concentration of functional constraints: high mutation rates and fluctuating selective pressures. This second scenario offers a plausible explanation for the high tolerance of natural proteins to mutations and for the spatial organization of their least tolerant amino acids, as revealed by sequence analysis and mutagenesis experiments. It also implies a faculty to adapt to new selective pressures that is consistent with observations. The model illustrates how several independent functional modules may emerge within the same protein structure, depending on the nature of past environmental fluctuations. Our model thus relates the evolutionary history of proteins to the geometry of their functional constraints, with implications for decoding and engineering protein sequences.

Topological frustration in βα-repeat proteins: sequence diversity modulates the conserved folding mechanisms of α/β/α sandwich proteins

PubMed Central

Hills, Ronald D.; Kathuria, Sagar V.; Wallace, Louise A.; Day, Iain J.; Brooks, Charles L.; Matthews, C. Robert

2010-01-01

The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of non-local interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation. To explore the relationship of sequence and topology in the folding of βα–repeat proteins, which are dominated by local interactions, a combined experimental and simulation analysis was performed on two members of the flavodoxin-like, α/β/α sandwich fold. Spo0F and the N-terminal receiver domain of NtrC (NT-NtrC) have similar topologies but low sequence identity, enabling a test of the effects of sequence on folding. Experimental results demonstrated that both response-regulator proteins fold via parallel channels through highly structured sub-millisecond intermediates before accessing their cis prolyl peptide bond-containing native conformations. Global analysis of the experimental results preferentially places these intermediates off the productive folding pathway. Sequence-sensitive Gō-model simulations conclude that frustration in the folding in Spo0F, corresponding to the appearance of the off-pathway intermediate, reflects competition for intra-subdomain van der Waals contacts between its N- and C-terminal subdomains. The extent of transient, premature structure appears to correlate with the number of isoleucine, leucine and valine (ILV) side-chains that form a large sequence-local cluster involving the central β-sheet and helices α2, α3 and α4. The failure to detect the off-pathway species in the simulations of NT-NtrC may reflect the reduced number of ILV side-chains in its corresponding hydrophobic cluster. The location of the hydrophobic clusters in the structure may also be related to the differing functional properties of these response regulators. Comparison with the results of previous experimental and simulation analyses on the homologous CheY argues that prematurely-folded unproductive intermediates are a common property of the βα-repeat motif. PMID:20226790

Functional Evolution of PLP-dependent Enzymes based on Active-Site Structural Similarities

PubMed Central

Catazaro, Jonathan; Caprez, Adam; Guru, Ashu; Swanson, David; Powers, Robert

2014-01-01

Families of distantly related proteins typically have very low sequence identity, which hinders evolutionary analysis and functional annotation. Slowly evolving features of proteins, such as an active site, are therefore valuable for annotating putative and distantly related proteins. To date, a complete evolutionary analysis of the functional relationship of an entire enzyme family based on active-site structural similarities has not yet been undertaken. Pyridoxal-5’-phosphate (PLP) dependent enzymes are primordial enzymes that diversified in the last universal ancestor. Using the Comparison of Protein Active Site Structures (CPASS) software and database, we show that the active site structures of PLP-dependent enzymes can be used to infer evolutionary relationships based on functional similarity. The enzymes successfully clustered together based on substrate specificity, function, and three-dimensional fold. This study demonstrates the value of using active site structures for functional evolutionary analysis and the effectiveness of CPASS. PMID:24920327

Functional evolution of PLP-dependent enzymes based on active-site structural similarities.

PubMed

Catazaro, Jonathan; Caprez, Adam; Guru, Ashu; Swanson, David; Powers, Robert

2014-10-01

Families of distantly related proteins typically have very low sequence identity, which hinders evolutionary analysis and functional annotation. Slowly evolving features of proteins, such as an active site, are therefore valuable for annotating putative and distantly related proteins. To date, a complete evolutionary analysis of the functional relationship of an entire enzyme family based on active-site structural similarities has not yet been undertaken. Pyridoxal-5'-phosphate (PLP) dependent enzymes are primordial enzymes that diversified in the last universal ancestor. Using the comparison of protein active site structures (CPASS) software and database, we show that the active site structures of PLP-dependent enzymes can be used to infer evolutionary relationships based on functional similarity. The enzymes successfully clustered together based on substrate specificity, function, and three-dimensional-fold. This study demonstrates the value of using active site structures for functional evolutionary analysis and the effectiveness of CPASS. © 2014 Wiley Periodicals, Inc.

Technical Failure of MR Elastography Examinations of the Liver: Experience from a Large Single-Center Study.

PubMed

Wagner, Mathilde; Corcuera-Solano, Idoia; Lo, Grace; Esses, Steven; Liao, Joseph; Besa, Cecilia; Chen, Nelson; Abraham, Ginu; Fung, Maggie; Babb, James S; Ehman, Richard L; Taouli, Bachir

2017-08-01

Purpose To assess the determinants of technical failure of magnetic resonance (MR) elastography of the liver in a large single-center study. Materials and Methods This retrospective study was approved by the institutional review board. Seven hundred eighty-one MR elastography examinations performed in 691 consecutive patients (mean age, 58 years; male patients, 434 [62.8%]) in a single center between June 2013 and August 2014 were retrospectively evaluated. MR elastography was performed at 3.0 T (n = 443) or 1.5 T (n = 338) by using a gradient-recalled-echo pulse sequence. MR elastography and anatomic image analysis were performed by two observers. Additional observers measured liver T2* and fat fraction. Technical failure was defined as no pixel value with a confidence index higher than 95% and/or no apparent shear waves imaged. Logistic regression analysis was performed to assess potential predictive factors of technical failure of MR elastography. Results The technical failure rate of MR elastography at 1.5 T was 3.5% (12 of 338), while it was higher, 15.3% (68 of 443), at 3.0 T. On the basis of univariate analysis, body mass index, liver iron deposition, massive ascites, use of 3.0 T, presence of cirrhosis, and alcoholic liver disease were all significantly associated with failure of MR elastography (P < .004); but on the basis of multivariable analysis, only body mass index, liver iron deposition, massive ascites, and use of 3.0 T were significantly associated with failure of MR elastography (P < .004). Conclusion The technical failure rate of MR elastography with a gradient-recalled-echo pulse sequence was low at 1.5 T but substantially higher at 3.0 T. Massive ascites, iron deposition, and high body mass index were additional independent factors associated with failure of MR elastography of the liver with a two-dimensional gradient-recalled-echo pulse sequence. © RSNA, 2017.

Failure rate of single-unit restorations on posterior vital teeth: A systematic review.

PubMed

Afrashtehfar, Kelvin I; Emami, Elham; Ahmadi, Motahareh; Eilayyan, Owis; Abi-Nader, Samer; Tamimi, Faleh

2017-03-01

No knowledge synthesis exists concerning when to use a direct restoration versus a complete-coverage indirect restoration in posterior vital teeth. The purpose of this systematic review was to identify the failure rate of conventional single-unit tooth-supported restorations in posterior permanent vital teeth as a function of remaining tooth structure. Four databases were searched electronically, and 8 selected journals were searched manually up to February 2015. Clinical studies of tooth-supported single-unit restorative treatments with a mean follow-up period of at least 3 years were selected. The outcome measured was the restorations' clinical or radiological failure. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, the Cochrane Collaboration procedures for randomized control trials, the Strengthening the Reporting of Observational Studies in Epidemiology criteria for observational studies, 2 reviewers independently applied eligibility criteria, extracted data, and assessed the quality of the evidence of the included studies using the American Association of Critical Care Nurses' system. The weighted-mean group 5-year failure rates of the restorations were reported according to the type of treatment and remaining tooth structure. A metaregression model was used to assess the correlation between the number of remaining tooth walls and the weighted-mean 5-year failure rates. Five randomized controlled trials and 9 observational studies were included and their quality ranged from low to moderate. These studies included a total of 358 crowns, 4804 composite resins, and 303582 amalgams. Data obtained from the randomized controlled trials showed that, regardless of the amount of remaining tooth structure, amalgams presented better outcomes than composite resins. Furthermore, in teeth with fewer than 2 remaining walls, high-quality observational studies demonstrated that crowns were better than amalgams. A clear inverse correlation was found between the amount of remaining tooth structure and restoration failure. Insufficient high-quality data are available to support one restorative treatment or material over another for the restoration of vital posterior teeth. However, the current evidence suggests that the failure rates of treatments may depend on the amount of remaining tooth structure and types of treatment. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

There is Diversity in Disorder-"In all Chaos there is a Cosmos, in all Disorder a Secret Order".

PubMed

Nielsen, Jakob T; Mulder, Frans A A

2016-01-01

The protein universe consists of a continuum of structures ranging from full order to complete disorder. As the structured part of the proteome has been intensively studied, stably folded proteins are increasingly well documented and understood. However, proteins that are fully, or in large part, disordered are much less well characterized. Here we collected NMR chemical shifts in a small database for 117 protein sequences that are known to contain disorder. We demonstrate that NMR chemical shift data can be brought to bear as an exquisite judge of protein disorder at the residue level, and help in validation. With the help of secondary chemical shift analysis we demonstrate that the proteins in the database span the full spectrum of disorder, but still, largely segregate into two classes; disordered with small segments of order scattered along the sequence, and structured with small segments of disorder inserted between the different structured regions. A detailed analysis reveals that the distribution of order/disorder along the sequence shows a complex and asymmetric distribution, that is highly protein-dependent. Access to ratified training data further suggests an avenue to improving prediction of disorder from sequence.

Probing the Structures of Viral RNA Regulatory Elements with SHAPE and Related Methodologies

PubMed Central

Rausch, Jason W.; Sztuba-Solinska, Joanna; Le Grice, Stuart F. J.

2018-01-01

Viral RNAs were selected by evolution to possess maximum functionality in a minimal sequence. Depending on the classification of the virus and the type of RNA in question, viral RNAs must alternately be replicated, spliced, transcribed, transported from the nucleus into the cytoplasm, translated and/or packaged into nascent virions, and in most cases, provide the sequence and structural determinants to facilitate these processes. One consequence of this compact multifunctionality is that viral RNA structures can be exquisitely complex, often involving intermolecular interactions with RNA or protein, intramolecular interactions between sequence segments separated by several thousands of nucleotides, or specialized motifs such as pseudoknots or kissing loops. The fluidity of viral RNA structure can also present a challenge when attempting to characterize it, as genomic RNAs especially are likely to sample numerous conformations at various stages of the virus life cycle. Here we review advances in chemoenzymatic structure probing that have made it possible to address such challenges with respect to cis-acting elements, full-length viral genomes and long non-coding RNAs that play a major role in regulating viral gene expression. PMID:29375504

Sequence-dependent DNA flexibility mediates DNase I cleavage.

PubMed

Heddi, Brahim; Abi-Ghanem, Josephine; Lavigne, Marc; Hartmann, Brigitte

2010-01-08

Understanding the preference of nonspecific proteins for certain DNA structural features requires an accurate description of the properties of free DNA, especially regarding their possible predisposition to adopt a conformation that favors the formation of a complex. Exploiting previous exhaustive NMR studies performed on free DNA oligomers, we investigated the molecular basis of DNase I sensitivity under conditions where DNase I binding limits the probability of cleavage. We showed that cleavage intensity was correlated with adjacent 3' phosphate linkage flexibility, monitored by (31)P chemical shifts. Examining NMR-refined DNA structures highlighted that sequence-dependent flexible phosphates were associated with large minor groove variations that may promote the affinity of DNase I, according to relevant DNA-protein complexes. In sum, this work demonstrates that specificity in DNA-DNase I interaction is mediated by DNA flexibility, which influences the induced-fit transitions required to form productive complexes.

The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison of glaucoma outcomes in black and white patients within treatment groups.

PubMed

2001-09-01

To compare in eyes of black and white patients the progression of glaucoma after failure of medical therapy and upon start of surgical intervention. Cohort study analysis of data from a randomized clinical trial. This multicenter study included open-angle glaucoma patients who had failed medical therapy: 451 eyes of 332 black patients, 325 eyes of 249 white patients. Eyes were randomly assigned to an argon laser trabeculoplasty (ALT)-trabeculectomy-trabeculectomy (ATT) sequence or a trabeculectomy-ALT-trabeculectomy (TAT) sequence; they had been followed for 7 to 11 years at database closure. Main outcome measures were decrease of visual field (DVF), sustained decrease of visual field (SDVF), decrease of visual acuity (DVA), sustained decrease of visual acuity (SDVA), and failure of first surgical glaucoma intervention. Statistical methods included logistic regression to obtain average adjusted black-white odds ratios for binary outcomes, and Cox regression to estimate adjusted black-white risk ratios for time-to-event outcomes. In the ATT sequence blacks were at lower risk than whites of failure of first intervention (ALT, RR = 0.68, P = 0.040). In the TAT sequence blacks were at higher risk than whites of failure of the first intervention (trabeculectomy, RR = 1.79, P = 0.033), of intraocular pressure > or =18 mm Hg (average OR = 1.41, P = 0.026), and of DVF (average OR = 1.78, P = 0.007). In both treatment sequences, the average number of prescribed medications was greater for blacks than whites (P < or = 0.002). The results support the hypothesis that after failure of medical therapy and upon initiation of surgical intervention, an initial intervention with trabeculectomy retards the progression of glaucoma more effectively in white than in black patients. The data provide a weak suggestion that an initial surgical intervention with ALT retards the progression of glaucoma more effectively in black than in white patients.

Complete convergence of randomly weighted END sequences and its application.

PubMed

Li, Penghua; Li, Xiaoqin; Wu, Kehan

2017-01-01

We investigate the complete convergence of partial sums of randomly weighted extended negatively dependent (END) random variables. Some results of complete moment convergence, complete convergence and the strong law of large numbers for this dependent structure are obtained. As an application, we study the convergence of the state observers of linear-time-invariant systems. Our results extend the corresponding earlier ones.

New constraints on mechanisms of remotely triggered seismicity at Long Valley Caldera

USGS Publications Warehouse

Brodsky, E.E.; Prejean, S.G.

2005-01-01

Regional-scale triggering of local earthquakes in the crust by seismic waves from distant main shocks has now been robustly documented for over a decade. Some of the most thoroughly recorded examples of repeated triggering of a single site from multiple, large earthquakes are measured in geothermal fields of the western United States like Long Valley Caldera. As one of the few natural cases where the causality of an earthquake sequence is apparent, triggering provides fundamental constraints on the failure processes in earthquakes. We show here that the observed triggering by seismic waves is inconsistent with any mechanism that depends on cumulative shaking as measured by integrated energy density. We also present evidence for a frequency-dependent triggering threshold. On the basis of the seismic records of 12 regional and teleseismic events recorded at Long Valley Caldera, long-period waves (>30 s) are more effective at generating local seismicity than short-period waves of comparable amplitude. If the properties of the system are stationary over time, the failure threshold for long-period waves is ~0.05 cm/s vertical shaking. Assuming a phase velocity of 3.5 km/s and an elastic modulus of 3.5 x 1010Pa, the threshold in terms of stress is 5 kPa. The frequency dependence is due in part to the attenuation of the surface waves with depth. Fluid flow through a porous medium can produce the rest of the observed frequency dependence of the threshold. If the threshold is not stationary with time, pore pressures that are >99.5% of lithostatic and vary over time by a factor of 4 could explain the observations with no frequency dependence of the triggering threshold. Copyright 2005 by the American Geophysical Union.

Making the Bend: DNA Tertiary Structure and Protein-DNA Interactions

PubMed Central

Harteis, Sabrina; Schneider, Sabine

2014-01-01

DNA structure functions as an overlapping code to the DNA sequence. Rapid progress in understanding the role of DNA structure in gene regulation, DNA damage recognition and genome stability has been made. The three dimensional structure of both proteins and DNA plays a crucial role for their specific interaction, and proteins can recognise the chemical signature of DNA sequence (“base readout”) as well as the intrinsic DNA structure (“shape recognition”). These recognition mechanisms do not exist in isolation but, depending on the individual interaction partners, are combined to various extents. Driving force for the interaction between protein and DNA remain the unique thermodynamics of each individual DNA-protein pair. In this review we focus on the structures and conformations adopted by DNA, both influenced by and influencing the specific interaction with the corresponding protein binding partner, as well as their underlying thermodynamics. PMID:25026169

Why Is There a Glass Ceiling for Threading Based Protein Structure Prediction Methods?

PubMed

Skolnick, Jeffrey; Zhou, Hongyi

2017-04-20

Despite their different implementations, comparison of the best threading approaches to the prediction of evolutionary distant protein structures reveals that they tend to succeed or fail on the same protein targets. This is true despite the fact that the structural template library has good templates for all cases. Thus, a key question is why are certain protein structures threadable while others are not. Comparison with threading results on a set of artificial sequences selected for stability further argues that the failure of threading is due to the nature of the protein structures themselves. Using a new contact map based alignment algorithm, we demonstrate that certain folds are highly degenerate in that they can have very similar coarse grained fractions of native contacts aligned and yet differ significantly from the native structure. For threadable proteins, this is not the case. Thus, contemporary threading approaches appear to have reached a plateau, and new approaches to structure prediction are required.

A multivariate prediction model for Rho-dependent termination of transcription.

PubMed

Nadiras, Cédric; Eveno, Eric; Schwartz, Annie; Figueroa-Bossi, Nara; Boudvillain, Marc

2018-06-21

Bacterial transcription termination proceeds via two main mechanisms triggered either by simple, well-conserved (intrinsic) nucleic acid motifs or by the motor protein Rho. Although bacterial genomes can harbor hundreds of termination signals of either type, only intrinsic terminators are reliably predicted. Computational tools to detect the more complex and diversiform Rho-dependent terminators are lacking. To tackle this issue, we devised a prediction method based on Orthogonal Projections to Latent Structures Discriminant Analysis [OPLS-DA] of a large set of in vitro termination data. Using previously uncharacterized genomic sequences for biochemical evaluation and OPLS-DA, we identified new Rho-dependent signals and quantitative sequence descriptors with significant predictive value. Most relevant descriptors specify features of transcript C>G skewness, secondary structure, and richness in regularly-spaced 5'CC/UC dinucleotides that are consistent with known principles for Rho-RNA interaction. Descriptors collectively warrant OPLS-DA predictions of Rho-dependent termination with a ∼85% success rate. Scanning of the Escherichia coli genome with the OPLS-DA model identifies significantly more termination-competent regions than anticipated from transcriptomics and predicts that regions intrinsically refractory to Rho are primarily located in open reading frames. Altogether, this work delineates features important for Rho activity and describes the first method able to predict Rho-dependent terminators in bacterial genomes.

Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation

PubMed Central

Carvalho, Alexandra T P; Gouveia, Leonor; Kanna, Charan Raju; Wärmländer, Sebastian K T S; Platts, Jamie A; Kamerlin, Shina Caroline Lynn

2014-01-01

We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding. PMID:25625845

Polymeric peptide pigments with sequence-encoded properties

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

Lampel, Ayala; McPhee, Scott A.; Park, Hang-Ah

Melanins are a family of heterogeneous polymeric pigments that provide ultraviolet (UV) light protection, structural support, coloration, and free radical scavenging. Formed by oxidative oligomerization of catecholic small molecules, the physical properties of melanins are influenced by covalent and noncovalent disorder. We report the use of tyrosine-containing tripeptides as tunable precursors for polymeric pigments. In these structures, phenols are presented in a (supra-)molecular context dictated by the positions of the amino acids in the peptide sequence. Oxidative polymerization can be tuned in a sequence-dependent manner, resulting in peptide sequence–encoded properties such as UV absorbance, morphology, coloration, and electrochemical properties overmore » a considerable range. Short peptides have low barriers to application and can be easily scaled, suggesting near-term applications in cosmetics and biomedicine.« less

Recognition of the DNA sequence by an inorganic crystal surface

PubMed Central

Sampaolese, Beatrice; Bergia, Anna; Scipioni, Anita; Zuccheri, Giampaolo; Savino, Maria; Samorì, Bruno; De Santis, Pasquale

2002-01-01

The sequence-dependent curvature is generally recognized as an important and biologically relevant property of DNA because it is involved in the formation and stability of association complexes with proteins. When a DNA tract, intrinsically curved for the periodical recurrence on the same strand of A-tracts phased with the B-DNA periodicity, is deposited on a flat surface, it exposes to that surface either a T- or an A-rich face. The surface of a freshly cleaved mica crystal recognizes those two faces and preferentially interacts with the former one. Statistical analysis of scanning force microscopy (SFM) images provides evidence of this recognition between an inorganic crystal surface and nanoscale structures of double-stranded DNA. This finding could open the way toward the use of the sequence-dependent adhesion to specific crystal faces for nanotechnological purposes. PMID:12361979

Opposite consequences of two transcription pauses caused by an intrinsic terminator oligo(U): antitermination versus termination by bacteriophage T7 RNA polymerase.

PubMed

Lee, Sooncheol; Kang, Changwon

2011-05-06

The RNA oligo(U) sequence, along with an immediately preceding RNA hairpin structure, is an essential cis-acting element for bacterial class I intrinsic termination. This sequence not only causes a pause in transcription during the beginning of the termination process but also facilitates transcript release at the end of the process. In this study, the oligo(U) sequence of the bacteriophage T7 intrinsic terminator Tφ, rather than the hairpin structure, induced pauses of phage T7 RNA polymerase not only at the termination site, triggering a termination process, but also 3 bp upstream, exerting an antitermination effect. The upstream pause presumably allowed RNA to form a thermodynamically more stable secondary structure rather than a terminator hairpin and to persist because the 5'-half of the terminator hairpin-forming sequence could be sequestered by a farther upstream sequence via sequence-specific hybridization, prohibiting formation of the terminator hairpin and termination. The putative antiterminator RNA structure lacked several base pairs essential for termination when probed using RNases A, T1, and V1. When the antiterminator was destabilized by incorporation of IMP into nascent RNA at G residue positions, antitermination was abolished. Furthermore, antitermination strength increased with more stable antiterminator secondary structures and longer pauses. Thus, the oligo(U)-mediated pause prior to the termination site can exert a cis-acting antitermination activity on intrinsic terminator Tφ, and the termination efficiency depends primarily on the termination-interfering pause that precedes the termination-facilitating pause at the termination site.

