Clinical and genetic features of cervical dystonia in a large multicenter cohort

PubMed Central

Vemula, Satya R.; Xiao, Jianfeng; Thompson, Misty M.; Perlmutter, Joel S.; Wright, Laura J.; Jinnah, H.A.; Rosen, Ami R.; Hedera, Peter; Comella, Cynthia L.; Weissbach, Anne; Junker, Johanna; Jankovic, Joseph; Barbano, Richard L.; Reich, Stephen G.; Rodriguez, Ramon L.; Berman, Brian D.; Chouinard, Sylvain; Severt, Lawrence; Agarwal, Pinky; Stover, Natividad P.

2016-01-01

Objective: To characterize the clinical and genetic features of cervical dystonia (CD). Methods: Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A. Results: The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort. Conclusions: Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD. PMID:27123488

Genome Editing of Structural Variations: Modeling and Gene Correction.

PubMed

Park, Chul-Yong; Sung, Jin Jea; Kim, Dong-Wook

2016-07-01

The analysis of chromosomal structural variations (SVs), such as inversions and translocations, was made possible by the completion of the human genome project and the development of genome-wide sequencing technologies. SVs contribute to genetic diversity and evolution, although some SVs can cause diseases such as hemophilia A in humans. Genome engineering technology using programmable nucleases (e.g., ZFNs, TALENs, and CRISPR/Cas9) has been rapidly developed, enabling precise and efficient genome editing for SV research. Here, we review advances in modeling and gene correction of SVs, focusing on inversion, translocation, and nucleotide repeat expansion. Copyright © 2016 Elsevier Ltd. All rights reserved.

CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3.

PubMed

Liu, Lin; Nardo, David; Li, Eric; Wang, Gary P

2016-03-13

CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution. We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts. The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups. ART-induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3.

On the Sequence-Directed Nature of Human Gene Mutation: The Role of Genomic Architecture and the Local DNA Sequence Environment in Mediating Gene Mutations Underlying Human Inherited Disease

PubMed Central

Cooper, David N.; Bacolla, Albino; Férec, Claude; Vasquez, Karen M.; Kehrer-Sawatzki, Hildegard; Chen, Jian-Min

2011-01-01

Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher-order features of the genomic architecture. The human genome is now recognized to contain ‘pervasive architectural flaws’ in that certain DNA sequences are inherently mutation-prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of non-canonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair, and may serve to increase mutation frequencies in generalized fashion (i.e. both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease. PMID:21853507

Detection of genomic structural variations in Guizhou indigenous pigs and the comparison with other breeds

PubMed Central

Ran, Xueqin; Wang, Jiafu; Li, Sheng; Liu, Jianfeng

2018-01-01

Genomic structural variation (SV) is noticed for the contribution to genetic diversity and phenotypic changes. Guizhou indigenous pig (GZP) has been raised for hundreds of years with many special characteristics. The present paper aimed to uncover the influence of SV on gene polymorphism and the genetic mechanisms of phenotypic traits for GZP. Eighteen GZPs were chosen for resequencing by Illumina sequencing platform. The confident SVs of GZP were called out by both programs of pindel and softSV simultaneously and compared with the SVs deduced from the genomic data of European pig (EUP) and the native pig outside of Guizhou, China (NPOG). A total of 39,166 SVs were detected and covered 27.37 Mb of pig genome. All of 76 SVs were confirmed in GZP pig population by PCR method. The SVs numbers in NPOG and GZP were about 1.8 to 1.9 times higher than that in EUP. And a SV hotspot was found out from the 20 Mb of chromosome X of GZP, which harbored 29 genes and focused on histone modification. More than half of SVs was positioned in the intergenic regions and about one third of SVs in the introns of genes. And we found that SVs tended to locate in genes produced multi-transcripts, in which a positive correlation was found out between the numbers of SV and the gene transcripts. It illustrated that the primary mode of SVs might function on the regulation of gene expression or the transcripts splicing process. A total of 1,628 protein-coding genes were disturbed by 1,956 SVs specific in GZP, in which 93 GZP-specific SV-related genes would lose their functions due to the SV interference and gathered in reproduction ability. Interestingly, the 1,628 protein-coding genes were mainly enriched in estrogen receptor binding, steroid hormone receptor binding, retinoic acid receptor binding, oxytocin signaling pathway, mTOR signaling pathway, axon guidance and cholinergic synapse pathways. It suggested that SV might be a reason for the strong adaptability and low fecundity of GZP, and 51 candidate genes would be useful for the configuration phenotype in Xiang pig breed. PMID:29558483

Detection of genomic structural variations in Guizhou indigenous pigs and the comparison with other breeds.