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis

PubMed Central

Du, Yushen; Wu, Nicholas C.; Jiang, Lin; Zhang, Tianhao; Gong, Danyang; Shu, Sara; Wu, Ting-Ting

2016-01-01

ABSTRACT Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available. PMID:27803181

Global Failure Modes in Composite Structures

NASA Technical Reports Server (NTRS)

Knauss, W. G.; Gonzalez, Luis

2001-01-01

Composite materials provide well-known advantages for space and aeronautical applications in terms of strength and rigidity to weight ratios and other mechanical properties. As a consequence, their use has experienced a constant increase in the past decades and it is anticipated that this trend will be maintained in the near future. At the same time, being these materials relatively new compared to metals, and having failure characteristics completely different from them, their damage growth and their failure mechanisms are not as well understood in a predictive sense. For example, while in metals fracture produces "clean" cracks with their well defined analytically stress fields at the crack tip, composite fracture is a more complex phenomenon. Instead of a crack, we confront a "damage zone" that may include fiber breakage, fiber microbuckling, fiber pullout, matrix cracking, delamination, debonding or any combination of all these different mechanisms. These phenomena are prevalent in any failure process through an aircraft structure, whether one addresses a global failure such as the ripping of a fuselage or wing section, or whether one is concerned with the failure initiation near a thickness change at stringers or other reinforcement. Thus the topic that has been under consideration has wide application in any real structure and is considered an essential contribution to the predictive failure analysis capability for aircraft containing composite components. The heterogeneity and the anisotropy of composites are not only advantageous but essential characteristics, yet these same features provide complex stress fields, especially in the presence of geometrical discontinuities such as notches, holes or cutouts or structural elements such as stiffeners, stringers, etc. To properly address the interaction between a damage/crack front and a hole with a stringer it is imperative that the stress and deformation fields of the former be (sufficiently well) characterized. The question of "scaling" is an essential concern in any structural materials investigation. For example, experiments in the past have shown that the "strength" of a composite depends on hole size. As a consequence the validity of traditional fracture mechanics concepts applied to composite materials failure must be questioned. The size of the fibers, the dimensions of the laminae, etc. together with the fact that, because of the layered anisotropy, the stress field is no longer two-dimensional, prevent the otherwise obviously confident use of "similarity concepts". Therefore, the question needs to be raised of whether in composites "size matters or not", i.e., whether the results obtained in a laboratory using small coupons are truly representative of the situation involving a full scale component.

Observations of Displacement-driven Maturation along a Subduction-Transform Edge Propagator Fault

NASA Astrophysics Data System (ADS)

Neely, J. S.; Furlong, K. P.

2016-12-01

The Solomon Islands-Vanuatu composite subduction zone represents a tectonically complex region along the Pacific-Australia plate boundary in the southwest Pacific Ocean. Here the Australia plate subducts under the Pacific plate in two parts - the Solomon Trench and the Vanuatu Trench - with the two segments separated by a transform fault produced by a tear in the approaching Australia plate. As a result of the Australia plate tearing, the two subducting sections are offset by the 280 km long San Cristobal Trough (SCT) transform fault, which acts as a Subduction-Transform Edge Propagator (STEP) fault. The formation of this transform fault provides an opportunity to study the evolution of a newly created transform plate boundary. As distance from the tear increases, both the magnitude and frequency of earthquakes along the transform increase reflecting the coalescence of fault segments into a through-going structure. Over the past few decades, there have been several instances of larger magnitude earthquakes migrating westward along the STEP through a rapid succession of events. A recent May 2015 sequence of MW 6.8, MW 6.9, and MW 6.8 earthquakes followed this pattern, with an east to west migration over three days. However, neither this 2015 sequence, nor a previous 1993 progression, ruptured into or nucleated a large earthquake within the region near the tear. SCT sequence termination outside the region of the newly formed fault occurs even though Coulomb Failure Stress analyses reveal that the tear end of the SCT is positively loaded for failure by the earthquake sequence. Changing seismicity patterns along the SCT are also mapped by b-value variations that correspond to the rupture patterns of these propagating sequences. These seismicity pattern changes along the SCT reveal a fault maturation process with strain localization driven by cumulative slip corresponding to approximately 80-100 km of displacement.

The influence of lay-up and thickness on composite impact damage and compression strength

NASA Technical Reports Server (NTRS)

Guynn, E. G.; Obrien, T. K.

1985-01-01

The effects of composite stacking sequence, thickness, and percentage of zero-degree plies on the size, shape, and distribution of delamination through the laminate thickness and on residual compression strength following impact were studied. Graphite/epoxy laminates were impacted with an 0.5 inch diameter aluminum sphere at a specific low or high velocity. Impact damage was measured nondestructively by ultrasonic C-scans and X-radiography and destructively by the deply technique, and compression strength tests were performed. It was found that differences in compression failure strain due to stacking sequence were small, while laminates with very low percentages of zero-degree plies had similar failure loads but higher failure strains than laminates with higher percentages of zero-degree plies. Failure strain did not correlate with planar impact damage area, and delaminations in impact regions were associated with matrix cracking.

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

Modular prediction of protein structural classes from sequences of twilight-zone identity with predicting sequences.

PubMed

Mizianty, Marcin J; Kurgan, Lukasz

2009-12-13

Knowledge of structural class is used by numerous methods for identification of structural/functional characteristics of proteins and could be used for the detection of remote homologues, particularly for chains that share twilight-zone similarity. In contrast to existing sequence-based structural class predictors, which target four major classes and which are designed for high identity sequences, we predict seven classes from sequences that share twilight-zone identity with the training sequences. The proposed MODular Approach to Structural class prediction (MODAS) method is unique as it allows for selection of any subset of the classes. MODAS is also the first to utilize a novel, custom-built feature-based sequence representation that combines evolutionary profiles and predicted secondary structure. The features quantify information relevant to the definition of the classes including conservation of residues and arrangement and number of helix/strand segments. Our comprehensive design considers 8 feature selection methods and 4 classifiers to develop Support Vector Machine-based classifiers that are tailored for each of the seven classes. Tests on 5 twilight-zone and 1 high-similarity benchmark datasets and comparison with over two dozens of modern competing predictors show that MODAS provides the best overall accuracy that ranges between 80% and 96.7% (83.5% for the twilight-zone datasets), depending on the dataset. This translates into 19% and 8% error rate reduction when compared against the best performing competing method on two largest datasets. The proposed predictor provides accurate predictions at 58% accuracy for membrane proteins class, which is not considered by majority of existing methods, in spite that this class accounts for only 2% of the data. Our predictive model is analyzed to demonstrate how and why the input features are associated with the corresponding classes. The improved predictions stem from the novel features that express collocation of the secondary structure segments in the protein sequence and that combine evolutionary and secondary structure information. Our work demonstrates that conservation and arrangement of the secondary structure segments predicted along the protein chain can successfully predict structural classes which are defined based on the spatial arrangement of the secondary structures. A web server is available at http://biomine.ece.ualberta.ca/MODAS/.

Modular prediction of protein structural classes from sequences of twilight-zone identity with predicting sequences

PubMed Central

2009-01-01

Background Knowledge of structural class is used by numerous methods for identification of structural/functional characteristics of proteins and could be used for the detection of remote homologues, particularly for chains that share twilight-zone similarity. In contrast to existing sequence-based structural class predictors, which target four major classes and which are designed for high identity sequences, we predict seven classes from sequences that share twilight-zone identity with the training sequences. Results The proposed MODular Approach to Structural class prediction (MODAS) method is unique as it allows for selection of any subset of the classes. MODAS is also the first to utilize a novel, custom-built feature-based sequence representation that combines evolutionary profiles and predicted secondary structure. The features quantify information relevant to the definition of the classes including conservation of residues and arrangement and number of helix/strand segments. Our comprehensive design considers 8 feature selection methods and 4 classifiers to develop Support Vector Machine-based classifiers that are tailored for each of the seven classes. Tests on 5 twilight-zone and 1 high-similarity benchmark datasets and comparison with over two dozens of modern competing predictors show that MODAS provides the best overall accuracy that ranges between 80% and 96.7% (83.5% for the twilight-zone datasets), depending on the dataset. This translates into 19% and 8% error rate reduction when compared against the best performing competing method on two largest datasets. The proposed predictor provides accurate predictions at 58% accuracy for membrane proteins class, which is not considered by majority of existing methods, in spite that this class accounts for only 2% of the data. Our predictive model is analyzed to demonstrate how and why the input features are associated with the corresponding classes. Conclusions The improved predictions stem from the novel features that express collocation of the secondary structure segments in the protein sequence and that combine evolutionary and secondary structure information. Our work demonstrates that conservation and arrangement of the secondary structure segments predicted along the protein chain can successfully predict structural classes which are defined based on the spatial arrangement of the secondary structures. A web server is available at http://biomine.ece.ualberta.ca/MODAS/. PMID:20003388

Models and analysis for multivariate failure time data

NASA Astrophysics Data System (ADS)

Shih, Joanna Huang

The goal of this research is to develop and investigate models and analytic methods for multivariate failure time data. We compare models in terms of direct modeling of the margins, flexibility of dependency structure, local vs. global measures of association, and ease of implementation. In particular, we study copula models, and models produced by right neutral cumulative hazard functions and right neutral hazard functions. We examine the changes of association over time for families of bivariate distributions induced from these models by displaying their density contour plots, conditional density plots, correlation curves of Doksum et al, and local cross ratios of Oakes. We know that bivariate distributions with same margins might exhibit quite different dependency structures. In addition to modeling, we study estimation procedures. For copula models, we investigate three estimation procedures. the first procedure is full maximum likelihood. The second procedure is two-stage maximum likelihood. At stage 1, we estimate the parameters in the margins by maximizing the marginal likelihood. At stage 2, we estimate the dependency structure by fixing the margins at the estimated ones. The third procedure is two-stage partially parametric maximum likelihood. It is similar to the second procedure, but we estimate the margins by the Kaplan-Meier estimate. We derive asymptotic properties for these three estimation procedures and compare their efficiency by Monte-Carlo simulations and direct computations. For models produced by right neutral cumulative hazards and right neutral hazards, we derive the likelihood and investigate the properties of the maximum likelihood estimates. Finally, we develop goodness of fit tests for the dependency structure in the copula models. We derive a test statistic and its asymptotic properties based on the test of homogeneity of Zelterman and Chen (1988), and a graphical diagnostic procedure based on the empirical Bayes approach. We study the performance of these two methods using actual and computer generated data.

Three-dimensional numerical simulations of crustal-scale wrenching using a non-linear failure criterion

NASA Astrophysics Data System (ADS)

Braun, Jean

1994-08-01

We have developed a three-dimensional finite element model to study wrench deformation of the crust regarded as an elasto-plastic material obeying Murrell's extension of Griffith's failure criterion. Numerical experiments using this model predict that the imposed basal wrenching is accommodated by an array of oblique Riedel-like shears and Y-shears (parallel to the direction of wrenching). The partitioning of deformation between the two types of structure depends on the width of the zone of imposed basal wrenching and the existence of a component of deformation in the x-direction (normal to the direction of wrenching). The Riedel shears are arranged in spiral-like structures that root into the basal wrench zone. In cross-section, the Riedel shears resemble wedge-shaped flower structures similar to those often observed in seismic cross-sections. The 'polarity' of the flower structures is positive (or palm-tree-like) in transpression experiments and negative (or tulip-like) in transtension experiments. The orientation of the Riedel shears throughout the crust obeys Mohr's hypothesis for incipient faulting combined with Murrell's failure criterion. The model also predicts plastic dilatancy inversely proportional to the square root of the confining pressure; this result agrees qualitatively with field observations and the results of sand-box experiments and quantitatively with direct measurement of dilatancy during high-pressure rock-deformation experiments.

Geometric phase coded metasurface: from polarization dependent directive electromagnetic wave scattering to diffusion-like scattering.

PubMed

Chen, Ke; Feng, Yijun; Yang, Zhongjie; Cui, Li; Zhao, Junming; Zhu, Bo; Jiang, Tian

2016-10-24

Ultrathin metasurface compromising various sub-wavelength meta-particles offers promising advantages in controlling electromagnetic wave by spatially manipulating the wavefront characteristics across the interface. The recently proposed digital coding metasurface could even simplify the design and optimization procedures due to the digitalization of the meta-particle geometry. However, current attempts to implement the digital metasurface still utilize several structural meta-particles to obtain certain electromagnetic responses, and requiring time-consuming optimization especially in multi-bits coding designs. In this regard, we present herein utilizing geometric phase based single structured meta-particle with various orientations to achieve either 1-bit or multi-bits digital metasurface. Particular electromagnetic wave scattering patterns dependent on the incident polarizations can be tailored by the encoded metasurfaces with regular sequences. On the contrast, polarization insensitive diffusion-like scattering can also been successfully achieved by digital metasurface encoded with randomly distributed coding sequences leading to substantial suppression of backward scattering in a broadband microwave frequency. The proposed digital metasurfaces provide simple designs and reveal new opportunities for controlling electromagnetic wave scattering with or without polarization dependence.

Geometric phase coded metasurface: from polarization dependent directive electromagnetic wave scattering to diffusion-like scattering

PubMed Central

Chen, Ke; Feng, Yijun; Yang, Zhongjie; Cui, Li; Zhao, Junming; Zhu, Bo; Jiang, Tian

2016-01-01

Ultrathin metasurface compromising various sub-wavelength meta-particles offers promising advantages in controlling electromagnetic wave by spatially manipulating the wavefront characteristics across the interface. The recently proposed digital coding metasurface could even simplify the design and optimization procedures due to the digitalization of the meta-particle geometry. However, current attempts to implement the digital metasurface still utilize several structural meta-particles to obtain certain electromagnetic responses, and requiring time-consuming optimization especially in multi-bits coding designs. In this regard, we present herein utilizing geometric phase based single structured meta-particle with various orientations to achieve either 1-bit or multi-bits digital metasurface. Particular electromagnetic wave scattering patterns dependent on the incident polarizations can be tailored by the encoded metasurfaces with regular sequences. On the contrast, polarization insensitive diffusion-like scattering can also been successfully achieved by digital metasurface encoded with randomly distributed coding sequences leading to substantial suppression of backward scattering in a broadband microwave frequency. The proposed digital metasurfaces provide simple designs and reveal new opportunities for controlling electromagnetic wave scattering with or without polarization dependence. PMID:27775064

Triphasic spike-timing-dependent plasticity organizes networks to produce robust sequences of neural activity

PubMed Central

Waddington, Amelia; Appleby, Peter A.; De Kamps, Marc; Cohen, Netta

2012-01-01

Synfire chains have long been proposed to generate precisely timed sequences of neural activity. Such activity has been linked to numerous neural functions including sensory encoding, cognitive and motor responses. In particular, it has been argued that synfire chains underlie the precise spatiotemporal firing patterns that control song production in a variety of songbirds. Previous studies have suggested that the development of synfire chains requires either initial sparse connectivity or strong topological constraints, in addition to any synaptic learning rules. Here, we show that this necessity can be removed by using a previously reported but hitherto unconsidered spike-timing-dependent plasticity (STDP) rule and activity-dependent excitability. Under this rule the network develops stable synfire chains that possess a non-trivial, scalable multi-layer structure, in which relative layer sizes appear to follow a universal function. Using computational modeling and a coarse grained random walk model, we demonstrate the role of the STDP rule in growing, molding and stabilizing the chain, and link model parameters to the resulting structure. PMID:23162457

Explosion/Blast Dynamics for Constellation Launch Vehicles Assessment

NASA Technical Reports Server (NTRS)

Baer, Mel; Crawford, Dave; Hickox, Charles; Kipp, Marlin; Hertel, Gene; Morgan, Hal; Ratzel, Arthur; Cragg, Clinton H.

2009-01-01

An assessment methodology is developed to guide quantitative predictions of adverse physical environments and the subsequent effects on the Ares-1 crew launch vehicle associated with the loss of containment of cryogenic liquid propellants from the upper stage during ascent. Development of the methodology is led by a team at Sandia National Laboratories (SNL) with guidance and support from a number of National Aeronautics and Space Administration (NASA) personnel. The methodology is based on the current Ares-1 design and feasible accident scenarios. These scenarios address containment failure from debris impact or structural response to pressure or blast loading from an external source. Once containment is breached, the envisioned assessment methodology includes predictions for the sequence of physical processes stemming from cryogenic tank failure. The investigative techniques, analysis paths, and numerical simulations that comprise the proposed methodology are summarized and appropriate simulation software is identified in this report.

Modeling joint restoration strategies for interdependent infrastructure systems

PubMed Central

Simonovic, Slobodan P.

2018-01-01

Life in the modern world depends on multiple critical services provided by infrastructure systems which are interdependent at multiple levels. To effectively respond to infrastructure failures, this paper proposes a model for developing optimal joint restoration strategy for interdependent infrastructure systems following a disruptive event. First, models for (i) describing structure of interdependent infrastructure system and (ii) their interaction process, are presented. Both models are considering the failure types, infrastructure operating rules and interdependencies among systems. Second, an optimization model for determining an optimal joint restoration strategy at infrastructure component level by minimizing the economic loss from the infrastructure failures, is proposed. The utility of the model is illustrated using a case study of electric-water systems. Results show that a small number of failed infrastructure components can trigger high level failures in interdependent systems; the optimal joint restoration strategy varies with failure occurrence time. The proposed models can help decision makers to understand the mechanisms of infrastructure interactions and search for optimal joint restoration strategy, which can significantly enhance safety of infrastructure systems. PMID:29649300

A New Challenge for Compression Algorithms: Genetic Sequences.

ERIC Educational Resources Information Center

Grumbach, Stephane; Tahi, Fariza

1994-01-01

Analyzes the properties of genetic sequences that cause the failure of classical algorithms used for data compression. A lossless algorithm, which compresses the information contained in DNA and RNA sequences by detecting regularities such as palindromes, is presented. This algorithm combines substitutional and statistical methods and appears to…

Management of adult-onset methylmalonic acidemia with hypotonia and acute respiratory failure: A case report.

PubMed

Zhao, Zhanqi; Chu, Chan-Ching; Chang, Mei-Yun; Chang, Hao-Tai; Hsu, Yeong-Long

2018-06-01

Methylmalonic acidemia (MMA) is an autosomal recessive disease of organic acidemia. We report a 26-year-old male who presented with metabolic acidosis, acute renal failure required hemodialysis and acute respiratory failure required mechanical ventilation support. Progressive hypotonia of muscles made weaning from mechanical ventilator difficult. High level of serum methylmalonic acid and the mut genotype sequences confirmed the diagnosis of this adult-onset MMA. Two mut genotype sequences were found by analyzing all coding exons and exon-intron junctions. One genotype was well documented (Exon 6 Mutation, c. 1280G>A. p. G427D, heterozygous). The other mut genotype sequence had never been reported elsewhere (Intron 6 Novel, c. 1333-13_c. 1333-8delTTTTTC, heterozygous). Diet modification, medication, regular hemodialysis and physical rehabilitation. Weaning strategy adjusted with help of electrical impedance tomography. The muscle power of the patient gradually recovered. Extubation of the patient was successful and he was discharged without oxygen required. This case gives us the lesson that MMA can be newly diagnosed in adult patient. A new mut genotype sequence was discovered. The use of electrical impedance tomography to select a suitable method for inspiratory muscle training was possible and useful.

SCHEMA computational design of virus capsid chimeras: calibrating how genome packaging, protection, and transduction correlate with calculated structural disruption.

PubMed

Ho, Michelle L; Adler, Benjamin A; Torre, Michael L; Silberg, Jonathan J; Suh, Junghae

2013-12-20

Adeno-associated virus (AAV) recombination can result in chimeric capsid protein subunits whose ability to assemble into an oligomeric capsid, package a genome, and transduce cells depends on the inheritance of sequence from different AAV parents. To develop quantitative design principles for guiding site-directed recombination of AAV capsids, we have examined how capsid structural perturbations predicted by the SCHEMA algorithm correlate with experimental measurements of disruption in seventeen chimeric capsid proteins. In our small chimera population, created by recombining AAV serotypes 2 and 4, we found that protection of viral genomes and cellular transduction were inversely related to calculated disruption of the capsid structure. Interestingly, however, we did not observe a correlation between genome packaging and calculated structural disruption; a majority of the chimeric capsid proteins formed at least partially assembled capsids and more than half packaged genomes, including those with the highest SCHEMA disruption. These results suggest that the sequence space accessed by recombination of divergent AAV serotypes is rich in capsid chimeras that assemble into 60-mer capsids and package viral genomes. Overall, the SCHEMA algorithm may be useful for delineating quantitative design principles to guide the creation of libraries enriched in genome-protecting virus nanoparticles that can effectively transduce cells. Such improvements to the virus design process may help advance not only gene therapy applications but also other bionanotechnologies dependent upon the development of viruses with new sequences and functions.

SCHEMA computational design of virus capsid chimeras: calibrating how genome packaging, protection, and transduction correlate with calculated structural disruption

PubMed Central

Ho, Michelle L.; Adler, Benjamin A.; Torre, Michael L.; Silberg, Jonathan J.; Suh, Junghae

2013-01-01

Adeno-associated virus (AAV) recombination can result in chimeric capsid protein subunits whose ability to assemble into an oligomeric capsid, package a genome, and transduce cells depends on the inheritance of sequence from different AAV parents. To develop quantitative design principles for guiding site-directed recombination of AAV capsids, we have examined how capsid structural perturbations predicted by the SCHEMA algorithm correlate with experimental measurements of disruption in seventeen chimeric capsid proteins. In our small chimera population, created by recombining AAV serotypes 2 and 4, we found that protection of viral genomes and cellular transduction were inversely related to calculated disruption of the capsid structure. Interestingly, however, we did not observe a correlation between genome packaging and calculated structural disruption; a majority of the chimeric capsid proteins formed at least partially assembled capsids and more than half packaged genomes, including those with the highest SCHEMA disruption. These results suggest that the sequence space accessed by recombination of divergent AAV serotypes is rich in capsid chimeras that assemble into 60-mer capsids and package viral genomes. Overall, the SCHEMA algorithm may be useful for delineating quantitative design principles to guide the creation of libraries enriched in genome-protecting virus nanoparticles that can effectively transduce cells. Such improvements to the virus design process may help advance not only gene therapy applications, but also other bionanotechnologies dependent upon the development of viruses with new sequences and functions. PMID:23899192

Preservation of protein clefts in comparative models.

PubMed

Piedra, David; Lois, Sergi; de la Cruz, Xavier

2008-01-16

Comparative, or homology, modelling of protein structures is the most widely used prediction method when the target protein has homologues of known structure. Given that the quality of a model may vary greatly, several studies have been devoted to identifying the factors that influence modelling results. These studies usually consider the protein as a whole, and only a few provide a separate discussion of the behaviour of biologically relevant features of the protein. Given the value of the latter for many applications, here we extended previous work by analysing the preservation of native protein clefts in homology models. We chose to examine clefts because of their role in protein function/structure, as they are usually the locus of protein-protein interactions, host the enzymes' active site, or, in the case of protein domains, can also be the locus of domain-domain interactions that lead to the structure of the whole protein. We studied how the largest cleft of a protein varies in comparative models. To this end, we analysed a set of 53507 homology models that cover the whole sequence identity range, with a special emphasis on medium and low similarities. More precisely we examined how cleft quality - measured using six complementary parameters related to both global shape and local atomic environment, depends on the sequence identity between target and template proteins. In addition to this general analysis, we also explored the impact of a number of factors on cleft quality, and found that the relationship between quality and sequence identity varies depending on cleft rank amongst the set of protein clefts (when ordered according to size), and number of aligned residues. We have examined cleft quality in homology models at a range of seq.id. levels. Our results provide a detailed view of how quality is affected by distinct parameters and thus may help the user of comparative modelling to determine the final quality and applicability of his/her cleft models. In addition, the large variability in model quality that we observed within each sequence bin, with good models present even at low sequence identities (between 20% and 30%), indicates that properly developed identification methods could be used to recover good cleft models in this sequence range.