PubMed

Liu, Chang; Ran, Xueqin; Wang, Jiafu; Li, Sheng; Liu, Jianfeng

2018-01-01

Genomic structural variation (SV) is noticed for the contribution to genetic diversity and phenotypic changes. Guizhou indigenous pig (GZP) has been raised for hundreds of years with many special characteristics. The present paper aimed to uncover the influence of SV on gene polymorphism and the genetic mechanisms of phenotypic traits for GZP. Eighteen GZPs were chosen for resequencing by Illumina sequencing platform. The confident SVs of GZP were called out by both programs of pindel and softSV simultaneously and compared with the SVs deduced from the genomic data of European pig (EUP) and the native pig outside of Guizhou, China (NPOG). A total of 39,166 SVs were detected and covered 27.37 Mb of pig genome. All of 76 SVs were confirmed in GZP pig population by PCR method. The SVs numbers in NPOG and GZP were about 1.8 to 1.9 times higher than that in EUP. And a SV hotspot was found out from the 20 Mb of chromosome X of GZP, which harbored 29 genes and focused on histone modification. More than half of SVs was positioned in the intergenic regions and about one third of SVs in the introns of genes. And we found that SVs tended to locate in genes produced multi-transcripts, in which a positive correlation was found out between the numbers of SV and the gene transcripts. It illustrated that the primary mode of SVs might function on the regulation of gene expression or the transcripts splicing process. A total of 1,628 protein-coding genes were disturbed by 1,956 SVs specific in GZP, in which 93 GZP-specific SV-related genes would lose their functions due to the SV interference and gathered in reproduction ability. Interestingly, the 1,628 protein-coding genes were mainly enriched in estrogen receptor binding, steroid hormone receptor binding, retinoic acid receptor binding, oxytocin signaling pathway, mTOR signaling pathway, axon guidance and cholinergic synapse pathways. It suggested that SV might be a reason for the strong adaptability and low fecundity of GZP, and 51 candidate genes would be useful for the configuration phenotype in Xiang pig breed.

Alternative role of HuD splicing variants in neuronal differentiation.

PubMed

Hayashi, Satoru; Yano, Masato; Igarashi, Mana; Okano, Hirotaka James; Okano, Hideyuki

2015-03-01

HuD is a neuronal RNA-binding protein that plays an important role in neuronal differentiation of the nervous system. HuD has been reported to have three RNA recognition motifs (RRMs) and three splice variants (SVs) that differ in their amino acid sequences between RRM2 and RRM3. This study investigates whether these SVs have specific roles in neuronal differentiation. In primary neural epithelial cells under differentiating conditions, HuD splice variant 1 (HuD-sv1), which is a general form, and HuD-sv2 were expressed at all tested times, whereas HuD-sv4 was transiently expressed at the beginning of differentiation, indicating that HuD-sv4 might play a role compared different from that of HuD-sv1. Indeed, HuD-sv4 did not promote neuronal differentiation in epithelial cells, whereas HuD-sv1 did promote neuronal differentiation. HuD-sv4 overexpression showed less neurite-inducing activity than HuD-sv1 in mouse neuroblastoma N1E-115 cells; however, HuD-sv4 showed stronger growth-arresting activity. HuD-sv1 was localized only in the cytoplasm, whereas HuD-sv4 was localized in both the cytoplasm and the nuclei. The Hu protein has been reported to be involved in translation and alternative splicing in the cytoplasm and nuclei, respectively. Consistent with this observation, HuD-sv1 showed translational activity on p21, which plays a role in growth arrest and neuronal differentiation, whereas HuD-sv4 did not. By contrast, HuD-sv4 showed stronger pre-mRNA splicing activity than did HuD-sv1 on Clasp2, which participates in cell division. Therefore, HuD SVs might play a role in controlling the timing of proliferation/differentiation switching by controlling the translation and alternative splicing of target genes. © 2014 Wiley Periodicals, Inc.