Using secondary structure to identify ribosomal numts: cautionary examples from the human genome.

PubMed

Olson, Link E; Yoder, Anne D

2002-01-01

The identification of inadvertently sequenced mitochondrial pseudogenes (numts) is critical to any study employing mitochondrial DNA sequence data. Failure to discriminate numts correctly can confound phylogenetic reconstruction and studies of molecular evolution. This is especially problematic for ribosomal mtDNA genes. Unlike protein-coding loci, whose pseudogenes tend to accumulate diagnostic frameshift or premature stop mutations, functional ribosomal genes are not constrained to maintain a reading frame and can accumulate insertion-deletion events of varying length, particularly in nonpairing regions. Several authors have advocated using structural features of the transcribed rRNA molecule to differentiate functional mitochondrial rRNA genes from their nuclear paralogs. We explored this approach using the mitochondrial 12S rRNA gene and three known 12S numts from the human genome in the context of anthropoid phylogeny and the inferred secondary structure of primate 12S rRNA. Contrary to expectation, each of the three human numts exhibits striking concordance with secondary structure models, with little, if any, indication of their pseudogene status, and would likely escape detection based on structural criteria alone. Furthermore, we show that the unwitting inclusion of a particularly ancient (18-25 Myr old) and surprisingly cryptic human numt in a phylogenetic analysis would yield a well-supported but dramatically incorrect conclusion regarding anthropoid relationships. Though we endorse the use of secondary structure models for inferring positional homology wholeheartedly, we caution against reliance on structural criteria for the discrimination of rRNA numts, given the potential fallibility of this approach.

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.

Evidence for the Concerted Evolution between Short Linear Protein Motifs and Their Flanking Regions

PubMed Central

Chica, Claudia; Diella, Francesca; Gibson, Toby J.

2009-01-01

Background Linear motifs are short modules of protein sequences that play a crucial role in mediating and regulating many protein–protein interactions. The function of linear motifs strongly depends on the context, e.g. functional instances mainly occur inside flexible regions that are accessible for interaction. Sometimes linear motifs appear as isolated islands of conservation in multiple sequence alignments. However, they also occur in larger blocks of sequence conservation, suggesting an active role for the neighbouring amino acids. Results The evolution of regions flanking 116 functional linear motif instances was studied. The conservation of the amino acid sequence and order/disorder tendency of those regions was related to presence/absence of the instance. For the majority of the analysed instances, the pairs of sequences conserving the linear motif were also observed to maintain a similar local structural tendency and/or to have higher local sequence conservation when compared to pairs of sequences where one is missing the linear motif. Furthermore, those instances have a higher chance to co–evolve with the neighbouring residues in comparison to the distant ones. Those findings are supported by examples where the regulation of the linear motif–mediated interaction has been shown to depend on the modifications (e.g. phosphorylation) at neighbouring positions or is thought to benefit from the binding versatility of disordered regions. Conclusion The results suggest that flanking regions are relevant for linear motif–mediated interactions, both at the structural and sequence level. More interestingly, they indicate that the prediction of linear motif instances can be enriched with contextual information by performing a sequence analysis similar to the one presented here. This can facilitate the understanding of the role of these predicted instances in determining the protein function inside the broader context of the cellular network where they arise. PMID:19584925

Precursor slope distress leading up to the 2010 Mount Meager landslide, British Columbia

NASA Astrophysics Data System (ADS)

Roberti, Gioachino; Ward, Brent; van Wyk de Vries, Benjamin; Friele, Pierre; Clague, John; Perotti, Luigi; Giardino, Marco

2017-04-01

Volcanoes are highly prone to landslides, in part due to erosion of the flanks by glaciers and streams. Mount Meager (British Columbia, Canada) is a glacier-clad volcano that is one of the most landslide-prone areas in Canada, due in part to glacial erosion. In 2010, the south flank of the volcano failed catastrophically, generating one of the largest (˜50 x 106 m 3) landslides in Canadian history. We document the evolution of the edifice up to the time of this failure using an archive of historic aerial photographs spanning the period from 1948 to 2006. Oblique digital photos taken after the landslide yielded information on the geology and internal structure of the volcano. All photos were processed with Structure from Motion (SfM) photogrammetry. We used the SfM products to produce pre-and post-failure geomorphic maps that document glacier and edifice changes. The maps show that a glacier below the 2010 landslide source area re-advanced in the 1980s, then rapidly retreated up to the present. Our photographic reconstruction documents 60 years of progressive development of tension cracks, bulging, and precursor failures (1998, 2009) at the toe of the 2010 failure zone. The final 2010 collapse was conditioned by glacial debuttressing and triggered by hot summer weather accompanied by ice and snow melt. Meltwater increased porewater pressures in fragmented and fractured material at the base of the 2010 failure zone, causing it to mobilize, which in turn triggered several secondary failures controlled by lithology and faults. The landslide retrogressed from the base of the slope to near the peak of Mount Meager and involved basement rock and the overlying volcanic sequence. Elsewhere on the flanks of Mount Meager, large fractures have developed in recently deglaciated areas, conditioning these slopes for collapse and debris avalanches. Potential failures in these areas have larger volumes than the 2010 landslide. Atmospheric warming over the next several decades will cause further loss of snow and glacier ice, and induce additional slope instability. Satellite- and ground-based monitoring of these slopes might provide advanced warning of future landslides and could be used to reduce risk in regions downstream of the volcano.

A programing system for research and applications in structural optimization

NASA Technical Reports Server (NTRS)

Sobieszczanski-Sobieski, J.; Rogers, J. L., Jr.

1981-01-01

The flexibility necessary for such diverse utilizations is achieved by combining, in a modular manner, a state-of-the-art optimization program, a production level structural analysis program, and user supplied and problem dependent interface programs. Standard utility capabilities in modern computer operating systems are used to integrate these programs. This approach results in flexibility of the optimization procedure organization and versatility in the formulation of constraints and design variables. Features shown in numerical examples include: variability of structural layout and overall shape geometry, static strength and stiffness constraints, local buckling failure, and vibration constraints.

Manufacturing of GLARE Parts and Structures

NASA Astrophysics Data System (ADS)

Sinke, J.

2003-07-01

GLARE is a hybrid material consisting of alternating layers of metal sheets and composite layers, requiring special attention when manufacturing of parts and structures is concerned. On one hand the applicable manufacturing processes for GLARE are limited, on the other hand, due to the constituents and composition of the laminate, it offers new opportunities for production. One of the opportunities is the manufacture of very large skin panels by lay-up techniques. Lay-up techniques are common for full composites, but uncommon for metallic structures. Nevertheless, large GLARE skin panels are made by lay-up processes. In addition, the sequences of forming and laminating processes, that can be selected, offer manufacturing options that are not applicable to metals or full composites. With respect to conventional manufacturing processes, the possibilities for Fibre Metal Laminates in general, are limited. The limits are partly due to the different failure modes, partly due to the properties of the constituents in the laminate. For machining processes: the wear of the cutting tools during machining operations of GLARE stems from the abrasive nature of the glass fibres. For the forming processes: the limited formability, expressed by a small failure strain, is related to the glass fibres. However, although these manufacturing issues may restrict the use of manufacturing processes for FMLs, application of these laminates in aircraft is not hindered.

Application of regenerative medicine for kidney diseases.

PubMed

Yokoo, Takashi; Fukui, Akira; Kobayashi, Eiji

2007-01-01

Following recent advancements of stem cell research, the potential for organ regeneration using somatic stem cells as an ultimate therapy for organ failure has increased. However, anatomically complicated organs such as the kidney and liver have proven more refractory to stem cell-based regenerative techniques. At present, kidney regeneration is considered to require one of two approaches depending on the type of renal failure, namely acute renal failure (ARF) and chronic renal failure (CRF).The kidney has the potential to regenerate itself provided that the damage is not too severe and the kidney's structure remains intact. Regenerative medicine for ARF should therefore aim to activate or support this potent. In cases of the irreversible damage to the kidney, which is most likely in patients with CRF undergoing long-term dialysis, self-renewal is totally lost. Thus, regenerative medicine for CRF will likely involve the establishment of a functional whole kidney de novo. This article reviews the challenges and recent advances in both approaches and discusses the potential approach of these novel strategies for clinical application.

Making Sense of Dynamic Systems: How Our Understanding of Stocks and Flows Depends on a Global Perspective.

PubMed

Fischer, Helen; Gonzalez, Cleotilde

2016-03-01

Stocks and flows (SF) are building blocks of dynamic systems: Stocks change through inflows and outflows, such as our bank balance changing with withdrawals and deposits, or atmospheric CO2 with absorptions and emissions. However, people make systematic errors when trying to infer the behavior of dynamic systems, termed SF failure, whose cognitive explanations are yet unknown. We argue that SF failure appears when people focus on specific system elements (local processing), rather than on the system structure and gestalt (global processing). Using a standard SF task (n = 148), SF failure decreased by (a) a global as opposed to local task format; (b) individual global as opposed to local processing styles; and (c) global as opposed to local perceptual priming. These results converge toward local processing as an explanation for SF failure. We discuss theoretical and practical implications on the connections between the scope of attention and understanding of dynamic systems. Copyright © 2015 Cognitive Science Society, Inc.

Data processing device test apparatus and method therefor

DOEpatents

Wilcox, Richard Jacob; Mulig, Jason D.; Eppes, David; Bruce, Michael R.; Bruce, Victoria J.; Ring, Rosalinda M.; Cole, Jr., Edward I.; Tangyunyong, Paiboon; Hawkins, Charles F.; Louie, Arnold Y.

2003-04-08

A method and apparatus mechanism for testing data processing devices are implemented. The test mechanism isolates critical paths by correlating a scanning microscope image with a selected speed path failure. A trigger signal having a preselected value is generated at the start of each pattern vector. The sweep of the scanning microscope is controlled by a computer, which also receives and processes the image signals returned from the microscope. The value of the trigger signal is correlated with a set of pattern lines being driven on the DUT. The trigger is either asserted or negated depending the detection of a pattern line failure and the particular line that failed. In response to the detection of the particular speed path failure being characterized, and the trigger signal, the control computer overlays a mask on the image of the device under test (DUT). The overlaid image provides a visual correlation of the failure with the structural elements of the DUT at the level of resolution of the microscope itself.

Terrestrial Laser Scanner for assessing rockfall susceptibility in the Cilento rocky coast (Southern Italy)

NASA Astrophysics Data System (ADS)

Sorrentino, Valerio; Matasci, Battista; Abellan, Antonio; Jaboyedoff, Michel; Marino, Ermanno; Pignalosa, Antonio; Santo, Antonio

2016-04-01

Rockfalls and other types of landslides are the dominant processes causing a retreat of sea cliffs. The coastal areas constitute an important tourist attraction and a large number of people rest beneath the cliffs on a daily basis, considerably increasing the risk associated to rockfalls. We present an approach to assess rockfall susceptibility at the cliff scale based on terrestrial laser scanner (TLS) point clouds. The test area is a coastal cliff situated in the southern part of the Cilento (Centola Municipality, Campania Region), in which a natural arch was formed. This cliff is constituted by heavy fractured carbonate rock mass with a strong structural control. In June 2015 TLS data were acquired with long-range scanner RIEGL VZ1000®. The structural analysis of the cliff was performed in the field and using Coltop 3D software on the point cloud. As a result, 10 discontinuity sets (joint, faults and bedding planes) were individuated and the different characteristics such as orientation, spacing and persistence were measured. The kinematically unstable areas were highlighted using a script that computes an index of susceptibility to rockfalls based on the spatial distribution of failure mechanisms. The susceptibility index computation is based on the average surface that every joint set (or combinations of two joint sets in the case of wedge failure) forms on the topography according to its spacing, trace length, and incidence angle. This susceptibility index also depends on the steepness of the joint set (or of the intersection line in the case of wedge failure). As a result the most important discontinuity sets in terms of potential planar failure, wedge failure and toppling were individuated and an assessment of rockfall susceptibility at the cliff scale was achieved. Results show that the kinematically feasible failures are not equally distributed along the cliff but concentrated on certain areas. The most susceptible areas for planar failure are related to the discontinuity set K10 (71/097), whereas for toppling the highest susceptibility is reached with K1 (60/218). Concerning wedge failure, the combination of K10 and K1 yields the highest susceptibility values. It shows also clustering with higher density which is probably related to regional structures. More detailed investigations of the rockfall susceptibility and failure mechanisms will be performed during the forthcoming months. The relationship with regional structures will be also investigated in more detail. Perspectives also include using the methodology on the other side of the natural arch in order to provide a global susceptibility assessment of the area.

Hydrodynamic Radii of Intrinsically Disordered Proteins Determined from Experimental Polyproline II Propensities

PubMed Central

Tomasso, Maria E.; Tarver, Micheal J.; Devarajan, Deepa; Whitten, Steven T.

2016-01-01

The properties of disordered proteins are thought to depend on intrinsic conformational propensities for polyproline II (PP II) structure. While intrinsic PP II propensities have been measured for the common biological amino acids in short peptides, the ability of these experimentally determined propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs) has not been established. Presented here are results from molecular simulations of disordered proteins showing that the hydrodynamic radius (R h) can be predicted from experimental PP II propensities with good agreement, even when charge-based considerations are omitted. The simulations demonstrate that R h and chain propensity for PP II structure are linked via a simple power-law scaling relationship, which was tested using the experimental R h of 22 IDPs covering a wide range of peptide lengths, net charge, and sequence composition. Charge effects on R h were found to be generally weak when compared to PP II effects on R h. Results from this study indicate that the hydrodynamic dimensions of IDPs are evidence of considerable sequence-dependent backbone propensities for PP II structure that qualitatively, if not quantitatively, match conformational propensities measured in peptides. PMID:26727467

Histoimmunogenetics Markup Language 1.0: Reporting next generation sequencing-based HLA and KIR genotyping.

PubMed

Milius, Robert P; Heuer, Michael; Valiga, Daniel; Doroschak, Kathryn J; Kennedy, Caleb J; Bolon, Yung-Tsi; Schneider, Joel; Pollack, Jane; Kim, Hwa Ran; Cereb, Nezih; Hollenbach, Jill A; Mack, Steven J; Maiers, Martin

2015-12-01

We present an electronic format for exchanging data for HLA and KIR genotyping with extensions for next-generation sequencing (NGS). This format addresses NGS data exchange by refining the Histoimmunogenetics Markup Language (HML) to conform to the proposed Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines (miring.immunogenomics.org). Our refinements of HML include two major additions. First, NGS is supported by new XML structures to capture additional NGS data and metadata required to produce a genotyping result, including analysis-dependent (dynamic) and method-dependent (static) components. A full genotype, consensus sequence, and the surrounding metadata are included directly, while the raw sequence reads and platform documentation are externally referenced. Second, genotype ambiguity is fully represented by integrating Genotype List Strings, which use a hierarchical set of delimiters to represent allele and genotype ambiguity in a complete and accurate fashion. HML also continues to enable the transmission of legacy methods (e.g. site-specific oligonucleotide, sequence-specific priming, and Sequence Based Typing (SBT)), adding features such as allowing multiple group-specific sequencing primers, and fully leveraging techniques that combine multiple methods to obtain a single result, such as SBT integrated with NGS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PredPPCrys: Accurate Prediction of Sequence Cloning, Protein Production, Purification and Crystallization Propensity from Protein Sequences Using Multi-Step Heterogeneous Feature Fusion and Selection

PubMed Central

Wang, Huilin; Wang, Mingjun; Tan, Hao; Li, Yuan; Zhang, Ziding; Song, Jiangning

2014-01-01

X-ray crystallography is the primary approach to solve the three-dimensional structure of a protein. However, a major bottleneck of this method is the failure of multi-step experimental procedures to yield diffraction-quality crystals, including sequence cloning, protein material production, purification, crystallization and ultimately, structural determination. Accordingly, prediction of the propensity of a protein to successfully undergo these experimental procedures based on the protein sequence may help narrow down laborious experimental efforts and facilitate target selection. A number of bioinformatics methods based on protein sequence information have been developed for this purpose. However, our knowledge on the important determinants of propensity for a protein sequence to produce high diffraction-quality crystals remains largely incomplete. In practice, most of the existing methods display poorer performance when evaluated on larger and updated datasets. To address this problem, we constructed an up-to-date dataset as the benchmark, and subsequently developed a new approach termed ‘PredPPCrys’ using the support vector machine (SVM). Using a comprehensive set of multifaceted sequence-derived features in combination with a novel multi-step feature selection strategy, we identified and characterized the relative importance and contribution of each feature type to the prediction performance of five individual experimental steps required for successful crystallization. The resulting optimal candidate features were used as inputs to build the first-level SVM predictor (PredPPCrys I). Next, prediction outputs of PredPPCrys I were used as the input to build second-level SVM classifiers (PredPPCrys II), which led to significantly enhanced prediction performance. Benchmarking experiments indicated that our PredPPCrys method outperforms most existing procedures on both up-to-date and previous datasets. In addition, the predicted crystallization targets of currently non-crystallizable proteins were provided as compendium data, which are anticipated to facilitate target selection and design for the worldwide structural genomics consortium. PredPPCrys is freely available at http://www.structbioinfor.org/PredPPCrys. PMID:25148528

Functional evolution and structural conservation in chimeric cytochromes p450: calibrating a structure-guided approach.

PubMed

Otey, Christopher R; Silberg, Jonathan J; Voigt, Christopher A; Endelman, Jeffrey B; Bandara, Geethani; Arnold, Frances H

2004-03-01

Recombination generates chimeric proteins whose ability to fold depends on minimizing structural perturbations that result when portions of the sequence are inherited from different parents. These chimeric sequences can display functional properties characteristic of the parents or acquire entirely new functions. Seventeen chimeras were generated from two CYP102 members of the functionally diverse cytochrome p450 family. Chimeras predicted to have limited structural disruption, as defined by the SCHEMA algorithm, displayed CO binding spectra characteristic of folded p450s. Even this small population exhibited significant functional diversity: chimeras displayed altered substrate specificities, a wide range in thermostabilities, up to a 40-fold increase in peroxidase activity, and ability to hydroxylate a substrate toward which neither parent heme domain shows detectable activity. These results suggest that SCHEMA-guided recombination can be used to generate diverse p450s for exploring function evolution within the p450 structural framework.

Structural and functional characterization of a calcium-activated cation channel from Tsukamurella paurometabola

NASA Astrophysics Data System (ADS)

Dhakshnamoorthy, Balasundaresan; Rohaim, Ahmed; Rui, Huan; Blachowicz, Lydia; Roux, Benoît

2016-09-01

The selectivity filter is an essential functional element of K+ channels that is highly conserved both in terms of its primary sequence and its three-dimensional structure. Here, we investigate the properties of an ion channel from the Gram-positive bacterium Tsukamurella paurometabola with a selectivity filter formed by an uncommon proline-rich sequence. Electrophysiological recordings show that it is a non-selective cation channel and that its activity depends on Ca2+ concentration. In the crystal structure, the selectivity filter adopts a novel conformation with Ca2+ ions bound within the filter near the pore helix where they are coordinated by backbone oxygen atoms, a recurrent motif found in multiple proteins. The binding of Ca2+ ion in the selectivity filter controls the widening of the pore as shown in crystal structures and in molecular dynamics simulations. The structural, functional and computational data provide a characterization of this calcium-gated cationic channel.

Hidden Markov model-derived structural alphabet for proteins: the learning of protein local shapes captures sequence specificity.

PubMed

Camproux, A C; Tufféry, P

2005-08-05

Understanding and predicting protein structures depend on the complexity and the accuracy of the models used to represent them. We have recently set up a Hidden Markov Model to optimally compress protein three-dimensional conformations into a one-dimensional series of letters of a structural alphabet. Such a model learns simultaneously the shape of representative structural letters describing the local conformation and the logic of their connections, i.e. the transition matrix between the letters. Here, we move one step further and report some evidence that such a model of protein local architecture also captures some accurate amino acid features. All the letters have specific and distinct amino acid distributions. Moreover, we show that words of amino acids can have significant propensities for some letters. Perspectives point towards the prediction of the series of letters describing the structure of a protein from its amino acid sequence.

From a marine neuropeptide to antimicrobial pseudopeptides containing aza-β(3)-amino acids: structure and activity

PubMed Central

Laurencin, Mathieu; Legrand, Baptiste; Duval, Emilie; Henry, Joël; Baudy-Floc'H, Michèle; Zatylny-Gaudin, Céline; Bondon, Arnaud

2012-01-01

Incorporation of aza-β3-amino acids into endogenous neuropeptide from mollusks (ALSGDAFLRF-NH2) with weak antimicrobial activities allows us to design new AMPs sequences. We find that, depending on the nature of the substitution, these could result either in inactive pseudopeptides or in a drastic enhancement of the antimicrobial activity without high cytotoxicity resulted. Structural studies perform by NMR and circular dichroism on the pseudopeptides show the impact of aza-β3-amino acids on the peptide structures. We obtain the first three-dimensional structures of pseudopeptides containing aza-β3-amino acids in aqueous micellar SDS and demonstrate that hydrazino turn can be formed in aqueous solution. Overall, these results demonstrate the ability to modulate AMPs activities through structural modifications induced by the nature and the position of these amino acid analogs in the peptide sequences. PMID:22320306

Modeling coding-sequence evolution within the context of residue solvent accessibility.

PubMed

Scherrer, Michael P; Meyer, Austin G; Wilke, Claus O

2012-09-12

Protein structure mediates site-specific patterns of sequence divergence. In particular, residues in the core of a protein (solvent-inaccessible residues) tend to be more evolutionarily conserved than residues on the surface (solvent-accessible residues). Here, we present a model of sequence evolution that explicitly accounts for the relative solvent accessibility of each residue in a protein. Our model is a variant of the Goldman-Yang 1994 (GY94) model in which all model parameters can be functions of the relative solvent accessibility (RSA) of a residue. We apply this model to a data set comprised of nearly 600 yeast genes, and find that an evolutionary-rate ratio ω that varies linearly with RSA provides a better model fit than an RSA-independent ω or an ω that is estimated separately in individual RSA bins. We further show that the branch length t and the transition-transverion ratio κ also vary with RSA. The RSA-dependent GY94 model performs better than an RSA-dependent Muse-Gaut 1994 (MG94) model in which the synonymous and non-synonymous rates individually are linear functions of RSA. Finally, protein core size affects the slope of the linear relationship between ω and RSA, and gene expression level affects both the intercept and the slope. Structure-aware models of sequence evolution provide a significantly better fit than traditional models that neglect structure. The linear relationship between ω and RSA implies that genes are better characterized by their ω slope and intercept than by just their mean ω.