A stochastic vortex structure method for interacting particles in turbulent shear flows

NASA Astrophysics Data System (ADS)

Dizaji, Farzad F.; Marshall, Jeffrey S.; Grant, John R.

2018-01-01

In a recent study, we have proposed a new synthetic turbulence method based on stochastic vortex structures (SVSs), and we have demonstrated that this method can accurately predict particle transport, collision, and agglomeration in homogeneous, isotropic turbulence in comparison to direct numerical simulation results. The current paper extends the SVS method to non-homogeneous, anisotropic turbulence. The key element of this extension is a new inversion procedure, by which the vortex initial orientation can be set so as to generate a prescribed Reynolds stress field. After validating this inversion procedure for simple problems, we apply the SVS method to the problem of interacting particle transport by a turbulent planar jet. Measures of the turbulent flow and of particle dispersion, clustering, and collision obtained by the new SVS simulations are shown to compare well with direct numerical simulation results. The influence of different numerical parameters, such as number of vortices and vortex lifetime, on the accuracy of the SVS predictions is also examined.

Sequence variants in the bovine silent information regulator 6, their linkage and their associations with body measurements and carcass quality traits in Qinchuan cattle.

PubMed

Gui, Linsheng; Jiang, Bijie; Zhang, Yaran; Zan, Linsen

2015-03-15

Silent information regulator 6 (SIRT6) belongs to the family of class III nicotinamide adenine dinucleotide (NAD)-dependent deacetylase and plays an essential role in DNA repair and metabolism. This study was conducted to detect potential polymorphisms of the bovine SIRT6 gene and explore their relationships with body measurement and carcass quality in Qinchuan cattle. Four sequence variants (SVs) were identified in intron 6, exon 7, exon 9, and 3' UTR, via sequencing technology conducted in 468 individual Qinchuan cattle. Eleven different haplotypes were identified, of which two major haplotypes had a frequency of 45.7% (-CACT-) and 14.8% (-CGTC-). Three SVs (SV2, SV3 and SV4) were significantly associated with some of the body measurements and carcass quality traits (P<0.05 or P<0.01), and the H2H7 (CC-GA-TT-TC) diplotype had better performance than other combinations. Our results suggest that some polymorphisms in SIRT6 are associated with production traits and may be used as candidates for marker-assisted selection (MAS) and management in beef cattle breeding programs. Copyright © 2015 Elsevier B.V. All rights reserved.

Predictability Experiments With the Navy Operational Global Atmospheric Prediction System

NASA Astrophysics Data System (ADS)

Reynolds, C. A.; Gelaro, R.; Rosmond, T. E.

2003-12-01

There are several areas of research in numerical weather prediction and atmospheric predictability, such as targeted observations and ensemble perturbation generation, where it is desirable to combine information about the uncertainty of the initial state with information about potential rapid perturbation growth. Singular vectors (SVs) provide a framework to accomplish this task in a mathematically rigorous and computationally feasible manner. In this study, SVs are calculated using the tangent and adjoint models of the Navy Operational Global Atmospheric Prediction System (NOGAPS). The analysis error variance information produced by the NRL Atmospheric Variational Data Assimilation System is used as the initial-time SV norm. These VAR SVs are compared to SVs for which total energy is both the initial and final time norms (TE SVs). The incorporation of analysis error variance information has a significant impact on the structure and location of the SVs. This in turn has a significant impact on targeted observing applications. The utility and implications of such experiments in assessing the analysis error variance estimates will be explored. Computing support has been provided by the Department of Defense High Performance Computing Center at the Naval Oceanographic Office Major Shared Resource Center at Stennis, Mississippi.

Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant

PubMed Central

Jacoby, Meagan A.; Duncavage, Eric J.; Chang, Gue Su; Miller, Christopher A.; Shao, Jin; Elliott, Kevin; Robinson, Joshua; Fulton, Robert S.; Fronick, Catrina C.; O’Laughlin, Michelle; Heath, Sharon E.; Welch, John S.; Link, Daniel C.; DiPersio, John F.; Westervelt, Peter; Ley, Timothy J.; Graubert, Timothy A.; Walter, Matthew J.

2018-01-01

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy. PMID:29515031

Discovery of somatic mutations in the progression of chronic myeloid leukemia by whole-exome sequencing.

PubMed

Huang, Y; Zheng, J; Hu, J D; Wu, Y A; Zheng, X Y; Liu, T B; Chen, F L

2014-02-19

We performed whole-exome sequencing in samples representing accelerated phase (AP) and blastic crisis (BC) in a subject with chronic myeloid leukemia (CML). A total of 12.74 Gb clean data were generated, achieving a mean depth coverage of 64.45 and 69.53 for AP and BC samples, respectively, of the target region. A total of 148 somatic variants were detected, including 76 insertions and deletions (indels), 64 single-nucleotide variations (SNV), and 8 structural variations (SV). On the basis of annotation and functional prediction analysis, we identified 3 SNVs and 6 SVs that showed a potential association with CML progression. Among the genes that harbor the identified variants, GATA2 has previously been reported to play important roles in the progression from AP to BC in CML. Identification of these genes will allow us to gain a better understanding of the pathological mechanism of CML and represents a critical advance toward new molecular diagnostic tests for the development of potential therapies for CML.

Anisotropic Stochastic Vortex Structure Method for Simulating Particle Collision in Turbulent Shear Flows

NASA Astrophysics Data System (ADS)

Dizaji, Farzad; Marshall, Jeffrey; Grant, John; Jin, Xing

2017-11-01

Accounting for the effect of subgrid-scale turbulence on interacting particles remains a challenge when using Reynolds-Averaged Navier Stokes (RANS) or Large Eddy Simulation (LES) approaches for simulation of turbulent particulate flows. The standard stochastic Lagrangian method for introducing turbulence into particulate flow computations is not effective when the particles interact via collisions, contact electrification, etc., since this method is not intended to accurately model relative motion between particles. We have recently developed the stochastic vortex structure (SVS) method and demonstrated its use for accurate simulation of particle collision in homogeneous turbulence; the current work presents an extension of the SVS method to turbulent shear flows. The SVS method simulates subgrid-scale turbulence using a set of randomly-positioned, finite-length vortices to generate a synthetic fluctuating velocity field. It has been shown to accurately reproduce the turbulence inertial-range spectrum and the probability density functions for the velocity and acceleration fields. In order to extend SVS to turbulent shear flows, a new inversion method has been developed to orient the vortices in order to generate a specified Reynolds stress field. The extended SVS method is validated in the present study with comparison to direct numerical simulations for a planar turbulent jet flow. This research was supported by the U.S. National Science Foundation under Grant CBET-1332472.

Diversity and Genome Analysis of Australian and Global Oilseed Brassica napus L. Germplasm Using Transcriptomics and Whole Genome Re-sequencing.

PubMed

Malmberg, M Michelle; Shi, Fan; Spangenberg, German C; Daetwyler, Hans D; Cogan, Noel O I

2018-01-01

Intensive breeding of Brassica napus has resulted in relatively low diversity, such that B. napus would benefit from germplasm improvement schemes that sustain diversity. As such, samples representative of global germplasm pools need to be assessed for existing population structure, diversity and linkage disequilibrium (LD). Complexity reduction genotyping-by-sequencing (GBS) methods, including GBS-transcriptomics (GBS-t), enable cost-effective screening of a large number of samples, while whole genome re-sequencing (WGR) delivers the ability to generate large numbers of unbiased genomic single nucleotide polymorphisms (SNPs), and identify structural variants (SVs). Furthermore, the development of genomic tools based on whole genomes representative of global oilseed diversity and orientated by the reference genome has substantial industry relevance and will be highly beneficial for canola breeding. As recent studies have focused on European and Chinese varieties, a global diversity panel as well as a substantial number of Australian spring types were included in this study. Focusing on industry relevance, 633 varieties were initially genotyped using GBS-t to examine population structure using 61,037 SNPs. Subsequently, 149 samples representative of global diversity were selected for WGR and both data sets used for a side-by-side evaluation of diversity and LD. The WGR data was further used to develop genomic resources consisting of a list of 4,029,750 high-confidence SNPs annotated using SnpEff, and SVs in the form of 10,976 deletions and 2,556 insertions. These resources form the basis of a reliable and repeatable system allowing greater integration between canola genomics studies, with a strong focus on breeding germplasm and industry applicability.