Stress and Reliability Analysis of a Metal-Ceramic Dental Crown

NASA Technical Reports Server (NTRS)

Anusavice, Kenneth J; Sokolowski, Todd M.; Hojjatie, Barry; Nemeth, Noel N.

1996-01-01

Interaction of mechanical and thermal stresses with the flaws and microcracks within the ceramic region of metal-ceramic dental crowns can result in catastrophic or delayed failure of these restorations. The objective of this study was to determine the combined influence of induced functional stresses and pre-existing flaws and microcracks on the time-dependent probability of failure of a metal-ceramic molar crown. A three-dimensional finite element model of a porcelain fused-to-metal (PFM) molar crown was developed using the ANSYS finite element program. The crown consisted of a body porcelain, opaque porcelain, and a metal substrate. The model had a 300 Newton load applied perpendicular to one cusp, a load of 30ON applied at 30 degrees from the perpendicular load case, directed toward the center, and a 600 Newton vertical load. Ceramic specimens were subjected to a biaxial flexure test and the load-to-failure of each specimen was measured. The results of the finite element stress analysis and the flexure tests were incorporated in the NASA developed CARES/LIFE program to determine the Weibull and fatigue parameters and time-dependent fracture reliability of the PFM crown. CARES/LIFE calculates the time-dependent reliability of monolithic ceramic components subjected to thermomechanical and/Or proof test loading. This program is an extension of the CARES (Ceramics Analysis and Reliability Evaluation of Structures) computer program.

Probabilistic Sizing and Verification of Space Ceramic Structures

NASA Astrophysics Data System (ADS)

Denaux, David; Ballhause, Dirk; Logut, Daniel; Lucarelli, Stefano; Coe, Graham; Laine, Benoit

2012-07-01

Sizing of ceramic parts is best optimised using a probabilistic approach which takes into account the preexisting flaw distribution in the ceramic part to compute a probability of failure of the part depending on the applied load, instead of a maximum allowable load as for a metallic part. This requires extensive knowledge of the material itself but also an accurate control of the manufacturing process. In the end, risk reduction approaches such as proof testing may be used to lower the final probability of failure of the part. Sizing and verification of ceramic space structures have been performed by Astrium for more than 15 years, both with Zerodur and SiC: Silex telescope structure, Seviri primary mirror, Herschel telescope, Formosat-2 instrument, and other ceramic structures flying today. Throughout this period of time, Astrium has investigated and developed experimental ceramic analysis tools based on the Weibull probabilistic approach. In the scope of the ESA/ESTEC study: “Mechanical Design and Verification Methodologies for Ceramic Structures”, which is to be concluded in the beginning of 2012, existing theories, technical state-of-the-art from international experts, and Astrium experience with probabilistic analysis tools have been synthesized into a comprehensive sizing and verification method for ceramics. Both classical deterministic and more optimised probabilistic methods are available, depending on the criticality of the item and on optimisation needs. The methodology, based on proven theory, has been successfully applied to demonstration cases and has shown its practical feasibility.

Evolution of coreceptor utilization to escape CCR5 antagonist therapy.

PubMed

Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

2016-07-01

The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A charge-dependent mechanism is responsible for the dynamic accumulation of proteins inside nucleoli.

PubMed

Musinova, Yana R; Kananykhina, Eugenia Y; Potashnikova, Daria M; Lisitsyna, Olga M; Sheval, Eugene V

2015-01-01

The majority of known nucleolar proteins are freely exchanged between the nucleolus and the surrounding nucleoplasm. One way proteins are retained in the nucleoli is by the presence of specific amino acid sequences, namely nucleolar localization signals (NoLSs). The mechanism by which NoLSs retain proteins inside the nucleoli is still unclear. Here, we present data showing that the charge-dependent (electrostatic) interactions of NoLSs with nucleolar components lead to nucleolar accumulation as follows: (i) known NoLSs are enriched in positively charged amino acids, but the NoLS structure is highly heterogeneous, and it is not possible to identify a consensus sequence for this type of signal; (ii) in two analyzed proteins (NF-κB-inducing kinase and HIV-1 Tat), the NoLS corresponds to a region that is enriched for positively charged amino acid residues; substituting charged amino acids with non-charged ones reduced the nucleolar accumulation in proportion to the charge reduction, and nucleolar accumulation efficiency was strongly correlated with the predicted charge of the tested sequences; and (iii) sequences containing only lysine or arginine residues (which were referred to as imitative NoLSs, or iNoLSs) are accumulated in the nucleoli in a charge-dependent manner. The results of experiments with iNoLSs suggested that charge-dependent accumulation inside the nucleoli was dependent on interactions with nucleolar RNAs. The results of this work are consistent with the hypothesis that nucleolar protein accumulation by NoLSs can be determined by the electrostatic interaction of positively charged regions with nucleolar RNAs rather than by any sequence-specific mechanism. Copyright © 2014 Elsevier B.V. All rights reserved.

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

Man, Viet Hoang; Pan, Feng; Sagui, Celeste, E-mail: sagui@ncsu.edu

We explore the use of a fast laser melting simulation approach combined with atomistic molecular dynamics simulations in order to determine the melting and healing responses of B-DNA and Z-DNA dodecamers with the same d(5′-CGCGCGCGCGCG-3′){sub 2} sequence. The frequency of the laser pulse is specifically tuned to disrupt Watson-Crick hydrogen bonds, thus inducing melting of the DNA duplexes. Subsequently, the structures relax and partially refold, depending on the field strength. In addition to the inherent interest of the nonequilibrium melting process, we propose that fast melting by an infrared laser pulse could be used as a technique for a fastmore » comparison of relative stabilities of same-sequence oligonucleotides with different secondary structures with full atomistic detail of the structures and solvent. This could be particularly useful for nonstandard secondary structures involving non-canonical base pairs, mismatches, etc.« less

Use Massive Parallel Sequencing and Exome Capture Technology to Sequence the Exome of Fanconi Anemia Children and Their Patents

ClinicalTrials.gov

2013-11-21

Fanconi Anemia; Autosomal or Sex Linked Recessive Genetic Disease; Bone Marrow Hematopoiesis Failure, Multiple Congenital Abnormalities, and Susceptibility to Neoplastic Diseases.; Hematopoiesis Maintainance.

Evaluation of a Progressive Failure Analysis Methodology for Laminated Composite Structures

NASA Technical Reports Server (NTRS)

Sleight, David W.; Knight, Norman F., Jr.; Wang, John T.

1997-01-01

A progressive failure analysis methodology has been developed for predicting the nonlinear response and failure of laminated composite structures. The progressive failure analysis uses C plate and shell elements based on classical lamination theory to calculate the in-plane stresses. Several failure criteria, including the maximum strain criterion, Hashin's criterion, and Christensen's criterion, are used to predict the failure mechanisms. The progressive failure analysis model is implemented into a general purpose finite element code and can predict the damage and response of laminated composite structures from initial loading to final failure.

In vitro selection of high temperature Zn(2+)-dependent DNAzymes.

PubMed

Nelson, Kevin E; Bruesehoff, Peter J; Lu, Yi

2005-08-01

In vitro selection of Zn(2+)-dependent RNA-cleaving DNAzymes with activity at 90 degrees C has yielded a diverse spool of selected sequences. The RNA cleavage efficiency was found in all cases to be specific for Zn(2+) over Pb(2+), Ca(2+), Cd(2+), Co(2+), Hg(2+), and Mg(2+). The Zn(2+)-dependent activity assay of the most active sequence showed that the DNAzyme possesses an apparent Zn(2+)-binding dissociation constant of 234 muM and that its activity increases with increasing temperatures from 50-90 degrees C. A fit of the Arrhenius plot data gave E(a) = 15.3 kcal mol(-1). Surprisingly, the selected Zn(2+)-dependent DNAzymes showed only a modest (approximately 3-fold) activity enhancement over the background rate of cleavage of random sequences containing a single embedded ribonucleotide within an otherwise DNA oligonucleotide. The result is attributable to the ability of DNA to sustain cleavage activity at high temperature with minimal secondary structure when Zn(2+) is present. Since this effect is highly specific for Zn(2+), this metal ion may play a special role in molecular evolution of nucleic acids at high temperature.

Independent Evolution of Six Families of Halogenating Enzymes

PubMed Central

Xu, Gangming; Wang, Bin-Gui

2016-01-01

Halogenated natural products are widespread in the environment, and the halogen atoms are typically vital to their bioactivities. Thus far, six families of halogenating enzymes have been identified: cofactor-free haloperoxidases (HPO), vanadium-dependent haloperoxidases (V-HPO), heme iron-dependent haloperoxidases (HI-HPO), non-heme iron-dependent halogenases (NI-HG), flavin-dependent halogenases (F-HG), and S-adenosyl-L-methionine (SAM)-dependent halogenases (S-HG). However, these halogenating enzymes with similar biological functions but distinct structures might have evolved independently. Phylogenetic and structural analyses suggest that the HPO, V-HPO, HI-HPO, NI-HG, F-HG, and S-HG enzyme families may have evolutionary relationships to the α/β hydrolases, acid phosphatases, peroxidases, chemotaxis phosphatases, oxidoreductases, and SAM hydroxide adenosyltransferases, respectively. These halogenating enzymes have established sequence homology, structural conservation, and mechanistic features within each family. Understanding the distinct evolutionary history of these halogenating enzymes will provide further insights into the study of their catalytic mechanisms and halogenation specificity. PMID:27153321

Crazing of nanocomposites with polymer-tethered nanoparticles

DOE PAGES

Meng, Dong; Kumar, Sanat K.; Ge, Ting; ...

2016-09-07

The crazing behavior of polymer nanocomposites formed by blending polymer grafted nanoparticles with an entangled polymer melt is studied by molecular dynamics simulations. We focus on the three key differences in the crazing behavior of a composite relative to the pure homopolymer matrix, namely, a lower yield stress, a smaller extension ratio, and a grafted chain length dependent failure stress. The yield behavior is found to be mostly controlled by the local nanoparticle-grafted polymer interfacial energy, with the grafted polymer-polymer matrix interfacial structure being of little to no relevance. Increasing the attraction between nanoparticle core and the grafted polymer inhibitsmore » void nucleation and leads to a higher yield stress. In the craze growth regime, the presence of “grafted chain” sections of ≈100 monomers alters the mechanical response of composite samples, giving rise to smaller extension ratios and higher drawing stresses than for the homopolymer matrix. As a result, the dominant failure mechanism of composite samples depends strongly on the length of the grafted chains, with disentanglement being the dominant mechanism for short chains, while bond breaking is the failure mode for chain lengths >10N e, where N e is the entanglement length.« less

Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice

PubMed Central

Bolasco, Giulia; Calogero, Raffaele; Carrara, Matteo; Al Banchaabouchi, Mumna; Bilbao, Daniel; Mazzoccoli, Gianluigi; Vinciguerra, Manlio

2012-01-01

Locally acting insulin growth factor isoform (mIGF-1) and the NAD+-dependent protein deacetylase SIRT1 are implicated in life and health span. Heart failure is associated with aging and is a major cause of death. mIGF-1 protects the heart from oxidative stresses via SIRT1. SIRT1 subcellular localization and its genomic regulation by mIGF-1 are unknown. We show here that SIRT1 is located in the nuclei of a significant fraction of cardiomyocytes. Using high throughput sequencing approaches in mIGF-1 transgenic mice, we identified new targets of the mIGF-1/SIRT1 signaling. In addition to its potent cardioprotective properties, cardiac-restricted mIGF-1 transgene induced systemic changes such as high blood pressure, leukocytosis and an enhanced fear response, in a SIRT1-dependent manner. Cardiac mIGF-1/SIRT1 signaling may thus modulate disparate systemic functions. PMID:22691943

JDet: interactive calculation and visualization of function-related conservation patterns in multiple sequence alignments and structures.

PubMed

Muth, Thilo; García-Martín, Juan A; Rausell, Antonio; Juan, David; Valencia, Alfonso; Pazos, Florencio

2012-02-15

We have implemented in a single package all the features required for extracting, visualizing and manipulating fully conserved positions as well as those with a family-dependent conservation pattern in multiple sequence alignments. The program allows, among other things, to run different methods for extracting these positions, combine the results and visualize them in protein 3D structures and sequence spaces. JDet is a multiplatform application written in Java. It is freely available, including the source code, at http://csbg.cnb.csic.es/JDet. The package includes two of our recently developed programs for detecting functional positions in protein alignments (Xdet and S3Det), and support for other methods can be added as plug-ins. A help file and a guided tutorial for JDet are also available.

Development of a novel biosensing system based on the structural change of a polymerized guanine-quadruplex DNA nanostructure.

PubMed

Morita, Yo; Yoshida, Wataru; Savory, Nasa; Han, Sung Woong; Tera, Masayuki; Nagasawa, Kazuo; Nakamura, Chikashi; Sode, Koji; Ikebukuro, Kazunori

2011-08-15

By inserting an adenosine aptamer into an aptamer that forms a G-quadruplex, we developed an adaptor molecule, named the Gq-switch, which links an electrode with flavin adenine dinucleotide-dependent glucose dehydrogenase (FADGDH) that is capable of transferring electron to a electrode directly. First, we selected an FADGDH-binding aptamer and identified that its sequence is composed of two blocks of consecutive six guanine bases and it forms a polymerized G-quadruplex structure. Then, we inserted a sequence of an adenosine aptamer between the two blocks of consecutive guanine bases, and we found it also bound to adenosine. Then we named it as Gq-switch. In the absence of adenosine, the Gq-switch-FADGDH complex forms a 30-nm high bulb-shaped structure that changes in the presence of adenosine to give an 8-nm high wire-shaped structure. This structural change brings the FADGDH sufficiently close to the electrode for electron transfer to occur, and the adenosine can be detected from the current produced by the FADGDH. Adenosine was successfully detected with a concentration dependency using the Gq-switch-FADGDH complex immobilized Au electrode by measuring response current to the addition of glucose. Copyright © 2011 Elsevier B.V. All rights reserved.

Damage tolerance of pressurized graphite/epoxy tape cylinders under uniaxial and biaxial loading. M.S. Thesis

NASA Technical Reports Server (NTRS)

Priest, Stacy Marie

1993-01-01

The damage tolerance behavior of internally pressurized, axially slit, graphite/epoxy tape cylinders was investigated. Specifically, the effects of axial stress, structural anisotropy, and subcritical damage were considered. In addition, the limitations of a methodology which uses coupon fracture data to predict cylinder failure were explored. This predictive methodology was previously shown to be valid for quasi-isotropic fabric and tape cylinders but invalid for structurally anisotropic (+/-45/90)(sub s) and (+/-45/0)(sub s) cylinders. The effects of axial stress and structural anisotropy were assessed by testing tape cylinders with (90/0/+/-45)(sub s), (+/-45/90)(sub s), and (+/-45/0)(sub s) layups in a uniaxial test apparatus, specially designed and built for this work, and comparing the results to previous tests conducted in biaxial loading. Structural anisotropy effects were also investigated by testing cylinders with the quasi-isotropic (0/+/-45/90)(sub s) layup which is a stacking sequence variation of the previously tested (90/0/+/-45)(sub s) layup with higher D(sub 16) and D(sub 26) terms but comparable D(sub 16) and D(sub 26) to D(sub 11) ratios. All cylinders tested and used for comparison are made from AS4/3501-6 graphite/epoxy tape and have a diameter of 305 mm. Cylinder slit lengths range from 12.7 to 50.8 mm. Failure pressures are lower for the uniaxially loaded cylinders in all cases. The smallest percent failure pressure decreases are observed for the (+/-45/90)(sub s) cylinders, while the greatest such decreases are observed for the (+/-45/0)(sub s) cylinders. The relative effects of the axial stress on the cylinder failure pressures do not correlate with the degree of structural coupling. The predictive methodology is not applicable for uniaxially loaded (+/-45/90)(sub s) and (+/-45/0)(sub s) cylinders, may be applicable for uniaxially loaded (90/0/+/-45)(sub s) cylinders, and is applicable for the biaxially loaded (90/0/+/-45)(sub s) and (0/+/-45/90)(sub s) cylinders. This indicates that the ratios of D(sub 16) and D(sub 26) to D(sub 11), as opposed to the absolute magnitudes of D(sub 16) and D(sub 26), may be important in the failure of these cylinders and in the applicability of the methodology. Discontinuities observed in the slit tip hoop strains for all the cylinders tested indicate that subcritical damage can play an important role in the failure of tape cylinders. This role varies with layup and loading condition and is likely coupled to the effects of structural anisotropy. Biaxial failure pressures may exceed the uniaxial values because the axial stress contributes to the formation of 0 deg ply splitting (accompanied by delamination) or similar stress-mitigating subcritical damage. The failure behavior of similar cylinders can also vary as a result of differences in the role of subcritical damage as observed for the case of a biaxially loaded (90/0/+/-45)(sub s) cylinder with a 12.7 mm slit. For this case, the methodology is valid when the initial coupon and cylinder fracture modes agree. However, the methodology underpredicts the failure pressure of the cylinder when a circumferential fracture path, suggestive of a 0 deg ply split, occurs at one slit tip. Thus, the failure behavior of some tape cylinders may be highly sensitive to the initial subcritical damage mechanism. Finite element analyses are recommended to determine how structural anisotropy and axial stress modify the slit tip stress states in cylinders from those found in flat plates since similarity of these stress states is a fundamental assumption of the current predictive methodology.

Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes.

PubMed

Zhao, Junhua; Wang, Guliang; Del Mundo, Imee M; McKinney, Jennifer A; Lu, Xiuli; Bacolla, Albino; Boulware, Stephen B; Zhang, Changsheng; Zhang, Haihua; Ren, Pengyu; Freudenreich, Catherine H; Vasquez, Karen M

2018-01-30

Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Principles underlying the Fourth Power Nature of Structured Shock Waves

NASA Astrophysics Data System (ADS)

Grady, Dennis

2017-06-01

Steady structured shock waves in materials including metals, glasses, compounds and solid mixtures, when represented through plots of Hugoniot stress against a measure of the strain rate through which the Hugoniot state is achieved, have consistently demonstrated a dependence to the fourth power. A perhaps deeper observation is that the product of the energy dissipated through the transition to the Hugoniot state and the time duration of the Hugoniot state event exhibits invariance independent of the Hugoniot amplitude. Invariance of the energy-time product and the fourth-power trend are to first order equivalent. Further, constancy of this energy-time product is observed in other dynamic critical state failure events including spall fracture, dynamic compaction and adiabatic shear failure. The presentation pursues the necessary background exposing the foregoing shock physics observations and explores possible statistical physics principals that may underlie the collective dynamic observations.

A Micromechanics-Based Method for Multiscale Fatigue Prediction

NASA Astrophysics Data System (ADS)

Moore, John Allan

An estimated 80% of all structural failures are due to mechanical fatigue, often resulting in catastrophic, dangerous and costly failure events. However, an accurate model to predict fatigue remains an elusive goal. One of the major challenges is that fatigue is intrinsically a multiscale process, which is dependent on a structure's geometric design as well as its material's microscale morphology. The following work begins with a microscale study of fatigue nucleation around non- metallic inclusions. Based on this analysis, a novel multiscale method for fatigue predictions is developed. This method simulates macroscale geometries explicitly while concurrently calculating the simplified response of microscale inclusions. Thus, providing adequate detail on multiple scales for accurate fatigue life predictions. The methods herein provide insight into the multiscale nature of fatigue, while also developing a tool to aid in geometric design and material optimization for fatigue critical devices such as biomedical stents and artificial heart valves.

In silico approaches reveal the potential for DNA sequence-dependent histone octamer affinity to influence chromatin structure in vivo.

PubMed

Fraser, Ross M; Allan, James; Simmen, Martin W

2006-12-08

Nucleosome positioning signals embedded within the DNA sequence have the potential to influence the detailed structure of the higher-order chromatin fibre. In two previous studies of long stretches of DNA, encompassing the chicken beta-globin and ovine beta-lactoglobulin genes, respectively, we mapped the relative affinity of every site for the core histone octamer. In both cases a periodic arrangement of the in vitro positioning sites suggests that they might influence the folding of a nucleosome chain into higher-order structure; this hypothesis was borne out in the case of the beta-lactoglobulin gene, where the distribution of the in vitro positioning sites is related to the positions nucleosomes actually occupy in sheep liver cells. Here, we have exploited the in vitro nucleosome positioning datasets to simulate nucleosomal organisation using in silico approaches. We use the high-resolution, quantitative positioning maps to define a one-dimensional positioning energy lattice, which can be populated with a defined number of nucleosomes. Monte Carlo techniques are employed to simulate the behaviour of the model at equilibrium to produce a set of configurations, which provide a probability-based occupancy map. Employing a variety of techniques we show that the occupancy maps are a sensitive function of the histone octamer density (nucleosome repeat length) and find that a minimal change in this property can produce dramatic localised changes in structure. Although simulations generally give rise to regular periodic nucleosomal arrangements, they often show octamer density-dependent discontinuities, which tend to co-localise with sequences that adopt distinctive chromatin structure in vivo. Furthermore, the overall organisation of simulated chromatin structures are more closely related to the situation in vivo than is the original in vitro positioning data, particularly at a nucleosome density corresponding to the in vivo state. Although our model is simplified, we argue that it provides a unique insight into the influence that DNA sequence can have in determining chromatin structure and could serve as a useful basis for the incorporation of other parameters.

RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory.

PubMed

Garcia-Martin, Juan Antonio; Bayegan, Amir H; Dotu, Ivan; Clote, Peter

2016-10-19

RNA inverse folding is the problem of finding one or more sequences that fold into a user-specified target structure s 0 , i.e. whose minimum free energy secondary structure is identical to the target s 0 . Here we consider the ensemble of all RNA sequences that have low free energy with respect to a given target s 0 . We introduce the program RNAdualPF, which computes the dual partition function Z ∗ , defined as the sum of Boltzmann factors exp(-E(a,s 0 )/RT) of all RNA nucleotide sequences a compatible with target structure s 0 . Using RNAdualPF, we efficiently sample RNA sequences that approximately fold into s 0 , where additionally the user can specify IUPAC sequence constraints at certain positions, and whether to include dangles (energy terms for stacked, single-stranded nucleotides). Moreover, since we also compute the dual partition function Z ∗ (k) over all sequences having GC-content k, the user can require that all sampled sequences have a precise, specified GC-content. Using Z ∗ , we compute the dual expected energy 〈E ∗ 〉, and use it to show that natural RNAs from the Rfam 12.0 database have higher minimum free energy than expected, thus suggesting that functional RNAs are under evolutionary pressure to be only marginally thermodynamically stable. We show that C. elegans precursor microRNA (pre-miRNA) is significantly non-robust with respect to mutations, by comparing the robustness of each wild type pre-miRNA sequence with 2000 [resp. 500] sequences of the same GC-content generated by RNAdualPF, which approximately [resp. exactly] fold into the wild type target structure. We confirm and strengthen earlier findings that precursor microRNAs and bacterial small noncoding RNAs display plasticity, a measure of structural diversity. We describe RNAdualPF, which rapidly computes the dual partition function Z ∗ and samples sequences having low energy with respect to a target structure, allowing sequence constraints and specified GC-content. Using different inverse folding software, another group had earlier shown that pre-miRNA is mutationally robust, even controlling for compositional bias. Our opposite conclusion suggests a cautionary note that computationally based insights into molecular evolution may heavily depend on the software used. C/C++-software for RNAdualPF is available at http://bioinformatics.bc.edu/clotelab/RNAdualPF .

Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity

PubMed Central

Luo, Jie; Taylor, Palmer; Losen, Mario; de Baets, Marc H.; Shelton, G. Diane; Lindstrom, Jon

2009-01-01

The main immunogenic region (MIR) is a conformation-dependent region at the extracellular apex of α1 subunits of muscle nicotinic acetylcholine receptor (AChR) that is the target of half or more of the autoantibodies to muscle AChRs in human myasthenia gravis and rat experimental autoimmune myasthenia gravis. By making chimeras of human α1 subunits with α7 subunits, both MIR epitopes recognized by rat mAbs and by the patient-derived human mAb 637 to the MIR were determined to consist of two discontiguous sequences, which are adjacent only in the native conformation. The MIR, including loop α1 67–76 in combination with the N-terminal α helix α1 1–14, conferred high-affinity binding for most rat mAbs to the MIR. However, an additional sequence corresponding to α1 15–32 was required for high-affinity binding of human mAb 637. A water soluble chimera of Aplysia acetylcholine binding protein with the same α1 MIR sequences substituted was recognized by a majority of human, feline, and canine MG sera. The presence of the α1 MIR sequences in α1/α7 chimeras greatly promoted AChR expression and significantly altered the sensitivity to activation. This reveals a structural and functional, as well as antigenic, significance of the MIR. PMID:19890000

Progressive levels of physical dependence to tobacco coincide with changes in the anterior cingulum bundle microstructure.

PubMed

Huang, Wei; DiFranza, Joseph R; Kennedy, David N; Zhang, Nanyin; Ziedonis, Douglas; Ursprung, Sanouri; King, Jean A

2013-01-01

The tobacco withdrawal syndrome indicates the development of neurophysiologic dependence. Clinical evidence indicates that neurophysiologic dependence develops through a set sequence of symptom presentation that can be assessed with a new 3-item survey measure of wanting, craving, and needing tobacco, the Level of Physical Dependence (PD). This study sought to determine if advancing neurophysiologic dependence as measured by the Level of PD correlates with characteristics of white matter structure measured by Fractional Anisotropy (FA). Diffusion-MRI based FA and diffusion tensor imaging probabilistic tractography were used to evaluate 11 smokers and 10 nonsmokers. FA was also examined in relation to two additional measures of dependence severity, the Hooked on Nicotine Checklist (HONC), and the Fagerström Test for Nicotine Dependence (FTND). Among smokers, FA in the left anterior cingulate bundle (ACb) correlated negatively with the Level of PD (r = -0.68, p = 0.02) and HONC scores (r = -0.65, p = 0.03), but the correlation for the FTND did not reach statistical significance (r = -49, p = 0.12). With advancing Levels of PD, the density of streamlines between the ACb and precuneus increased (r = -0.67, p<0.05) and those between the ACb and white matter projecting to the superior-frontal cortex (r = -0.86, p = 0.0006) decreased significantly. The correlations between neural structure and both the clinical Level of PD survey measure and the HONC suggest that the Level of PD and the HONC may reflect the microstructural integrity of white matter, as influenced by tobacco abuse. Given that the Level of PD is measuring a sequence of symptoms of neurophysiologic dependence that develops over time, the correlation between the Level of PD and neural structure suggests that these features might represent neuroplastic changes that develop over time to support the development of neurophysiologic dependence.

Structural failure; International Symposium on Structural Crashworthiness, 2nd, Massachusetts Institute of Technology, Cambridge, June 6-8, 1988, Invited Lectures

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

Wierzbicki, T.; Jones, N.

1989-01-01

The book discusses the fragmentation of solids under dynamic loading, the debris-impact protection of space structures, the controlled fracturing of structures by shock-wave interaction and focusing, the tearing of thin metal sheets, and the dynamic inelastic failure of beams, and dynamic rupture of shells. Consideration is also given to investigations of the failure of brittle and composite materials by numerical methods, the energy absorption of polymer matrix composite structures (frictional effects), the mechanics of deep plastic collapse of thin-walled structures, the denting and bending of tubular beams under local loads, the dynamic bending collapse of strain-softening cantilever beams, and themore » failure of bar structures under repeated loading. Other topics discussed are on the behavior of composite and metallic superstructures under blast loading, the catastrophic failure modes of marine structures, and industrial experience with structural failure.« less

Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure.

PubMed

van Oort, Ralph J; McCauley, Mark D; Dixit, Sayali S; Pereira, Laetitia; Yang, Yi; Respress, Jonathan L; Wang, Qiongling; De Almeida, Angela C; Skapura, Darlene G; Anderson, Mark E; Bers, Donald M; Wehrens, Xander H T

2010-12-21

approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca(2+) release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca(2+) remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. mice in which the S2814 Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca(2+) release events, resulting in reduced sarcoplasmic reticulum Ca(2+) load on confocal microscopy. These Ca(2+) release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca(2+)/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.

Effects of a hospital-based education programme on self-care behaviour, care dependency and quality of life in patients with heart failure--a randomised controlled trial.

PubMed

Köberich, Stefan; Lohrmann, Christa; Mittag, Oskar; Dassen, Theo

2015-06-01

To evaluate the effects of a nurse-led, hospital-based heart failure specific education session with a three-month telephone follow-up on self-care behaviour, care dependency and quality of life for patients with chronic heart failure. Patient education in patients with heart failure is able to promote heart failure-specific self-care, to reduce mortality, morbidity and rehospitalisation rates and to enhance quality of life, especially if heart failure education is embedded in a multidisciplinary approach. Evidence of the effect of a nurse-led self-care education, quality of life and care dependency in addition to standard medical treatment in Germany is lacking. Nonblinded, prospective, single-centre, randomised controlled trial. Sixty-four patients were allocated either to the intervention group or to the control group. Patients in the intervention group received education about heart failure self-care with a consecutive telephone follow-up over three months in addition to standard medical treatment. Patients in the control group received standard medical treatment only. Data of 110 patients (58 in the intervention group and 52 in the control group) with a mean age of 62 years and mean left ventricular ejection fraction of 28·2% could be analysed. Self-care education had a significant influence on overall heart failure self-care but not on quality of life and care dependency. A single education session with a consecutive telephone follow-up is able to improve overall self-care behaviours but not quality of life. Care dependency was not influenced by the education session. The easy to implement and short educational intervention has a positive effect on self-care behaviour for patients with heart failure. However, there was no effect on quality of life and care dependency. To improve quality of life and to influence care dependency, different measures have to be applied. © 2015 John Wiley & Sons Ltd.

Landslide Frequency and Failure Mechanisms at NE Gela Basin (Strait of Sicily)

NASA Astrophysics Data System (ADS)

Kuhlmann, J.; Asioli, A.; Trincardi, F.; Klügel, A.; Huhn, K.

2017-11-01

Despite intense research by both academia and industry, the parameters controlling slope stability at continental margins are often speculated upon. Lack of core recovery and age control on failed sediments prevent the assessment of failure timing/frequency and the role of prefailure architecture as shaped by paleoenvironmental changes. This study uses an integrated chronological framework from two boreholes and complementary ultrahigh-resolution acoustic profiling in order to assess (1) the frequency of submarine landsliding at the continental margin of NE Gela Basin and (2) the associated mechanisms of failure. Accurate age control was achieved through absolute radiocarbon dating and indirect dating relying on isotope stratigraphic and micropaleontological reconstructions. A total of nine major slope failure events have been recognized that occurred within the last 87 kyr ( 10 kyr return frequency), though there is evidence for additional syndepositional, small-scaled transport processes of lower volume. Preferential failure involves translational movement of mudflows along subhorizontal surfaces that are induced by sedimentological changes relating to prefailure stratal architecture. Along with sequence-stratigraphic boundaries reflecting paleoenvironmental fluctuations, recovered core material suggests that intercalated volcaniclastic layers are key to the basal confinement and lateral movement of these events in the study area. Another major predisposing factor is given by rapid loading of fine-grained homogenous strata and successive generation of excess pore pressure, as expressed by several fluid escape structures. Recurrent failure, however, requires repeated generation of favorable conditions, and seismic activity, though low if compared to many other Mediterranean settings, is shown to represent a legitimate trigger mechanism.

Manned space flight nuclear system safety. Volume 3: Reactor system preliminary nuclear safety analysis. Part 2A: Accident model document, appendix

NASA Technical Reports Server (NTRS)

1972-01-01

The detailed abort sequence trees for the reference zirconium hydride (ZrH) reactor power module that have been generated for each phase of the reference Space Base program mission are presented. The trees are graphical representations of causal sequences. Each tree begins with the phase identification and the dichotomy between success and failure. The success branch shows the mission phase objective as being achieved. The failure branch is subdivided, as conditions require, into various primary initiating abort conditions.

Long- and short-time analysis of heartbeat sequences: correlation with mortality risk in congestive heart failure patients.

PubMed

Allegrini, P; Balocchi, R; Chillemi, S; Grigolini, P; Hamilton, P; Maestri, R; Palatella, L; Raffaelli, G

2003-06-01

We analyze RR heartbeat sequences with a dynamic model that satisfactorily reproduces both the long- and the short-time statistical properties of heart beating. These properties are expressed quantitatively by means of two significant parameters, the scaling delta concerning the asymptotic effects of long-range correlation, and the quantity 1-pi establishing the amount of uncorrelated fluctuations. We find a correlation between the position in the phase space (delta, pi) of patients with congestive heart failure and their mortality risk.

Microwave-assisted acid and base hydrolysis of intact proteins containing disulfide bonds for protein sequence analysis by mass spectrometry.

PubMed

Reiz, Bela; Li, Liang

2010-09-01

Controlled hydrolysis of proteins to generate peptide ladders combined with mass spectrometric analysis of the resultant peptides can be used for protein sequencing. In this paper, two methods of improving the microwave-assisted protein hydrolysis process are described to enable rapid sequencing of proteins containing disulfide bonds and increase sequence coverage, respectively. It was demonstrated that proteins containing disulfide bonds could be sequenced by MS analysis by first performing hydrolysis for less than 2 min, followed by 1 h of reduction to release the peptides originally linked by disulfide bonds. It was shown that a strong base could be used as a catalyst for microwave-assisted protein hydrolysis, producing complementary sequence information to that generated by microwave-assisted acid hydrolysis. However, using either acid or base hydrolysis, amide bond breakages in small regions of the polypeptide chains of the model proteins (e.g., cytochrome c and lysozyme) were not detected. Dynamic light scattering measurement of the proteins solubilized in an acid or base indicated that protein-protein interaction or aggregation was not the cause of the failure to hydrolyze certain amide bonds. It was speculated that there were some unknown local structures that might play a role in preventing an acid or base from reacting with the peptide bonds therein. 2010 American Society for Mass Spectrometry. Published by Elsevier Inc. All rights reserved.

Purification and sequence characterization of chondroitin sulfate and dermatan sulfate from fishes.

PubMed

Lin, Na; Mo, Xiaoli; Yang, Yang; Zhang, Hong

2017-04-01

Chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from skins or bones of salmon (Salmo salar), snakehead (Channa argus), monkfish (Lophius litulon) and skipjack tuna (Katsuwonus pelamis). Size, structural sequences and sulfate groups of oligosaccharides in the purified CS and DS could be characterized and identified using high performance liquid chromatography (HPLC) combined with Orbitrap mass spectrometry. CS and DS chain structure varies depending on origin, but motif structure appears consistent. Structures of CS and DS oligosaccharides with different size and sulfate groups were compared between fishes and other animals, and results showed that some minor differences of special structures could be identified by hydrophilic interaction chromatography-liquid chromatography-fourier transform-mass/mass spectrometry (HILIC-LC-FT-MS/MS). For example, data showed that salmon and skipjack CS had a higher percentage content of high-level sulfated oligosaccharides than that porcine CS. In addition, structural information of different origins of CS and DS was analyzed by principal component analysis (PCA) and results showed that CS and DS samples could be differentiated according to their molecular conformation and oligosaccharide fragments information. Understanding CS and DS structure derived from different origins may lead to the production of CS or DS with unique disaccharides or oligosaccharides sequence composition and biological functions.

Novel Mutation in Cytochrome B of Plasmodium falciparum in One of Two Atovaquone-Proguanil Treatment Failures in Travelers Returning From Same Site in Nigeria

PubMed Central

Plucinski, Mateusz M.; Huber, Curtis S.; Akinyi, Sheila; Dalton, Willard; Eschete, Mary; Grady, Katharine; Silva-Flannery, Luciana; Mathison, Blaine A.; Udhayakumar, Venkatachalam; Arguin, Paul M.; Barnwell, John W.

2014-01-01

Background  Atovaquone-proguanil (AP) is the most commonly used treatment for uncomplicated Plasmodium falciparum malaria in the United States. Apparent AP treatment failures were reported 7 months apart in 2 American travelers who stayed in the same compound for foreign workers in Rivers State, Nigeria. Methods  We analyzed pretreatment (day 0) and day of failure samples from both travelers for mutations in the P falciparum cytochrome B (pfcytb) and dihydrofolate reductase (pfdhfr) genes associated with resistance to atovaquone and cycloguanil, the active metabolite of proguanil, respectively. We genotyped the parasites and sequenced their mitochondrial genomes. Results  On day 0, both travelers had proguanil-resistant genotypes but atovaquone-sensitive cytb sequences. Day of failure samples exhibited mutations in cytb for both travelers. One traveler had the common Y268S mutation, whereas the other traveler had a previously unreported mutation, I258M. The travelers had unrelated parasite genotypes and different mitochondrial genomes. Conclusions  Despite the infections likely having been contracted in the same site, there is no evidence that the cases were related. The mutations likely arose independently during the acute infection or treatment. Our results highlight the importance of genotyping parasites and sequencing the full cytb and dhfr genes in AP failures to rule out transmission of AP-resistant strains and identify novel mechanisms of AP resistance. PMID:25734129

Optimal packaging of FIV genomic RNA depends upon a conserved long-range interaction and a palindromic sequence within gag.

PubMed

Rizvi, Tahir A; Kenyon, Julia C; Ali, Jahabar; Aktar, Suriya J; Phillip, Pretty S; Ghazawi, Akela; Mustafa, Farah; Lever, Andrew M L

2010-10-15

The feline immunodeficiency virus (FIV) is a lentivirus that is related to human immunodeficiency virus (HIV), causing a similar pathology in cats. It is a potential small animal model for AIDS and the FIV-based vectors are also being pursued for human gene therapy. Previous studies have mapped the FIV packaging signal (ψ) to two or more discontinuous regions within the 5' 511 nt of the genomic RNA and structural analyses have determined its secondary structure. The 5' and 3' sequences within ψ region interact through extensive long-range interactions (LRIs), including a conserved heptanucleotide interaction between R/U5 and gag. Other secondary structural elements identified include a conserved 150 nt stem-loop (SL2) and a small palindromic stem-loop within gag open reading frame that might act as a viral dimerization initiation site. We have performed extensive mutational analysis of these sequences and structures and ascertained their importance in FIV packaging using a trans-complementation assay. Disrupting the conserved heptanucleotide LRI to prevent base pairing between R/U5 and gag reduced packaging by 2.8-5.5 fold. Restoration of pairing using an alternative, non-wild type (wt) LRI sequence restored RNA packaging and propagation to wt levels, suggesting that it is the structure of the LRI, rather than its sequence, that is important for FIV packaging. Disrupting the palindrome within gag reduced packaging by 1.5-3-fold, but substitution with a different palindromic sequence did not restore packaging completely, suggesting that the sequence of this region as well as its palindromic nature is important. Mutation of individual regions of SL2 did not have a pronounced effect on FIV packaging, suggesting that either it is the structure of SL2 as a whole that is necessary for optimal packaging, or that there is redundancy within this structure. The mutational analysis presented here has further validated the previously predicted RNA secondary structure of FIV ψ. Copyright © 2010 Elsevier Ltd. All rights reserved.

Deciphering the Hidden Informational Content of Protein Sequences

PubMed Central

Liu, Ming; Hua, Qing-xin; Hu, Shi-Quan; Jia, Wenhua; Yang, Yanwu; Saith, Sunil Evan; Whittaker, Jonathan; Arvan, Peter; Weiss, Michael A.

2010-01-01

Protein sequences encode both structure and foldability. Whereas the interrelationship of sequence and structure has been extensively investigated, the origins of folding efficiency are enigmatic. We demonstrate that the folding of proinsulin requires a flexible N-terminal hydrophobic residue that is dispensable for the structure, activity, and stability of the mature hormone. This residue (PheB1 in placental mammals) is variably positioned within crystal structures and exhibits 1H NMR motional narrowing in solution. Despite such flexibility, its deletion impaired insulin chain combination and led in cell culture to formation of non-native disulfide isomers with impaired secretion of the variant proinsulin. Cellular folding and secretion were maintained by hydrophobic substitutions at B1 but markedly perturbed by polar or charged side chains. We propose that, during folding, a hydrophobic side chain at B1 anchors transient long-range interactions by a flexible N-terminal arm (residues B1–B8) to mediate kinetic or thermodynamic partitioning among disulfide intermediates. Evidence for the overall contribution of the arm to folding was obtained by alanine scanning mutagenesis. Together, our findings demonstrate that efficient folding of proinsulin requires N-terminal sequences that are dispensable in the native state. Such arm-dependent folding can be abrogated by mutations associated with β-cell dysfunction and neonatal diabetes mellitus. PMID:20663888

Map showing ground failures from the Greenville/Mount Diablo earthquake sequence of January 1980, Northern California

USGS Publications Warehouse

Wilson, R.C.; Wieczorek, G.F.; Keefer, D.K.; Harp, E.L.; Tannaci, N.E.

1985-01-01

Information about the individual ground failures may be obtained from the map and the brief descriptions in table 1. The following text is a general discussion of the distribution and the mechanisms of the ground failures, followed by a discussion of the effects of wet winter conditions and of topographic amplification on the distribution and mechanisms of slope failure, and it concludes with a description of our (unsuccessful) efforts to locate any ground failures due to liquefaction. The discussion is intended not only to describe the GMDES slope failures but also to place them into the larger general context of seismically induced slope failures.

Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with Alpha-Alpha Domain Architecture that Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence

PubMed Central

Harris, Golda G.; Lombardi, Patrick M.; Pemberton, Travis A.; Matsui, Tsutomu; Weiss, Thomas M.; Cole, Kathryn E.; Köksal, Mustafa; Murphy, Frank V.; Vedula, L. Sangeetha; Chou, Wayne K.W.; Cane, David E.; Christianson, David W.

2015-01-01

Geosmin synthase from Streptomyces coelicolor (ScGS) catalyzes an unusual, metal-dependent terpenoid cyclization and fragmentation reaction sequence. Two distinct active sites are required for catalysis: the N-terminal domain catalyzes the ionization and cyclization of farnesyl diphosphate to form germacradienol and inorganic pyrophosphate (PPi), and the C-terminal domain catalyzes the protonation, cyclization, and fragmentation of germacradienol to form geosmin and acetone through a retro-Prins reaction. A unique αα domain architecture is predicted for ScGS based on amino acid sequence: each domain contains the metal-binding motifs typical of a class I terpenoid cyclase, and each domain requires Mg2+ for catalysis. Here, we report the X-ray crystal structure of the unliganded N-terminal domain of ScGS and the structure of its complex with 3 Mg2+ ions and alendronate. These structures highlight conformational changes required for active site closure and catalysis. Although neither full-length ScGS nor constructs of the C-terminal domain could be crystallized, homology models of the C-terminal domain were constructed based on ~36% sequence identity with the N-terminal domain. Small-angle X-ray scattering experiments yield low resolution molecular envelopes into which the N-terminal domain crystal structure and the C-terminal domain homology model were fit, suggesting possible αα domain architectures as frameworks for bifunctional catalysis. PMID:26598179

Fabric controls on the brittle failure of folded gneiss and schist

NASA Astrophysics Data System (ADS)

Agliardi, Federico; Zanchetta, Stefano; Crosta, Giovanni B.

2014-12-01

We experimentally studied the brittle failure behaviour of folded gneiss and schist. Rock fabric and petrography were characterised by meso-structural analyses, optical microscopy, X-ray diffraction, and SEM imaging. Uniaxial compression, triaxial compression and indirect tension laboratory tests were performed to characterise their strength and stress-strain behaviour. Fracture patterns generated in compression were resolved in 3D through X-ray computed tomography at different resolutions (30 to 625 μm). Uniaxial compression tests revealed relatively low and scattered values of unconfined compressive strength (UCS) and Young's modulus, with no obvious relationships with the orientation of foliation. Samples systematically failed in four brittle modes, involving different combinations of shear fractures along foliation or parallel to fold axial planes, or the development of cm-scale shear zones. Fracture quantification and microstructural analysis show that different failure modes occur depending on the mutual geometrical arrangement and degree of involvement of two distinct physical anisotropies, i.e. the foliation and the fold axial planes. The Axial Plane Anisotropy (APA) is related to micro-scale grain size reduction and shape preferred orientation within quartz-rich domains, and to mechanical rotation or initial crenulation cleavage within phyllosilicate-rich domains at fold hinge zones. In quartz-rich rocks (gneiss), fracture propagation through quartz aggregates forming the APA corresponds to higher fracture energy and strength than found for fracture through phyllosilicate-rich domains. This results in a strong dependence of strength on the failure mode. Conversely, in phyllosilicate-rich rocks (schist), all the failure modes are dominated by the strength of phyllosilicates, resulting in a sharp reduction of strength anisotropy.

Genesis Failure Investigation Report

NASA Technical Reports Server (NTRS)

Klein, John

2004-01-01

The-Genesis mission to collect solar-wind samples and return them to Earth for detailed analysis proceeded successfully for 3.5 years. During reentry on September 8, 2004, a failure in the entry, descent and landing sequence resulted in a crash landing of the Genesis sample return capsule. This document describes the findings of the avionics sub-team that supported the accident investigation of the JPL Failure Review Board.

Edge effects and delamination failures

NASA Technical Reports Server (NTRS)

Herakovich, C. T.