Gustaf: Detecting and correctly classifying SVs in the NGS twilight zone.

PubMed

Trappe, Kathrin; Emde, Anne-Katrin; Ehrlich, Hans-Christian; Reinert, Knut

2014-12-15

The landscape of structural variation (SV) including complex duplication and translocation patterns is far from resolved. SV detection tools usually exhibit low agreement, are often geared toward certain types or size ranges of variation and struggle to correctly classify the type and exact size of SVs. We present Gustaf (Generic mUlti-SpliT Alignment Finder), a sound generic multi-split SV detection tool that detects and classifies deletions, inversions, dispersed duplications and translocations of ≥ 30 bp. Our approach is based on a generic multi-split alignment strategy that can identify SV breakpoints with base pair resolution. We show that Gustaf correctly identifies SVs, especially in the range from 30 to 100 bp, which we call the next-generation sequencing (NGS) twilight zone of SVs, as well as larger SVs >500 bp. Gustaf performs better than similar tools in our benchmark and is furthermore able to correctly identify size and location of dispersed duplications and translocations, which otherwise might be wrongly classified, for example, as large deletions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

SVS: data and knowledge integration in computational biology.

PubMed

Zycinski, Grzegorz; Barla, Annalisa; Verri, Alessandro

2011-01-01

In this paper we present a framework for structured variable selection (SVS). The main concept of the proposed schema is to take a step towards the integration of two different aspects of data mining: database and machine learning perspective. The framework is flexible enough to use not only microarray data, but other high-throughput data of choice (e.g. from mass spectrometry, microarray, next generation sequencing). Moreover, the feature selection phase incorporates prior biological knowledge in a modular way from various repositories and is ready to host different statistical learning techniques. We present a proof of concept of SVS, illustrating some implementation details and describing current results on high-throughput microarray data.

Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2

PubMed Central

Kononenko, Natalia L.; Diril, M. Kasim; Puchkov, Dmytro; Kintscher, Michael; Koo, Seong Joo; Pfuhl, Gerit; Winter, York; Wienisch, Martin; Klingauf, Jürgen; Breustedt, Jörg; Schmitz, Dietmar; Maritzen, Tanja; Haucke, Volker

2013-01-01

Neurotransmission depends on the exocytic fusion of synaptic vesicles (SVs) and their subsequent reformation either by clathrin-mediated endocytosis or budding from bulk endosomes. How synapses are able to rapidly recycle SVs to maintain SV pool size, yet preserve their compositional identity, is poorly understood. We demonstrate that deletion of the endocytic adaptor stonin 2 (Stn2) in mice compromises the fidelity of SV protein sorting, whereas the apparent speed of SV retrieval is increased. Loss of Stn2 leads to selective missorting of synaptotagmin 1 to the neuronal surface, an elevated SV pool size, and accelerated SV protein endocytosis. The latter phenotype is mimicked by overexpression of endocytosis-defective variants of synaptotagmin 1. Increased speed of SV protein retrieval in the absence of Stn2 correlates with an up-regulation of SV reformation from bulk endosomes. Our results are consistent with a model whereby Stn2 is required to preserve SV protein composition but is dispensable for maintaining the speed of SV recycling. PMID:23345427

Prediction of Stroke Subtype and Recanalization Using Susceptibility Vessel Sign on Susceptibility-Weighted Magnetic Resonance Imaging.

PubMed

Kang, Dong-Wan; Jeong, Han-Gil; Kim, Do Yeon; Yang, Wookjin; Lee, Seung-Hoon

2017-06-01

The susceptibility vessel sign (SVS) is a hypointense signal visualized because of the susceptibility effect of thrombi, sensitively detected on susceptibility-weighted magnetic resonance imaging. The relationship of SVS parameters with the stroke subtype and recanalization status after endovascular treatment remains uncertain. The data from 89 patients with acute stroke caused by anterior circulation infarcts who underwent susceptibility-weighted magnetic resonance imaging before endovascular treatment were examined. Independent reviewers, blinded to the stroke subtype and recanalization status, measured the SVS diameter, length, and estimated volume. The intra- and interrater agreements of the SVS parameters were assessed. The SVS was identified in 78% of the patients. SVS was more commonly associated with cardioembolism than with noncardioembolism ( P =0.01). The SVS diameter ( P <0.01) and length ( P =0.01) were larger in the cardioembolism group. The SVS diameter was larger in the recanalization group (thrombolysis in cerebral infarction ≥2b) than in the nonrecanalization group ( P =0.04). Multivariable analysis revealed that the SVS diameter was an independent predictor of cardioembolism (adjusted odds ratio, 1.97; 95% confidence interval, 1.34-2.90; P <0.01). There was no significant association between the SVS volume and the recanalization status (adjusted odds ratio, 1.003; 95% confidence interval, 0.999-1.006; P =0.12). The optimal cutoff value of the SVS diameter for the cardioembolism was 5.5 mm (sensitivity, 45.6%; specificity, 93.8%). Increased SVS diameter on susceptibility-weighted magnetic resonance imaging may predict cardioembolism. No clear association was found between SVS volume and endovascular recanalization. © 2017 The Authors.

COSMOS: accurate detection of somatic structural variations through asymmetric comparison between tumor and normal samples

PubMed Central

Yamagata, Koichi; Yamanishi, Ayako; Kokubu, Chikara; Takeda, Junji; Sese, Jun

2016-01-01

An important challenge in cancer genomics is precise detection of structural variations (SVs) by high-throughput short-read sequencing, which is hampered by the high false discovery rates of existing analysis tools. Here, we propose an accurate SV detection method named COSMOS, which compares the statistics of the mapped read pairs in tumor samples with isogenic normal control samples in a distinct asymmetric manner. COSMOS also prioritizes the candidate SVs using strand-specific read-depth information. Performance tests on modeled tumor genomes revealed that COSMOS outperformed existing methods in terms of F-measure. We also applied COSMOS to an experimental mouse cell-based model, in which SVs were induced by genome engineering and gamma-ray irradiation, followed by polymerase chain reaction-based confirmation. The precision of COSMOS was 84.5%, while the next best existing method was 70.4%. Moreover, the sensitivity of COSMOS was the highest, indicating that COSMOS has great potential for cancer genome analysis. PMID:26833260

Comparing Mycobacterium tuberculosis genomes using genome topology networks.

PubMed

Jiang, Jianping; Gu, Jianlei; Zhang, Liang; Zhang, Chenyi; Deng, Xiao; Dou, Tonghai; Zhao, Guoping; Zhou, Yan

2015-02-14

Over the last decade, emerging research methods, such as comparative genomic analysis and phylogenetic study, have yielded new insights into genotypes and phenotypes of closely related bacterial strains. Several findings have revealed that genomic structural variations (SVs), including gene gain/loss, gene duplication and genome rearrangement, can lead to different phenotypes among strains, and an investigation of genes affected by SVs may extend our knowledge of the relationships between SVs and phenotypes in microbes, especially in pathogenic bacteria. In this work, we introduce a 'Genome Topology Network' (GTN) method based on gene homology and gene locations to analyze genomic SVs and perform phylogenetic analysis. Furthermore, the concept of 'unfixed ortholog' has been proposed, whose members are affected by SVs in genome topology among close species. To improve the precision of 'unfixed ortholog' recognition, a strategy to detect annotation differences and complete gene annotation was applied. To assess the GTN method, a set of thirteen complete M. tuberculosis genomes was analyzed as a case study. GTNs with two different gene homology-assigning methods were built, the Clusters of Orthologous Groups (COG) method and the orthoMCL clustering method, and two phylogenetic trees were constructed accordingly, which may provide additional insights into whole genome-based phylogenetic analysis. We obtained 24 unfixable COG groups, of which most members were related to immunogenicity and drug resistance, such as PPE-repeat proteins (COG5651) and transcriptional regulator TetR gene family members (COG1309). The GTN method has been implemented in PERL and released on our website. The tool can be downloaded from http://homepage.fudan.edu.cn/zhouyan/gtn/ , and allows re-annotating the 'lost' genes among closely related genomes, analyzing genes affected by SVs, and performing phylogenetic analysis. With this tool, many immunogenic-related and drug resistance-related genes were found to be affected by SVs in M. tuberculosis genomes. We believe that the GTN method will be suitable for the exploration of genomic SVs in connection with biological features of bacterial strains, and that GTN-based phylogenetic analysis will provide additional insights into whole genome-based phylogenetic analysis.