1989-01-01

The fundamental relationship between the morphology of a composite laminate and the resulting free edge effects is explored and related to delamination failures. Cross-ply, angle-ply, and quasi-isotropic laminates are discussed in detail. It is shown that the local mismatch in elastic properties of adjacent layers and the global stacking sequence of a laminate both have a significant influence on the interlaminar stresses and delamination failures.

Distributed collaborative probabilistic design of multi-failure structure with fluid-structure interaction using fuzzy neural network of regression

NASA Astrophysics Data System (ADS)

Song, Lu-Kai; Wen, Jie; Fei, Cheng-Wei; Bai, Guang-Chen

2018-05-01

To improve the computing efficiency and precision of probabilistic design for multi-failure structure, a distributed collaborative probabilistic design method-based fuzzy neural network of regression (FR) (called as DCFRM) is proposed with the integration of distributed collaborative response surface method and fuzzy neural network regression model. The mathematical model of DCFRM is established and the probabilistic design idea with DCFRM is introduced. The probabilistic analysis of turbine blisk involving multi-failure modes (deformation failure, stress failure and strain failure) was investigated by considering fluid-structure interaction with the proposed method. The distribution characteristics, reliability degree, and sensitivity degree of each failure mode and overall failure mode on turbine blisk are obtained, which provides a useful reference for improving the performance and reliability of aeroengine. Through the comparison of methods shows that the DCFRM reshapes the probability of probabilistic analysis for multi-failure structure and improves the computing efficiency while keeping acceptable computational precision. Moreover, the proposed method offers a useful insight for reliability-based design optimization of multi-failure structure and thereby also enriches the theory and method of mechanical reliability design.

Chirality- and sequence-selective successive self-sorting via specific homo- and complementary-duplex formations

PubMed Central

Makiguchi, Wataru; Tanabe, Junki; Yamada, Hidekazu; Iida, Hiroki; Taura, Daisuke; Ousaka, Naoki; Yashima, Eiji

2015-01-01

Self-recognition and self-discrimination within complex mixtures are of fundamental importance in biological systems, which entirely rely on the preprogrammed monomer sequences and homochirality of biological macromolecules. Here we report artificial chirality- and sequence-selective successive self-sorting of chiral dimeric strands bearing carboxylic acid or amidine groups joined by chiral amide linkers with different sequences through homo- and complementary-duplex formations. A mixture of carboxylic acid dimers linked by racemic-1,2-cyclohexane bis-amides with different amide sequences (NHCO or CONH) self-associate to form homoduplexes in a completely sequence-selective way, the structures of which are different from each other depending on the linker amide sequences. The further addition of an enantiopure amide-linked amidine dimer to a mixture of the racemic carboxylic acid dimers resulted in the formation of a single optically pure complementary duplex with a 100% diastereoselectivity and complete sequence specificity stabilized by the amidinium–carboxylate salt bridges, leading to the perfect chirality- and sequence-selective duplex formation. PMID:26051291

Structure of human POFUT2: insights into thrombospondin type 1 repeat fold and O-fucosylation

PubMed Central

Chen, Chun-I; Keusch, Jeremy J; Klein, Dominique; Hess, Daniel; Hofsteenge, Jan; Gut, Heinz

2012-01-01

Protein O-fucosylation is a post-translational modification found on serine/threonine residues of thrombospondin type 1 repeats (TSR). The fucose transfer is catalysed by the enzyme protein O-fucosyltransferase 2 (POFUT2) and >40 human proteins contain the TSR consensus sequence for POFUT2-dependent fucosylation. To better understand O-fucosylation on TSR, we carried out a structural and functional analysis of human POFUT2 and its TSR substrate. Crystal structures of POFUT2 reveal a variation of the classical GT-B fold and identify sugar donor and TSR acceptor binding sites. Structural findings are correlated with steady-state kinetic measurements of wild-type and mutant POFUT2 and TSR and give insight into the catalytic mechanism and substrate specificity. By using an artificial mini-TSR substrate, we show that specificity is not primarily encoded in the TSR protein sequence but rather in the unusual 3D structure of a small part of the TSR. Our findings uncover that recognition of distinct conserved 3D fold motifs can be used as a mechanism to achieve substrate specificity by enzymes modifying completely folded proteins of very wide sequence diversity and biological function. PMID:22588082

Robustness and Vulnerability of Networks with Dynamical Dependency Groups.

PubMed

Bai, Ya-Nan; Huang, Ning; Wang, Lei; Wu, Zhi-Xi

2016-11-28

The dependency property and self-recovery of failure nodes both have great effects on the robustness of networks during the cascading process. Existing investigations focused mainly on the failure mechanism of static dependency groups without considering the time-dependency of interdependent nodes and the recovery mechanism in reality. In this study, we present an evolving network model consisting of failure mechanisms and a recovery mechanism to explore network robustness, where the dependency relations among nodes vary over time. Based on generating function techniques, we provide an analytical framework for random networks with arbitrary degree distribution. In particular, we theoretically find that an abrupt percolation transition exists corresponding to the dynamical dependency groups for a wide range of topologies after initial random removal. Moreover, when the abrupt transition point is above the failure threshold of dependency groups, the evolving network with the larger dependency groups is more vulnerable; when below it, the larger dependency groups make the network more robust. Numerical simulations employing the Erdős-Rényi network and Barabási-Albert scale free network are performed to validate our theoretical results.

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

Yu, Bingbin; Karr, Dale G.; Song, Huimin

It is a fact that developing offshore wind energy has become more and more serious worldwide in recent years. Many of the promising offshore wind farm locations are in cold regions that may have ice cover during wintertime. The challenge of possible ice loads on offshore wind turbines raises the demand of modeling capacity of dynamic wind turbine response under the joint action of ice, wind, wave, and current. The simulation software FAST is an open source computer-aided engineering (CAE) package maintained by the National Renewable Energy Laboratory. In this paper, a new module of FAST for assessing the dynamicmore » response of offshore wind turbines subjected to ice forcing is presented. In the ice module, several models are presented which involve both prescribed forcing and coupled response. For conditions in which the ice forcing is essentially decoupled from the structural response, ice forces are established from existing models for brittle and ductile ice failure. For conditions in which the ice failure and the structural response are coupled, such as lock-in conditions, a rate-dependent ice model is described, which is developed in conjunction with a new modularization framework for FAST. In this paper, analytical ice mechanics models are presented that incorporate ice floe forcing, deformation, and failure. For lower speeds, forces slowly build until the ice strength is reached and ice fails resulting in a quasi-static condition. For intermediate speeds, the ice failure can be coupled with the structural response and resulting in coinciding periods of the ice failure and the structural response. A third regime occurs at high speeds of encounter in which brittle fracturing of the ice feature occurs in a random pattern, which results in a random vibration excitation of the structure. An example wind turbine response is simulated under ice loading of each of the presented models. This module adds to FAST the capabilities for analyzing the response of wind turbines subjected to forces resulting from ice impact on the turbine support structure. The conditions considered in this module are specifically addressed in the International Organization for Standardization (ISO) standard 19906:2010 for arctic offshore structures design consideration. Special consideration of lock-in vibrations is required due to the detrimental effects of such response with regard to fatigue and foundation/soil response. Finally, the use of FAST for transient, time domain simulation with the new ice module is well suited for such analyses.« less

In vitro synthesis of minus-strand RNA by an isolated cereal yellow dwarf virus RNA-dependent RNA polymerase requires VPg and a stem-loop structure at the 3' end of the virus RNA.

PubMed

Osman, Toba A M; Coutts, Robert H A; Buck, Kenneth W

2006-11-01

Cereal yellow dwarf virus (CYDV) RNA has a 5'-terminal genome-linked protein (VPg). We have expressed the VPg region of the CYDV genome in bacteria and used the purified protein (bVPg) to raise an antiserum which was able to detect free VPg in extracts of CYDV-infected oat plants. A template-dependent RNA-dependent RNA polymerase (RdRp) has been produced from a CYDV membrane-bound RNA polymerase by treatment with BAL 31 nuclease. The RdRp was template specific, being able to utilize templates from CYDV plus- and minus-strand RNAs but not those of three unrelated viruses, Red clover necrotic mosaic virus, Cucumber mosaic virus, and Tobacco mosaic virus. RNA synthesis catalyzed by the RdRp required a 3'-terminal GU sequence and the presence of bVPg. Additionally, synthesis of minus-strand RNA on a plus-strand RNA template required the presence of a putative stem-loop structure near the 3' terminus of CYDV RNA. The base-paired stem, a single-nucleotide (A) bulge in the stem, and the sequence of a tetraloop were all required for the template activity. Evidence was produced showing that minus-strand synthesis in vitro was initiated by priming by bVPg at the 3' end of the template. The data are consistent with a model in which the RdRp binds to the stem-loop structure which positions the active site to recognize the 3'-terminal GU sequence for initiation of RNA synthesis by the addition of an A residue to VPg.

Conformation-dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing.

PubMed

Doolan, Kyle M; Colby, David W

2015-01-30

Prion diseases are caused by a structural rearrangement of the cellular prion protein, PrP(C), into a disease-associated conformation, PrP(Sc), which may be distinguished from one another using conformation-specific antibodies. We used mutational scanning by cell-surface display to screen 1341 PrP single point mutants for attenuated interaction with four anti-PrP antibodies, including several with conformational specificity. Single-molecule real-time gene sequencing was used to quantify enrichment of mutants, returning 26,000 high-quality full-length reads for each screened population on average. Relative enrichment of mutants correlated to the magnitude of the change in binding affinity. Mutations that diminished binding of the antibody ICSM18 represented the core of contact residues in the published crystal structure of its complex. A similarly located binding site was identified for D18, comprising discontinuous residues in helix 1 of PrP, brought into close proximity to one another only when the alpha helix is intact. The specificity of these antibodies for the normal form of PrP likely arises from loss of this conformational feature after conversion to the disease-associated form. Intriguingly, 6H4 binding was found to depend on interaction with the same residues, among others, suggesting that its ability to recognize both forms of PrP depends on a structural rearrangement of the antigen. The application of mutational scanning and deep sequencing provides residue-level resolution of positions in the protein-protein interaction interface that are critical for binding, as well as a quantitative measure of the impact of mutations on binding affinity. Copyright © 2014 Elsevier Ltd. All rights reserved.

In Vitro Synthesis of Minus-Strand RNA by an Isolated Cereal Yellow Dwarf Virus RNA-Dependent RNA Polymerase Requires VPg and a Stem-Loop Structure at the 3′ End of the Virus RNA▿

PubMed Central

Osman, Toba A. M.; Coutts, Robert H. A.; Buck, Kenneth W.

2006-01-01

Cereal yellow dwarf virus (CYDV) RNA has a 5′-terminal genome-linked protein (VPg). We have expressed the VPg region of the CYDV genome in bacteria and used the purified protein (bVPg) to raise an antiserum which was able to detect free VPg in extracts of CYDV-infected oat plants. A template-dependent RNA-dependent RNA polymerase (RdRp) has been produced from a CYDV membrane-bound RNA polymerase by treatment with BAL 31 nuclease. The RdRp was template specific, being able to utilize templates from CYDV plus- and minus-strand RNAs but not those of three unrelated viruses, Red clover necrotic mosaic virus, Cucumber mosaic virus, and Tobacco mosaic virus. RNA synthesis catalyzed by the RdRp required a 3′-terminal GU sequence and the presence of bVPg. Additionally, synthesis of minus-strand RNA on a plus-strand RNA template required the presence of a putative stem-loop structure near the 3′ terminus of CYDV RNA. The base-paired stem, a single-nucleotide (A) bulge in the stem, and the sequence of a tetraloop were all required for the template activity. Evidence was produced showing that minus-strand synthesis in vitro was initiated by priming by bVPg at the 3′ end of the template. The data are consistent with a model in which the RdRp binds to the stem-loop structure which positions the active site to recognize the 3′-terminal GU sequence for initiation of RNA synthesis by the addition of an A residue to VPg. PMID:16928757

Characterization of host-dependent mutations of apple fruit crinkle viroid replicating in newly identified experimental hosts suggests maintenance of stem-loop structures in the left-hand half of the molecule is important for replication.

PubMed

Suzuki, Takahiro; Fujibayashi, Misato; Hataya, Tatsuji; Taneda, Akito; He, Ying-Hong; Tsushima, Taro; Duraisamy, Ganesh Selvaraj; Siglová, Kristyna; Matoušek, Jaroslav; Sano, Teruo

2017-03-01

Apple fruit crinkle viroid (AFCVd) is a tentative member of the genus Apscaviroid, family Pospiviroidae. AFCVd has a narrow host range and is known to infect apple, hop and persimmon as natural hosts. In this study, tomato, cucumber and wild hop have been identified as new experimental herbaceous hosts. Foliar symptoms were very mild or virtually undetectable, but fruits of infected tomato were small, cracked and distorted. These symptoms resemble those observed on some AFCVd-sensitive apple cultivars. After transfer to tomato, cucumber and wild hop, sequence changes were detected in a natural AFCVd isolate from hop, and major variants in tomato, cucumber and wild hop differed in 10, 8 or 2 nucleotides, respectively, from the predominant one in the inoculum. The major variants in tomato and cucumber were almost identical, and the one in wild hop was very similar to the one in cultivated hop. Detailed analyses of the host-dependent sequence changes that appear in a naturally occurring AFCVd isolate from hop after transfer to tomato using small RNA deep sequence data and infectivity studies with dimeric RNA transcripts followed by progeny analysis indicate that the major AFCVd variant in tomato emerged by selection of a minor variant present in the inoculum (i.e. hop) followed by one to two host-dependent de novo mutations. Comparison of the secondary structures of major variants in hop, tomato and persimmon after transfer to tomato suggested that maintenance of stem-loop structures in the left-hand half of the molecule is critical for infection.

What factors determine the severity of hepatitis A-related acute liver failure?

PubMed

Ajmera, V; Xia, G; Vaughan, G; Forbi, J C; Ganova-Raeva, L M; Khudyakov, Y; Opio, C K; Taylor, R; Restrepo, R; Munoz, S; Fontana, R J; Lee, W M

2011-07-01

The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were sub-genotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P < 0.01). At another centre, a mother and her son presented with HAV and liver failure within 1 month of each other. Predictors of spontaneous survival included detectable serum HAV RNA, while age, gender, HAV genotype and nucleotide substitutions were not associated with outcome. The more frequent appearance of rapid viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare sub-genotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes. © 2010 Blackwell Publishing Ltd.

What factors determine the severity of hepatitis A-related acute liver failure?

PubMed Central

Ajmera, V.; Xia, G.; Vaughan, G.; Forbi, J. C.; Ganova-Raeva, L. M.; Khudyakov, Y.; Opio, C. K.; Taylor, R.; Restrepo, R.; Munoz, S.; Fontana, R. J.; Lee, W. M.

2016-01-01

SUMMARY The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were subgenotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P < 0.01). At another centre, a mother and her son presented with HAV and liver failure within 1 month of each other. Predictors of spontaneous survival included detectable serum HAV RNA, while age, gender, HAV genotype and nucleotide substitutions were not associated with outcome. The more frequent appearance of rapid viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare subgenotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes. PMID:21143345

A study of graphite-epoxy laminate failures due to high transverse shear strains using the multi-span-beam shear test procedure

NASA Technical Reports Server (NTRS)

Jegley, Dawn C.

1989-01-01

The multi-span-beam shear test procedure is used to study failure mechanisms in graphite-epoxy laminates due to high transverse shear strains induced by severe local bending deformations in test specimens. Results of a series of tests on specimens with a variety of stacking sequences, including some with adhesive interleaving, are presented. These results indicate that laminates with stacking sequences with several + or - 45 and 90 deg plies next to each other are more susceptible to failures due to high transverse shear strains than laminates with + or - 45 and 0 deg plies next to each other or with + or - 45 deg plies next to layers of adhesive interleaving. Results of these tests are compared with analytical results based on finite elements.

Correlation of Local Effects of DNA Sequence and Position of Beta-Alanine Inserts with Polyamide-DNA Complex Binding Affinities and Kinetics

PubMed Central

Wang, Shuo; Nanjunda, Rupesh; Aston, Karl; Bashkin, James K.; Wilson, W. David

2012-01-01

In order to better understand the effects of β-alanine (β) substitution and the number of heterocycles on DNA binding affinity and selectivity, the interactions of an eight-ring hairpin polyamide (PA) and two β derivatives as well as a six-heterocycle analog have been investigated with their cognate DNA sequence, 5′-TGGCTT-3′. Binding selectivity and the effects of β have been investigated with the cognate and five mutant DNAs. A set of powerful and complementary methods have been employed for both energetic and structural evaluations: UV-melting, biosensor-surface plasmon resonance, isothermal titration calorimetry, circular dichroism and a DNA ligation ladder global structure assay. The reduced number of heterocycles in the six-ring PA weakens the binding affinity; however, the smaller PA aggregates significantly less than the larger PAs, and allows us to obtain the binding thermodynamics. The PA-DNA binding enthalpy is large and negative with a large negative ΔCp, and is the primary driving component of the Gibbs free energy. The complete SPR binding results clearly show that β substitutions can substantially weaken the binding affinity of hairpin PAs in a position-dependent manner. More importantly, the changes in PA binding to the mutant DNAs further confirm the position-dependent effects on PA-DNA interaction affinity. Comparison of mutant DNA sequences also shows a different effect in recognition of T•A versus A•T base pairs. The effects of DNA mutations on binding of a single PA as well as the effects of the position of β substitution on binding tell a clear and very important story about sequence dependent binding of PAs to DNA. PMID:23167504

An XRCC4 Splice Mutation Associated With Severe Short Stature, Gonadal Failure, and Early-Onset Metabolic Syndrome

PubMed Central

de Bruin, Christiaan; Mericq, Verónica; Andrew, Shayne F.; van Duyvenvoorde, Hermine A.; Verkaik, Nicole S.; Losekoot, Monique; Porollo, Aleksey; Garcia, Hernán; Kuang, Yi; Hanson, Dan; Clayton, Peter; van Gent, Dik C.; Wit, Jan M.; Hwa, Vivian

2015-01-01

Context: Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly. Objective: To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. Design: Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. Setting: An academic pediatric endocrinology clinic. Patients or Other Participants: Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, −6.8 SD score; P2, −4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28. Intervention(s): Single nucleotide polymorphism microarray and exome sequencing. Results: Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect. Conclusions: In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition. PMID:25742519

Thermal stability characterization of SiC ceramic fibers. II. Fractography and structure

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

Sawyer, L.C.; Chen, R.T.; Haimbach, F.,IV

1986-08-01

SiC ceramic fibers (Nicalon) exhibit tensile strength reduction following thermal treatment in air, argon and nitrogen environments above 1200 C. Grain-size variations have been observed in the treated fibers by X-ray diffraction and electron microscopy. Fractography studies show that strength reduction occurs in all thermal treatments, although the mechanism of fiber failure varies depending upon the specific environment. Structure-property relations will be developed as mechanical testing and fractography of the thermally treated fibers are associated with tensile strength loss mechanisms. 16 references.

Crazing in Polymeric and Composite Systems

DTIC Science & Technology

1988-04-30

Characterization of Random Microstructural Systems , Proceedings, International Conference on Structure, Solid Mechanics and Engineering Design in Civil...AND COMPOSITE SYSTEMS 12. PERSONAL AUTHOR(S) HSIAO, C. C. 13a. TYPE OF REPORT J13b. TIME COVERED 14. DATE OF REPORT (Year, Month, Day) 15. PAGE COUNT...study of the failure of composite systems under stress is important both theoretically and practically. This program aims to develop time dependent

Prediction of beta-turns and beta-turn types by a novel bidirectional Elman-type recurrent neural network with multiple output layers (MOLEBRNN).

PubMed

Kirschner, Andreas; Frishman, Dmitrij

2008-10-01

Prediction of beta-turns from amino acid sequences has long been recognized as an important problem in structural bioinformatics due to their frequent occurrence as well as their structural and functional significance. Because various structural features of proteins are intercorrelated, secondary structure information has been often employed as an additional input for machine learning algorithms while predicting beta-turns. Here we present a novel bidirectional Elman-type recurrent neural network with multiple output layers (MOLEBRNN) capable of predicting multiple mutually dependent structural motifs and demonstrate its efficiency in recognizing three aspects of protein structure: beta-turns, beta-turn types, and secondary structure. The advantage of our method compared to other predictors is that it does not require any external input except for sequence profiles because interdependencies between different structural features are taken into account implicitly during the learning process. In a sevenfold cross-validation experiment on a standard test dataset our method exhibits the total prediction accuracy of 77.9% and the Mathew's Correlation Coefficient of 0.45, the highest performance reported so far. It also outperforms other known methods in delineating individual turn types. We demonstrate how simultaneous prediction of multiple targets influences prediction performance on single targets. The MOLEBRNN presented here is a generic method applicable in a variety of research fields where multiple mutually depending target classes need to be predicted. http://webclu.bio.wzw.tum.de/predator-web/.

Complementary molecular information changes our perception of food web structure

PubMed Central

Wirta, Helena K.; Hebert, Paul D. N.; Kaartinen, Riikka; Prosser, Sean W.; Várkonyi, Gergely; Roslin, Tomas

2014-01-01

How networks of ecological interactions are structured has a major impact on their functioning. However, accurately resolving both the nodes of the webs and the links between them is fraught with difficulties. We ask whether the new resolution conferred by molecular information changes perceptions of network structure. To probe a network of antagonistic interactions in the High Arctic, we use two complementary sources of molecular data: parasitoid DNA sequenced from the tissues of their hosts and host DNA sequenced from the gut of adult parasitoids. The information added by molecular analysis radically changes the properties of interaction structure. Overall, three times as many interaction types were revealed by combining molecular information from parasitoids and hosts with rearing data, versus rearing data alone. At the species level, our results alter the perceived host specificity of parasitoids, the parasitoid load of host species, and the web-wide role of predators with a cryptic lifestyle. As the northernmost network of host–parasitoid interactions quantified, our data point exerts high leverage on global comparisons of food web structure. However, how we view its structure will depend on what information we use: compared with variation among networks quantified at other sites, the properties of our web vary as much or much more depending on the techniques used to reconstruct it. We thus urge ecologists to combine multiple pieces of evidence in assessing the structure of interaction webs, and suggest that current perceptions of interaction structure may be strongly affected by the methods used to construct them. PMID:24449902

G-quadruplex prediction in E. coli genome reveals a conserved putative G-quadruplex-Hairpin-Duplex switch.