Linking canopy reflectance to crop structure and photosynthesis to capture and interpret spatiotemporal dimensions of per-field photosynthetic productivity

NASA Astrophysics Data System (ADS)

Xue, Wei; Jeong, Seungtaek; Ko, Jonghan; Tenhunen, John

2017-03-01

Nitrogen and water availability alter canopy structure and physiology, and thus crop growth, yielding large impacts on ecosystem-regulating/production provisions. However, to date, explicitly quantifying such impacts remains challenging partially due to lack of adequate methodology to capture spatial dimensions of ecosystem changes associated with nitrogen and water effects. A data fitting, where close-range remote-sensing measurements of vegetation indices derived from a handheld instrument and an unmanned aerial vehicle (UAV) system are linked to in situ leaf and canopy photosynthetic traits, was applied to capture and interpret inter- and intra-field variations in gross primary productivity (GPP) in lowland rice grown under flooded conditions (paddy rice, PD) subject to three nitrogen application rates and under rainfed conditions (RF) in an East Asian monsoon region of South Korea. Spatial variations (SVs) in both GPP and light use efficiency (LUEcabs) early in the growing season were enlarged by nitrogen addition. The nutritional effects narrowed over time. A shift in planting culture from flooded to rainfed conditions strengthened SVs in GPP and LUEcabs. Intervention of prolonged drought late in the growing season dramatically intensified SVs that were supposed to seasonally decrease. Nevertheless, nitrogen addition effects on SV of LUEcabs at the early growth stage made PD fields exert greater SVs than RF fields. SVs of GPP across PD and RF rice fields were likely related to leaf area index (LAI) development less than to LUEcabs, while numerical analysis suggested that considering strength in LUEcabs and its spatial variation for the same crop type tends to be vital for better evaluation in landscape/regional patterns of ecosystem photosynthetic productivity at critical phenology stages.

Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying.

PubMed

Craye, Goedele; Löbmann, Korbinian; Grohganz, Holger; Rades, Thomas; Laitinen, Riikka

2015-12-03

In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin-lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture upon ball milling. In addition, a spray-dried formulation of SVS without LYS was prepared. Energy-dispersive X-ray spectroscopy (EDS) revealed that SLS coated the SVS and SVS-LYS particles upon spray drying. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that in the spray-dried formulations the remaining crystallinity originated from SLS only. The best dissolution properties and a "spring and parachute" effect were found for SVS spray-dried from a 5% SLS solution without LYS. Despite the presence of at least partially crystalline SLS in the mixtures, all the studied formulations were able to significantly extend the stability of amorphous SVS compared to previous co-amorphous formulations of SVS. The best stability (at least 12 months in dry conditions) was observed when SLS was spray-dried with SVS (and LYS). In conclusion, spray drying of SVS and LYS from aqueous surfactant solutions was able to produce formulations with improved physical stability for amorphous SVS.

Association analysis of bovine Foxa2 gene single sequence variant and haplotype combinations with growth traits in Chinese cattle.

PubMed

Liu, Mei; Li, Mijie; Wang, Shaoqiang; Xu, Yao; Lan, Xianyong; Li, Zhuanjian; Lei, Chuzhao; Yang, Dongying; Jia, Yutang; Chen, Hong