PubMed

Kaplan, Oktay I; Berber, Burak; Hekim, Nezih; Doluca, Osman

2016-11-02

Many studies show that short non-coding sequences are widely conserved among regulatory elements. More and more conserved sequences are being discovered since the development of next generation sequencing technology. A common approach to identify conserved sequences with regulatory roles relies on topological changes such as hairpin formation at the DNA or RNA level. G-quadruplexes, non-canonical nucleic acid topologies with little established biological roles, are increasingly considered for conserved regulatory element discovery. Since the tertiary structure of G-quadruplexes is strongly dependent on the loop sequence which is disregarded by the generally accepted algorithm, we hypothesized that G-quadruplexes with similar topology and, indirectly, similar interaction patterns, can be determined using phylogenetic clustering based on differences in the loop sequences. Phylogenetic analysis of 52 G-quadruplex forming sequences in the Escherichia coli genome revealed two conserved G-quadruplex motifs with a potential regulatory role. Further analysis revealed that both motifs tend to form hairpins and G quadruplexes, as supported by circular dichroism studies. The phylogenetic analysis as described in this work can greatly improve the discovery of functional G-quadruplex structures and may explain unknown regulatory patterns. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

The production of Multiple Small Peptaibol Families by Single 14-Module Peptide Synthetases in Trichoderma/Hypocrea

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

Degenkolb, Thomas; Aghchehb, Razieh Karimi; Dieckmann, Ralf

2012-03-01

The most common peptaibibiotic structures are 11-residue peptaibols found widely distributed in the genus Trichoderma/Hypocrea. Frequently associated are 14-residue peptaibols sharing partial sequence identity. Genome sequencing projects of 3 Trichoderma strains of the major clades reveal the presence of up to 3 types of nonribosomal peptide synthetases with 7, 14, or 18-20 amino acid adding modules. We here provide evidence that the 14-module NRPS type found in T. virens, T. reesei (teleomorph Hypocrea jecorina) and T. atroviride produces both 11- and 14- residue peptaibols based on the disruption of the respective NRPS gene of T. reesei, and bioinformatic analysis ofmore » their amino acid activating domains and modules. The structures of these peptides may be predicted from the gene structures and have been confirmed by analysis of families of 11- and 14-residue peptaibols from the strain 618, termed hypojecorins A (23 sequences determined, 4 new) and B (3 new sequences), and the recently established trichovirins A from T. virens. The distribution of 11- and 14-residue products is strain-specific and depends on growth conditions as well. Possible mechanisms of module skipping are discussed.« less

Inability of Prevotella bryantii to Form a Functional Shine-Dalgarno Interaction Reflects Unique Evolution of Ribosome Binding Sites in Bacteroidetes

PubMed Central

Accetto, Tomaž; Avguštin, Gorazd

2011-01-01

The Shine-Dalgarno (SD) sequence is a key element directing the translation to initiate at the authentic start codons and also enabling translation initiation to proceed in 5′ untranslated mRNA regions (5′-UTRs) containing moderately strong secondary structures. Bioinformatic analysis of almost forty genomes from the major bacterial phylum Bacteroidetes revealed, however, a general absence of SD sequence, drop in GC content and consequently reduced tendency to form secondary structures in 5′-UTRs. The experiments using the Prevotella bryantii TC1-1 expression system were in agreement with these findings: neither addition nor omission of SD sequence in the unstructured 5′-UTR affected the level of the reporter protein, non-specific nuclease NucB. Further, NucB level in P. bryantii TC1-1, contrary to hMGFP level in Escherichia coli, was five times lower when SD sequence formed part of the secondary structure with a folding energy -5,2 kcal/mol. Also, the extended SD sequences did not affect protein levels as in E. coli. It seems therefore that a functional SD interaction does not take place during the translation initiation in P. bryanttii TC1-1 and possibly other members of phylum Bacteroidetes although the anti SD sequence is present in 16S rRNA genes of their genomes. We thus propose that in the absence of the SD sequence interaction, the selection of genuine start codons in Bacteroidetes is accomplished by binding of ribosomal protein S1 to unstructured 5′-UTR as opposed to coding region which is inaccessible due to mRNA secondary structure. Additionally, we found that sequence logos of region preceding the start codons may be used as taxonomical markers. Depending on whether complete sequence logo or only part of it, such as information content and base proportion at specific positions, is used, bacterial genera or families and in some cases even bacterial phyla can be distinguished. PMID:21857964

Selection of homeotic proteins for binding to a human DNA replication origin.

PubMed

de Stanchina, E; Gabellini, D; Norio, P; Giacca, M; Peverali, F A; Riva, S; Falaschi, A; Biamonti, G

2000-06-09

We have previously shown that a cell cycle-dependent nucleoprotein complex assembles in vivo on a 74 bp sequence within the human DNA replication origin associated to the Lamin B2 gene. Here, we report the identification, using a one-hybrid screen in yeast, of three proteins interacting with the 74 bp sequence. All of them, namely HOXA13, HOXC10 and HOXC13, are orthologues of the Abdominal-B gene of Drosophila melanogaster and are members of the homeogene family of developmental regulators. We describe the complete open reading frame sequence of HOXC10 and HOXC13 along with the structure of the HoxC13 gene. The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. We also show that HOXC10 expression is cell-type-dependent and positively correlates with cell proliferation. Copyright 2000 Academic Press.

System reliability approaches for advanced propulsion system structures

NASA Technical Reports Server (NTRS)

Cruse, T. A.; Mahadevan, S.

1991-01-01

This paper identifies significant issues that pertain to the estimation and use of system reliability in the design of advanced propulsion system structures. Linkages between the reliabilities of individual components and their effect on system design issues such as performance, cost, availability, and certification are examined. The need for system reliability computation to address the continuum nature of propulsion system structures and synergistic progressive damage modes has been highlighted. Available system reliability models are observed to apply only to discrete systems. Therefore a sequential structural reanalysis procedure is formulated to rigorously compute the conditional dependencies between various failure modes. The method is developed in a manner that supports both top-down and bottom-up analyses in system reliability.

Con Edison power failure of July 13 and 14, 1977. Final staff report

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

None

1978-06-01

On July 13, 1977 the entire electric load of the Con Edison system was lost, plunging New York City and Westchester County into darkness. The collapse resulted from a combination of natural events, equipment malfunctions, questionable system-design features, and operating errors. An attempt is made in this report to answer the following: what were the specific causes of the failure; if equipment malfunctions and operator errors contributed, could they have been prevented; to what extent was Con Edison prepared to handle such an emergency; and did Con Edison plan prudently reserve generation, for reserve transmission capability, for automatic equipment tomore » protect its system, and for proper operator response to a critical situation. Following the introductory and summary section, additional sections include: the Consolidated Edison system; prevention of bulk power-supply interruptions; the sequence of failure and restoration; analysis of the July 1977 power failure; restoration sequence and equipment damage assessment; and other investigations of the blackout. (MCW)« less

Scale effects in the response and failure of fiber reinforced composite laminates loaded in tension and in flexure

NASA Technical Reports Server (NTRS)

Jackson, Karen E.; Kellas, Sotiris; Morton, John

1992-01-01

The feasibility of using scale model testing for predicting the full-scale behavior of flat composite coupons loaded in tension and beam-columns loaded in flexure is examined. Classical laws of similitude are applied to fabricate and test replica model specimens to identify scaling effects in the load response, strength, and mode of failure. Experiments were performed on graphite-epoxy composite specimens having different laminate stacking sequences and a range of scaled sizes. From the experiments it was deduced that the elastic response of scaled composite specimens was independent of size. However, a significant scale effect in strength was observed. In addition, a transition in failure mode was observed among scaled specimens of certain laminate stacking sequences. A Weibull statistical model and a fracture mechanics based model were applied to predict the strength scale effect since standard failure criteria cannot account for the influence of absolute specimen size on strength.

Sequence features of viral and human Internal Ribosome Entry Sites predictive of their activity

PubMed Central

Elias-Kirma, Shani; Nir, Ronit; Segal, Eran

2017-01-01

Translation of mRNAs through Internal Ribosome Entry Sites (IRESs) has emerged as a prominent mechanism of cellular and viral initiation. It supports cap-independent translation of select cellular genes under normal conditions, and in conditions when cap-dependent translation is inhibited. IRES structure and sequence are believed to be involved in this process. However due to the small number of IRESs known, there have been no systematic investigations of the determinants of IRES activity. With the recent discovery of thousands of novel IRESs in human and viruses, the next challenge is to decipher the sequence determinants of IRES activity. We present the first in-depth computational analysis of a large body of IRESs, exploring RNA sequence features predictive of IRES activity. We identified predictive k-mer features resembling IRES trans-acting factor (ITAF) binding motifs across human and viral IRESs, and found that their effect on expression depends on their sequence, number and position. Our results also suggest that the architecture of retroviral IRESs differs from that of other viruses, presumably due to their exposure to the nuclear environment. Finally, we measured IRES activity of synthetically designed sequences to confirm our prediction of increasing activity as a function of the number of short IRES elements. PMID:28922394

Creep Life of Ceramic Components Using a Finite-Element-Based Integrated Design Program (CARES/CREEP)

NASA Technical Reports Server (NTRS)

Powers, L. M.; Jadaan, O. M.; Gyekenyesi, J. P.

1998-01-01

The desirable properties of ceramics at high temperatures have generated interest in their use for structural application such as in advanced turbine engine systems. Design lives for such systems can exceed 10,000 hours. The long life requirement necessitates subjecting the components to relatively low stresses. The combination of high temperatures and low stresses typically places failure for monolithic ceramics in the creep regime. The objective of this paper is to present a design methodology for predicting the lifetimes of structural components subjected to creep rupture conditions. This methodology utilizes commercially available finite element packages and takes into account the time-varying creep strain distributions (stress relaxation). The creep life, of a component is discretized into short time steps, during which the stress and strain distributions are assumed constant. The damage is calculated for each time step based on a modified Monkman-Grant creep rupture criterion. Failure is assumed to occur when the normalized accumulated damage at any point in the component is greater than or equal to unity. The corresponding time will be the creep rupture life for that component. Examples are chosen to demonstrate the Ceramics Analysis and Reliability Evaluation of Structures/CREEP (CARES/CREEP) integrated design program, which is written for the ANSYS finite element package. Depending on the component size and loading conditions, it was found that in real structures one of two competing failure modes (creep or slow crack growth) will dominate. Applications to benchmark problems and engine components are included.

Creep Life of Ceramic Components Using a Finite-Element-Based Integrated Design Program (CARES/CREEP)

NASA Technical Reports Server (NTRS)

Gyekenyesi, J. P.; Powers, L. M.; Jadaan, O. M.

1998-01-01

The desirable properties of ceramics at high temperatures have generated interest in their use for structural applications such as in advanced turbine systems. Design lives for such systems can exceed 10,000 hours. The long life requirement necessitates subjecting the components to relatively low stresses. The combination of high temperatures and low stresses typically places failure for monolithic ceramics in the creep regime. The objective of this paper is to present a design methodology for predicting the lifetimes of structural components subjected to creep rupture conditions. This methodology utilized commercially available finite element packages and takes into account the time-varying creep strain distributions (stress relaxation). The creep life of a component is discretized into short time steps, during which the stress and strain distributions are assumed constant. The damage is calculated for each time step based on a modified Monkman-Grant creep rupture criterion. Failure is assumed to occur when the normalized accumulated damage at any point in the component is greater than or equal to unity. The corresponding time will be the creep rupture life for that component. Examples are chosen to demonstrate the CARES/CREEP (Ceramics Analysis and Reliability Evaluation of Structures/CREEP) integrated design programs, which is written for the ANSYS finite element package. Depending on the component size and loading conditions, it was found that in real structures one of two competing failure modes (creep or slow crack growth) will dominate. Applications to benechmark problems and engine components are included.

Loading mode dependent effective properties of octet-truss lattice structures using 3D-printing

NASA Astrophysics Data System (ADS)

Challapalli, Adithya

Cellular materials, often called lattice materials, are increasingly receiving attention for their ultralight structures with high specific strength, excellent impact absorption, acoustic insulation, heat dissipation media and compact heat exchangers. In alignment with emerging additive manufacturing (AM) technology, realization of the structural applications of the lattice materials appears to be becoming faster. Considering the direction dependent material properties of the products with AM, by directionally dependent printing resolution, effective moduli of lattice structures appear to be directionally dependent. In this paper, a constitutive model of a lattice structure, which is an octet-truss with a base material having an orthotropic material property considering AM is developed. In a case study, polyjet based 3D printing material having an orthotropic property with a 9% difference in the principal direction provides difference in the axial and shear moduli in the octet-truss by 2.3 and 4.6%. Experimental validation for the effective properties of a 3D printed octet-truss is done for uniaxial tension and compression test. The theoretical value based on the micro-buckling of truss member are used to estimate the failure strength. Modulus value appears a little overestimate compared with the experiment. Finite element (FE) simulations for uniaxial compression and tension of octettruss lattice materials are conducted. New effective properties for the octet-truss lattice structure are developed considering the observed behavior of the octet-truss structure under macroscopic compression and tension trough simulations.

High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA.

PubMed

Chandrananda, Dineika; Thorne, Natalie P; Bahlo, Melanie

2015-06-17

High-throughput sequencing of cell-free DNA fragments found in human plasma has been used to non-invasively detect fetal aneuploidy, monitor organ transplants and investigate tumor DNA. However, many biological properties of this extracellular genetic material remain unknown. Research that further characterizes circulating DNA could substantially increase its diagnostic value by allowing the application of more sophisticated bioinformatics tools that lead to an improved signal to noise ratio in the sequencing data. In this study, we investigate various features of cell-free DNA in plasma using deep-sequencing data from two pregnant women (>70X, >50X) and compare them with matched cellular DNA. We utilize a descriptive approach to examine how the biological cleavage of cell-free DNA affects different sequence signatures such as fragment lengths, sequence motifs at fragment ends and the distribution of cleavage sites along the genome. We show that the size distributions of these cell-free DNA molecules are dependent on their autosomal and mitochondrial origin as well as the genomic location within chromosomes. DNA mapping to particular microsatellites and alpha repeat elements display unique size signatures. We show how cell-free fragments occur in clusters along the genome, localizing to nucleosomal arrays and are preferentially cleaved at linker regions by correlating the mapping locations of these fragments with ENCODE annotation of chromatin organization. Our work further demonstrates that cell-free autosomal DNA cleavage is sequence dependent. The region spanning up to 10 positions on either side of the DNA cleavage site show a consistent pattern of preference for specific nucleotides. This sequence motif is present in cleavage sites localized to nucleosomal cores and linker regions but is absent in nucleosome-free mitochondrial DNA. These background signals in cell-free DNA sequencing data stem from the non-random biological cleavage of these fragments. This sequence structure can be harnessed to improve bioinformatics algorithms, in particular for CNV and structural variant detection. Descriptive measures for cell-free DNA features developed here could also be used in biomarker analysis to monitor the changes that occur during different pathological conditions.

History dependence in insect flight decisions during odor tracking.

PubMed

Pang, Rich; van Breugel, Floris; Dickinson, Michael; Riffell, Jeffrey A; Fairhall, Adrienne

2018-02-01

Natural decision-making often involves extended decision sequences in response to variable stimuli with complex structure. As an example, many animals follow odor plumes to locate food sources or mates, but turbulence breaks up the advected odor signal into intermittent filaments and puffs. This scenario provides an opportunity to ask how animals use sparse, instantaneous, and stochastic signal encounters to generate goal-oriented behavioral sequences. Here we examined the trajectories of flying fruit flies (Drosophila melanogaster) and mosquitoes (Aedes aegypti) navigating in controlled plumes of attractive odorants. While it is known that mean odor-triggered flight responses are dominated by upwind turns, individual responses are highly variable. We asked whether deviations from mean responses depended on specific features of odor encounters, and found that odor-triggered turns were slightly but significantly modulated by two features of odor encounters. First, encounters with higher concentrations triggered stronger upwind turns. Second, encounters occurring later in a sequence triggered weaker upwind turns. To contextualize the latter history dependence theoretically, we examined trajectories simulated from three normative tracking strategies. We found that neither a purely reactive strategy nor a strategy in which the tracker learned the plume centerline over time captured the observed history dependence. In contrast, "infotaxis", in which flight decisions maximized expected information gain about source location, exhibited a history dependence aligned in sign with the data, though much larger in magnitude. These findings suggest that while true plume tracking is dominated by a reactive odor response it might also involve a history-dependent modulation of responses consistent with the accumulation of information about a source over multi-encounter timescales. This suggests that short-term memory processes modulating decision sequences may play a role in natural plume tracking.

History dependence in insect flight decisions during odor tracking

PubMed Central

van Breugel, Floris; Dickinson, Michael; Riffell, Jeffrey A.; Fairhall, Adrienne

2018-01-01

Natural decision-making often involves extended decision sequences in response to variable stimuli with complex structure. As an example, many animals follow odor plumes to locate food sources or mates, but turbulence breaks up the advected odor signal into intermittent filaments and puffs. This scenario provides an opportunity to ask how animals use sparse, instantaneous, and stochastic signal encounters to generate goal-oriented behavioral sequences. Here we examined the trajectories of flying fruit flies (Drosophila melanogaster) and mosquitoes (Aedes aegypti) navigating in controlled plumes of attractive odorants. While it is known that mean odor-triggered flight responses are dominated by upwind turns, individual responses are highly variable. We asked whether deviations from mean responses depended on specific features of odor encounters, and found that odor-triggered turns were slightly but significantly modulated by two features of odor encounters. First, encounters with higher concentrations triggered stronger upwind turns. Second, encounters occurring later in a sequence triggered weaker upwind turns. To contextualize the latter history dependence theoretically, we examined trajectories simulated from three normative tracking strategies. We found that neither a purely reactive strategy nor a strategy in which the tracker learned the plume centerline over time captured the observed history dependence. In contrast, “infotaxis”, in which flight decisions maximized expected information gain about source location, exhibited a history dependence aligned in sign with the data, though much larger in magnitude. These findings suggest that while true plume tracking is dominated by a reactive odor response it might also involve a history-dependent modulation of responses consistent with the accumulation of information about a source over multi-encounter timescales. This suggests that short-term memory processes modulating decision sequences may play a role in natural plume tracking. PMID:29432454

Dual Megathrust Slip Behaviors of the 2014 Iquique Earthquake Sequence

NASA Astrophysics Data System (ADS)

Meng, L.; Huang, H.; Burgmann, R.; Ampuero, J. P.; Strader, A. E.

2014-12-01

The transition between seismic rupture and aseismic creep is of central interest to better understand the mechanics of subduction processes. A M 8.2 earthquake occurred on April 1st, 2014 in the Iquique seismic gap of Northern Chile. This event was preceded by a 2-week-long foreshock sequence including a M 6.7 earthquake. Repeating earthquakes are found among the foreshock sequence that migrated towards the mainshock area, suggesting a large scale slow-slip event on the megathrust preceding the mainshock. The variations of the recurrence time of repeating earthquakes highlights the diverse seismic and aseismic slip behaviors on different megathrust segments. The repeaters that were active only before the mainshock recurred more often and were distributed in areas of substantial coseismic slip, while other repeaters occurred both before and after the mainshock in the area complementary to the mainshock rupture. The spatial and temporal distribution of the repeating earthquakes illustrate the essential role of propagating aseismic slip in leading up to the mainshock and aftershock activities. Various finite fault models indicate that the coseismic slip generally occurred down-dip from the foreshock activity and the mainshock hypocenter. Source imaging by teleseismic back-projection indicates an initial down-dip propagation stage followed by a rupture-expansion stage. In the first stage, the finite fault models show slow initiation with low amplitude moment rate at low frequency (< 0.1 Hz), while back-projection shows a steady initiation at high frequency (> 0.5 Hz). This indicates frequency-dependent manifestations of seismic radiation in the low-stress foreshock region. In the second stage, the high-frequency rupture remains within an area of low gravity anomaly, suggesting possible upper-crustal structures that promote high-frequency generation. Back-projection also shows an episode of reverse rupture propagation which suggests a delayed failure of asperities in the foreshock area. Our results highlight the complexity of the interactions between large-scale aseismic slow-slip and dynamic ruptures of megathrust earthquakes.

Stepwise Mechanism of Temperature-Dependent Coacervation of the Elastin-like Peptide Analogue Dimer, (C(WPGVG)3)2.

PubMed

Tatsubo, Daiki; Suyama, Keitaro; Miyazaki, Masaya; Maeda, Iori; Nose, Takeru

2018-03-13

Elastin-like peptides (ELPs) are distinct, repetitive, hydrophobic sequences, such as (VPGVG) n , that exhibit coacervation, the property of reversible, temperature-dependent self-association and dissociation. ELPs can be found in elastin and have been developed as new scaffold biomaterials. However, the detailed relationship between their amino acid sequences and coacervation properties remains obscure because of the structural flexibility of ELPs. In this study, we synthesized a novel, dimeric ELP analogue (H-C(WPGVG) 3 -NH 2 ) 2 , henceforth abbreviated (CW3)2, and analyzed its self-assembly properties and structural factors as indicators of coacervation. Turbidity measurements showed that (CW3)2 demonstrated coacervation at a concentration much lower than that of its monomeric form and another ELP. In addition, the coacervate held water-soluble dye molecules. Thus, potent and distinct coacervation was obtained with a remarkably short sequence of (CW3)2. Furthermore, fluorescence microscopy, dynamic light scattering, and optical microscopy revealed that the coacervation of (CW3)2 was a stepwise process. The structural factors of (CW3)2 were analyzed by molecular dynamics simulations and circular dichroism spectroscopy. These measurements indicated that helical structures primarily consisting of proline and glycine became more disordered at high temperatures with concurrent, significant exposure of their hydrophobic surfaces. This extreme change in the hydrophobic surface contributes to the potent coacervation observed for (CW3)2. These results provide important insights into more efficient applications of ELPs and their analogues, as well as the coacervation mechanisms of ELP and elastin.

Insights into the Aggregation Mechanism of PolyQ Proteins with Different Glutamine Repeat Lengths.

PubMed

Yushchenko, Tetyana; Deuerling, Elke; Hauser, Karin

2018-04-24

Polyglutamine (polyQ) diseases, including Huntington's disease, result from the aggregation of an abnormally expanded polyQ repeat in the affected protein. The length of the polyQ repeat is essential for the disease's onset; however, the molecular mechanism of polyQ aggregation is still poorly understood. Controlled conditions and initiation of the aggregation process are prerequisites for the detection of transient intermediate states. We present an attenuated total reflection Fourier-transform infrared spectroscopic approach combined with protein immobilization to study polyQ aggregation dependent on the polyQ length. PolyQ proteins were engineered mimicking the mammalian N-terminus fragment of the Huntingtin protein and containing a polyQ sequence with the number of glutamines below (Q11), close to (Q38), and above (Q56) the disease threshold. A monolayer of the polyQ construct was chemically immobilized on the internal reflection element of the attenuated total reflection cell, and the aggregation was initiated via enzymatic cleavage. Structural changes of the polyQ sequence were monitored by time-resolved infrared difference spectroscopy. We observed faster aggregation kinetics for the longer sequences, and furthermore, we could distinguish β-structured intermediates for the different constructs, allowing us to propose aggregation mechanisms dependent on the repeat length. Q11 forms a β-structured aggregate by intermolecular interaction of stretched monomers, whereas Q38 and Q56 undergo conformational changes to various β-structured intermediates, including intramolecular β-sheets. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Comparison of topological clustering within protein networks using edge metrics that evaluate full sequence, full structure, and active site microenvironment similarity.

PubMed

Leuthaeuser, Janelle B; Knutson, Stacy T; Kumar, Kiran; Babbitt, Patricia C; Fetrow, Jacquelyn S

2015-09-01

The development of accurate protein function annotation methods has emerged as a major unsolved biological problem. Protein similarity networks, one approach to function annotation via annotation transfer, group proteins into similarity-based clusters. An underlying assumption is that the edge metric used to identify such clusters correlates with functional information. In this contribution, this assumption is evaluated by observing topologies in similarity networks using three different edge metrics: sequence (BLAST), structure (TM-Align), and active site similarity (active site profiling, implemented in DASP). Network topologies for four well-studied protein superfamilies (enolase, peroxiredoxin (Prx), glutathione transferase (GST), and crotonase) were compared with curated functional hierarchies and structure. As expected, network topology differs, depending on edge metric; comparison of topologies provides valuable information on structure/function relationships. Subnetworks based on active site similarity correlate with known functional hierarchies at a single edge threshold more often than sequence- or structure-based networks. Sequence- and structure-based networks are useful for identifying sequence and domain similarities and differences; therefore, it is important to consider the clustering goal before deciding appropriate edge metric. Further, conserved active site residues identified in enolase and GST active site subnetworks correspond with published functionally important residues. Extension of this analysis yields predictions of functionally determinant residues for GST subgroups. These results support the hypothesis that active site similarity-based networks reveal clusters that share functional details and lay the foundation for capturing functionally relevant hierarchies using an approach that is both automatable and can deliver greater precision in function annotation than current similarity-based methods. © 2015 The Authors Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society.

Comparison of topological clustering within protein networks using edge metrics that evaluate full sequence, full structure, and active site microenvironment similarity

PubMed Central

Leuthaeuser, Janelle B; Knutson, Stacy T; Kumar, Kiran; Babbitt, Patricia C; Fetrow, Jacquelyn S

2015-01-01

The development of accurate protein function annotation methods has emerged as a major unsolved biological problem. Protein similarity networks, one approach to function annotation via annotation transfer, group proteins into similarity-based clusters. An underlying assumption is that the edge metric used to identify such clusters correlates with functional information. In this contribution, this assumption is evaluated by observing topologies in similarity networks using three different edge metrics: sequence (BLAST), structure (TM-Align), and active site similarity (active site profiling, implemented in DASP). Network topologies for four well-studied protein superfamilies (enolase, peroxiredoxin (Prx), glutathione transferase (GST), and crotonase) were compared with curated functional hierarchies and structure. As expected, network topology differs, depending on edge metric; comparison of topologies provides valuable information on structure/function relationships. Subnetworks based on active site similarity correlate with known functional hierarchies at a single edge threshold more often than sequence- or structure-based networks. Sequence- and structure-based networks are useful for identifying sequence and domain similarities and differences; therefore, it is important to consider the clustering goal before deciding appropriate edge metric. Further, conserved active site residues identified in enolase and GST active site subnetworks correspond with published functionally important residues. Extension of this analysis yields predictions of functionally determinant residues for GST subgroups. These results support the hypothesis that active site similarity-based networks reveal clusters that share functional details and lay the foundation for capturing functionally relevant hierarchies using an approach that is both automatable and can deliver greater precision in function annotation than current similarity-based methods. PMID:26073648

RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution.

PubMed

Venkataraman, Sangita; Prasad, Burra V L S; Selvarajan, Ramasamy

2018-02-10

RNA dependent RNA polymerase (RdRp) is one of the most versatile enzymes of RNA viruses that is indispensable for replicating the genome as well as for carrying out transcription. The core structural features of RdRps are conserved, despite the divergence in their sequences. The structure of RdRp resembles that of a cupped right hand and consists of fingers, palm and thumb subdomains. The catalysis involves the participation of conserved aspartates and divalent metal ions. Complexes of RdRps with substrates, inhibitors and metal ions provide a comprehensive view of their functional mechanism and offer valuable insights regarding the development of antivirals. In this article, we provide an overview of the structural aspects of RdRps and their complexes from the Group III, IV and V viruses and their structure-based phylogeny.

RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution

PubMed Central

Venkataraman, Sangita; Prasad, Burra V L S; Selvarajan, Ramasamy

2018-01-01

RNA dependent RNA polymerase (RdRp) is one of the most versatile enzymes of RNA viruses that is indispensable for replicating the genome as well as for carrying out transcription. The core structural features of RdRps are conserved, despite the divergence in their sequences. The structure of RdRp resembles that of a cupped right hand and consists of fingers, palm and thumb subdomains. The catalysis involves the participation of conserved aspartates and divalent metal ions. Complexes of RdRps with substrates, inhibitors and metal ions provide a comprehensive view of their functional mechanism and offer valuable insights regarding the development of antivirals. In this article, we provide an overview of the structural aspects of RdRps and their complexes from the Group III, IV and V viruses and their structure-based phylogeny. PMID:29439438

Optical Sensing of the Fatigue Damage State of CFRP under Realistic Aeronautical Load Sequences

PubMed Central

Zuluaga-Ramírez, Pablo; Arconada, Álvaro; Frövel, Malte; Belenguer, Tomás; Salazar, Félix

2015-01-01

We present an optical sensing methodology to estimate the fatigue damage state of structures made of carbon fiber reinforced polymer (CFRP), by measuring variations on the surface roughness. Variable amplitude loads (VAL), which represent realistic loads during aeronautical missions of fighter aircraft (FALSTAFF) have been applied to coupons until failure. Stiffness degradation and surface roughness variations have been measured during the life of the coupons obtaining a Pearson correlation of 0.75 between both variables. The data were compared with a previous study for Constant Amplitude Load (CAL) obtaining similar results. Conclusions suggest that the surface roughness measured in strategic zones is a useful technique for structural health monitoring of CFRP structures, and that it is independent of the type of load applied. Surface roughness can be measured in the field by optical techniques such as speckle, confocal perfilometers and interferometry, among others. PMID:25760056

Sensitivity study on durability variables of marine concrete structures

NASA Astrophysics Data System (ADS)

Zhou, Xin'gang; Li, Kefei

2013-06-01

In order to study the influence of parameters on durability of marine concrete structures, the parameter's sensitivity analysis was studied in this paper. With the Fick's 2nd law of diffusion and the deterministic sensitivity analysis method (DSA), the sensitivity factors of apparent surface chloride content, apparent chloride diffusion coefficient and its time dependent attenuation factor were analyzed. The results of the analysis show that the impact of design variables on concrete durability was different. The values of sensitivity factor of chloride diffusion coefficient and its time dependent attenuation factor were higher than others. Relative less error in chloride diffusion coefficient and its time dependent attenuation coefficient induces a bigger error in concrete durability design and life prediction. According to probability sensitivity analysis (PSA), the influence of mean value and variance of concrete durability design variables on the durability failure probability was studied. The results of the study provide quantitative measures of the importance of concrete durability design and life prediction variables. It was concluded that the chloride diffusion coefficient and its time dependent attenuation factor have more influence on the reliability of marine concrete structural durability. In durability design and life prediction of marine concrete structures, it was very important to reduce the measure and statistic error of durability design variables.

The Structure of the RNA-Dependent RNA Polymerase of a Permutotetravirus Suggests a Link between Primer-Dependent and Primer-Independent Polymerases

PubMed Central

Ferrero, Diego S.; Buxaderas, Mònica; Rodríguez, José F.; Verdaguer, Núria

2015-01-01

Thosea asigna virus (TaV), an insect virus belonging to the Permutatetraviridae family, has a positive-sense single-stranded RNA (ssRNA) genome with two overlapping open reading frames, encoding for the replicase and capsid proteins. The particular TaV replicase includes a structurally unique RNA-dependent RNA polymerase (RdRP) with a sequence permutation in the palm sub-domain, where the active site is anchored. This non-canonical arrangement of the RdRP palm is also found in double-stranded RNA viruses of the Birnaviridae family. Both virus families also share a conserved VPg sequence motif at the polymerase N-terminus which in birnaviruses appears to be used to covalently link a fraction of the replicase molecules to the 5’-end of the genomic segments. Birnavirus VPgs are presumed to be used as primers for replication initiation. Here we have solved the crystal structure of the TaV RdRP, the first non-canonical RdRP of a ssRNA virus, in its apo- form and bound to different substrates. The enzyme arranges as a stable dimer maintained by mutual interactions between the active site cleft of one molecule and the flexible N-terminal tail of the symmetrically related RdRP. The latter, partially mimicking the RNA template backbone, is involved in regulating the polymerization activity. As expected from previous sequence-based bioinformatics predictions, the overall architecture of the TaV enzyme shows important resemblances with birnavirus polymerases. In addition, structural comparisons and biochemical analyses reveal unexpected similarities between the TaV RdRP and those of Flaviviruses. In particular, a long loop protruding from the thumb domain towards the central enzyme cavity appears to act as a platform for de novo initiation of RNA replication. Our findings strongly suggest an unexpected evolutionary relationship between the RdRPs encoded by these distant ssRNA virus groups. PMID:26625123

A galaxy of folds.

PubMed

Alva, Vikram; Remmert, Michael; Biegert, Andreas; Lupas, Andrei N; Söding, Johannes

2010-01-01

Many protein classification systems capture homologous relationships by grouping domains into families and superfamilies on the basis of sequence similarity. Superfamilies with similar 3D structures are further grouped into folds. In the absence of discernable sequence similarity, these structural similarities were long thought to have originated independently, by convergent evolution. However, the growth of databases and advances in sequence comparison methods have led to the discovery of many distant evolutionary relationships that transcend the boundaries of superfamilies and folds. To investigate the contributions of convergent versus divergent evolution in the origin of protein folds, we clustered representative domains of known structure by their sequence similarity, treating them as point masses in a virtual 2D space which attract or repel each other depending on their pairwise sequence similarities. As expected, families in the same superfamily form tight clusters. But often, superfamilies of the same fold are linked with each other, suggesting that the entire fold evolved from an ancient prototype. Strikingly, some links connect superfamilies with different folds. They arise from modular peptide fragments of between 20 and 40 residues that co-occur in the connected folds in disparate structural contexts. These may be descendants of an ancestral pool of peptide modules that evolved as cofactors in the RNA world and from which the first folded proteins arose by amplification and recombination. Our galaxy of folds summarizes, in a single image, most known and many yet undescribed homologous relationships between protein superfamilies, providing new insights into the evolution of protein domains.

An analytical and experimental investigation of the response of the curved, composite frame/skin specimens

NASA Technical Reports Server (NTRS)

Moas, Eduardo; Boitnott, Richard L.; Griffin, O. Hayden, Jr.

1994-01-01

Six-foot diameter, semicircular graphite/epoxy specimens representative of generic aircraft frames were loaded quasi-statistically to determine their load response and failure mechanisms for large deflections that occur in airplanes crashes. These frame/skin specimens consisted of a cylindrical skin section co-cured with a semicircular I-frame. The skin provided the necessary lateral stiffness to keep deformations in the plane of the frame in order to realistically represent deformations as they occur in actual fuselage structures. Various frame laminate stacking sequences and geometries were evaluated by statically loading the specimen until multiple failures occurred. Two analytical methods were compared for modeling the frame/skin specimens: a two-dimensional shell finite element analysis and a one-dimensional, closed-form, curved beam solution derived using an energy method. Flange effectivities were included in the beam analysis to account for the curling phenomenon that occurs in thin flanges of curved beams. Good correlation was obtained between experimental results and the analytical predictions of the linear response of the frames prior to the initial failure. The specimens were found to be useful for evaluating composite frame designs.

Nucleosome Positioning and Epigenetics

NASA Astrophysics Data System (ADS)

Schwab, David; Bruinsma, Robijn

2008-03-01

The role of chromatin structure in gene regulation has recently taken center stage in the field of epigenetics, phenomena that change the phenotype without changing the DNA sequence. Recent work has also shown that nucleosomes, a complex of DNA wrapped around a histone octamer, experience a sequence dependent energy landscape due to the variation in DNA bend stiffness with sequence composition. In this talk, we consider the role nucleosome positioning might play in the formation of heterochromatin, a compact form of DNA generically responsible for gene silencing. In particular, we discuss how different patterns of nucleosome positions, periodic or random, could either facilitate or suppress heterochromatin stability and formation.

Optimization of Composite Material System and Lay-up to Achieve Minimum Weight Pressure Vessel

NASA Astrophysics Data System (ADS)

Mian, Haris Hameed; Wang, Gang; Dar, Uzair Ahmed; Zhang, Weihong

2013-10-01

The use of composite pressure vessels particularly in the aerospace industry is escalating rapidly because of their superiority in directional strength and colossal weight advantage. The present work elucidates the procedure to optimize the lay-up for composite pressure vessel using finite element analysis and calculate the relative weight saving compared with the reference metallic pressure vessel. The determination of proper fiber orientation and laminate thickness is very important to decrease manufacturing difficulties and increase structural efficiency. In the present work different lay-up sequences for laminates including, cross-ply [ 0 m /90 n ] s , angle-ply [ ±θ] ns , [ 90/±θ] ns and [ 0/±θ] ns , are analyzed. The lay-up sequence, orientation and laminate thickness (number of layers) are optimized for three candidate composite materials S-glass/epoxy, Kevlar/epoxy and Carbon/epoxy. Finite element analysis of composite pressure vessel is performed by using commercial finite element code ANSYS and utilizing the capabilities of ANSYS Parametric Design Language and Design Optimization module to automate the process of optimization. For verification, a code is developed in MATLAB based on classical lamination theory; incorporating Tsai-Wu failure criterion for first-ply failure (FPF). The results of the MATLAB code shows its effectiveness in theoretical prediction of first-ply failure strengths of laminated composite pressure vessels and close agreement with the FEA results. The optimization results shows that for all the composite material systems considered, the angle-ply [ ±θ] ns is the optimum lay-up. For given fixed ply thickness the total thickness of laminate is obtained resulting in factor of safety slightly higher than two. Both Carbon/epoxy and Kevlar/Epoxy resulted in approximately same laminate thickness and considerable percentage of weight saving, but S-glass/epoxy resulted in weight increment.

A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita.

PubMed

Du, Hongchun; Guo, Yubiao; Ma, Di; Tang, Kejing; Cai, Decheng; Luo, Yifeng; Xie, Canmao

2018-05-01

Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear. Here, we report the case of a 32-year-old woman presented with irritating cough for 2 years and progressive breathlessness for 6 months. The patient was diagnosed with DC based on the following clinical evidences. Along with some family members, she had the typical mucocutaneous triad and pulmonary fibrosis. A heterozygous mutation (c.844C>T), located in exon 6 of TINF2 gene, that changed arginine to cysteine (Arg282Cys) was identified in this proband by whole exome sequencing. The patient received corticosteroid therapy but refused to receive lung transplantation. The proband died of respiratory failure 4 months after the diagnosis. The missense mutation was located in the conserved region of TINF2 gene and predicted to be deleterious by altering the protein structure. Lung transplantation should be considered for improved survival of patients with DC, and pulmonary fibrosis. Whole exome and whole genome sequencing should be widely used in the identification of such rare genetic variants for clinical diagnosis. The study of DC with pulmonary fibrosis can provide a more appropriate means of clinical research and therapy to the unfortunate patients who suffer from this rare disorder.

Using the self-select paradigm to delineate the nature of speech motor programming.

PubMed

Wright, David L; Robin, Don A; Rhee, Jooyhun; Vaculin, Amber; Jacks, Adam; Guenther, Frank H; Fox, Peter T

2009-06-01

The authors examined the involvement of 2 speech motor programming processes identified by S. T. Klapp (1995, 2003) during the articulation of utterances differing in syllable and sequence complexity. According to S. T. Klapp, 1 process, INT, resolves the demands of the programmed unit, whereas a second process, SEQ, oversees the serial order demands of longer sequences. A modified reaction time paradigm was used to assess INT and SEQ demands. Specifically, syllable complexity was dependent on syllable structure, whereas sequence complexity involved either repeated or unique syllabi within an utterance. INT execution was slowed when articulating single syllables in the form CCCV compared to simpler CV syllables. Planning unique syllables within a multisyllabic utterance rather than repetitions of the same syllable slowed INT but not SEQ. The INT speech motor programming process, important for mental syllabary access, is sensitive to changes in both syllable structure and the number of unique syllables in an utterance.

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

Ma, Xiang; Zhang, Shuai; Jiao, Fang

Two-step nucleation pathways in which disordered, amorphous, or dense liquid states precede appearance of crystalline phases have been reported for a wide range of materials, but the dynamics of such pathways are poorly understood. Moreover, whether these pathways are general features of crystallizing systems or a consequence of system-specific structural details that select for direct vs two-step processes is unknown. Using atomic force microscopy to directly observe crystallization of sequence-defined polymers, we show that crystallization pathways are indeed sequence dependent. When a short hydrophobic region is added to a sequence that directly forms crystalline particles, crystallization instead follows a two-stepmore » pathway that begins with creation of disordered clusters of 10-20 molecules and is characterized by highly non-linear crystallization kinetics in which clusters transform into ordered structures that then enter the growth phase. The results shed new light on non-classical crystallization mechanisms and have implications for design of self-assembling polymer systems.« less

Stress Transfer and Structural Failure of Bilayered Material Systems

NASA Astrophysics Data System (ADS)

Prieto-Munoz, Pablo Arthur

Bilayered material systems are common in naturally formed or artificially engineered structures. Understanding how loads transfer within these structural systems is necessary to predict failure and develop effective designs. Existing methods for evaluating the stress transfer in bilayered materials are limited to overly simplified models or require experimental calibration. As a result, these methods have failed to accurately account for such structural failures as the creep induced roofing panel collapse of Boston's I-90 connector tunnel, which was supported by adhesive anchors. The one-dimensional stress analyses currently used for adhesive anchor design cannot account for viscoelastic creep failure, and consequently results in dangerously under-designed structural systems. In this dissertation, a method for determining the two-dimensional stress and displacement fields for a generalized bilayered material system is developed, and proposes a closed-form analytical solution. A general linear-elastic solution is first proposed by decoupling the elastic governing equations from one another through the so-called plane assumption. Based on this general solution, an axisymmetric problem and a plane strain problem are formulated. These are applied to common bilayered material systems such as: (1) concrete adhesive anchors, (2) material coatings, (3) asphalt pavements, and (4) layered sedimentary rocks. The stress and displacement fields determined by this analytical analysis are validated through the use of finite element models. Through the correspondence principle, the linear-elastic solution is extended to consider time-dependent viscoelastic material properties, thus facilitating the analysis of adhesive anchors and asphalt pavements while incorporating their viscoelastic material behavior. Furthermore, the elastic stress analysis can explain the fracturing phenomenon of material coatings, pavements, and layered rocks, successfully predicting their fracture saturation ratio---which is the ratio of fracture spacing to the thickness of the weak layer where an increase in load will not cause any new fractures to form. Moreover, these specific material systems are looked at in the context of existing and novel experimental results, further demonstrating the advantage of the stress transfer analysis proposed. This research provides a closed-form stress solution for various structural systems that is applied to different failure analyses. The versatility of this method is in the flexibility and the ease upon which the stress and displacement field results can be applied to existing stress- or displacement-based structural failure criteria. As presented, this analysis can be directly used to: (1) design adhesive anchoring systems for long-term creep loading, (2) evaluate the fracture mechanics behind bilayered material coatings and pavement overlay systems, and (3) determine the fracture spacing to layer thickness ratio of layered sedimentary rocks. As is shown in the four material systems presented, this general solution has far reaching applications in facilitating design and analysis of typical bilayered structural systems.

Laser-induced periodic surface structures on zinc oxide crystals upon two-colour femtosecond double-pulse irradiation

NASA Astrophysics Data System (ADS)

Höhm, S.; Rosenfeld, A.; Krüger, J.; Bonse, J.

2017-03-01

In order to study the temporally distributed energy deposition in the formation of laser-induced periodic surface structures (LIPSS) on single-crystalline zinc oxide (ZnO), two-colour double-fs-pulse experiments were performed. Parallel or cross-polarised double-pulse sequences at 400 and 800 nm wavelength were generated by a Mach-Zehnder interferometer, exhibiting inter-pulse delays up to a few picoseconds between the sub-ablation 50-fs-pulses. Twenty two-colour double-pulse sequences were collinearly focused by a spherical mirror to the sample surface. The resulting LIPSS periods and areas were analysed by scanning electron microscopy. The delay-dependence of these LIPSS characteristics shows a dissimilar behaviour when compared to the semiconductor silicon, the dielectric fused silica, or the metal titanium. A wavelength-dependent plasmonic mechanism is proposed to explain the delay-dependence of the LIPSS on ZnO when considering multi-photon excitation processes. Our results support the involvement of nonlinear processes for temporally overlapping pulses. These experiments extend previous two-colour studies on the indirect semiconductor silicon towards the direct wide band-gap semiconductor ZnO and further manifest the relevance of the ultrafast energy deposition for LIPSS formation.

A Generalized Orthotropic Elasto-Plastic Material Model for Impact Analysis

NASA Astrophysics Data System (ADS)

Hoffarth, Canio

Composite materials are now beginning to provide uses hitherto reserved for metals in structural systems such as airframes and engine containment systems, wraps for repair and rehabilitation, and ballistic/blast mitigation systems. These structural systems are often subjected to impact loads and there is a pressing need for accurate prediction of deformation, damage and failure. There are numerous material models that have been developed to analyze the dynamic impact response of polymer matrix composites. However, there are key features that are missing in those models that prevent them from providing accurate predictive capabilities. In this dissertation, a general purpose orthotropic elasto-plastic computational constitutive material model has been developed to predict the response of composites subjected to high velocity impacts. The constitutive model is divided into three components - deformation model, damage model and failure model, with failure to be added at a later date. The deformation model generalizes the Tsai-Wu failure criteria and extends it using a strain-hardening-based orthotropic yield function with a non-associative flow rule. A strain equivalent formulation is utilized in the damage model that permits plastic and damage calculations to be uncoupled and capture the nonlinear unloading and local softening of the stress-strain response. A diagonal damage tensor is defined to account for the directionally dependent variation of damage. However, in composites it has been found that loading in one direction can lead to damage in multiple coordinate directions. To account for this phenomena, the terms in the damage matrix are semi-coupled such that the damage in a particular coordinate direction is a function of the stresses and plastic strains in all of the coordinate directions. The overall framework is driven by experimental tabulated temperature and rate-dependent stress-strain data as well as data that characterizes the damage matrix and failure. The developed theory has been implemented in a commercial explicit finite element analysis code, LS-DYNARTM, as MAT213. Several verification and validation tests using a commonly available carbon-fiber composite, Toyobo's T800/F3900, have been carried and the results show that the theory and implementation are efficient, robust and accurate.