2014-02-25

Forkhead box A2 (Foxa2) has been recognized as one of the most potent transcriptional activators that is implicated in the control of feeding behavior and energy homeostasis. However, similar researches about the effects of genetic variations of Foxa2 gene on growth traits are lacking. Therefore, this study detected Foxa2 gene polymorphisms by DNA pool sequencing, PCR-RFLP and PCR-ACRS methods in 822 individuals from three Chinese cattle breeds. The results showed that four sequence variants (SVs) were screened, including two mutations (SV1, g. 7005 C>T and SV2, g. 7044 C>G) in intron 4, one mutation (SV3, g. 8449 A>G) in exon 5 and one mutation (SV4, g. 8537 T>C) in the 3'UTR. Notably, association analysis of the single mutations with growth traits in total individuals (at 24months) revealed that significant statistical difference was found in four SVs, and SV4 locus was highly significantly associated with growth traits throughout all three breeds (P<0.05 or P<0.01). Meanwhile, haplotype combination CCCCAGTC also indicated remarkably associated to better chest girth and body weight in Jiaxian Red cattle (P<0.05). We herein described a comprehensive study on the variability of bovine Foxa2 gene that was predictive of molecular markers in cattle breeding for the first time. Copyright © 2013 Elsevier B.V. All rights reserved.

Initial development of a metric to describe the level of safety associated with piloting an aircraft with synthetic vision systems (SVS) displays

NASA Astrophysics Data System (ADS)

Bartolone, Anthony P.; Glaab, Louis J.; Hughes, Monica F.; Parrish, Russell V.

2005-05-01

Synthetic Vision Systems (SVS) displays provide pilots with a continuous view of terrain combined with integrated guidance symbology in an effort to increase situation awareness (SA) and decrease workload during operations in Instrument Meteorological Conditions (IMC). It is hypothesized that SVS displays can replicate the safety and operational flexibility of flight in Visual Meteorological Conditions (VMC), regardless of actual out-the-window (OTW) visibility or time of day. Throughout the course of recent SVS research, significant progress has been made towards evolving SVS displays as well as demonstrating their ability to increase SA compared to conventional avionics in a variety of conditions. While a substantial amount of data has been accumulated demonstrating the capabilities of SVS displays, the ability of SVS to replicate the safety and operational flexibility of VMC flight performance in all visibility conditions is unknown to any specific degree. The previous piloted simulations and flight tests have shown better SA and path precision is achievable with SVS displays without causing an increase in workload, however none of the previous SVS research attempted to fully capture the significance of SVS displays in terms of their contribution to safety or operational benefits. In order to more fully quantify the relationship of flight operations in IMC with SVS displays to conventional operations conducted in VMC, a fundamental comparison to current day general aviation (GA) flight instruments was warranted. Such a comparison could begin to establish the extent to which SVS display concepts are capable of maintaining an "equivalent level of safety" with the round dials they could one day replace, for both current and future operations. Such a comparison was the focus of the SVS-ES experiment conducted under the Aviation Safety and Security Program's (AvSSP) GA Element of the SVS Project at NASA Langley Research Center in Hampton, Virginia. A combination of subjective and objective data measures were used in this preliminary research to quantify the relationship between selected components of safety that are associated with flying an approach. Four information display methods ranging from a "round dials" baseline through a fully integrated SVS package that includes terrain, pathway based guidance, and a strategic navigation display, were investigated in this high fidelity simulation experiment. In addition, a broad spectrum of pilots, representative of the GA population, were employed for testing in an attempt to enable greater application of the results and determine if "equivalent levels of safety" are achievable through the incorporation of SVS technology regardless of a pilot's flight experience.

Single visit surgery for pediatric ambulatory surgical procedures: a satisfaction and cost analysis.

PubMed

Olson, Jacob K; Deming, Lisa A; King, Denis R; Rager, Terrence M; Gartner, Sarah; Huibregtse, Natalie; Moss, R Lawrence; Besner, Gail E

2017-10-10

Single visit surgery (SVS) consists of same-day pre-operative assessment and operation with telephone post-operative follow-up. This reduces family time commitment to 1 hospital trip rather than 2-3. We began SVS for ambulatory patients with clear surgical indications in 2013. We sought to determine family satisfaction, cost savings to families, and institutional financial feasibility of SVS. SVS patients were compared to age/case matched conventional surgery (CS) patients. Satisfaction was assessed by post-operative telephone survey. Family costs were calculated as the sum of lost revenue (based on median income) and transportation costs ($0.50/mile). Satisfaction was high in both groups (98% for SVS vs. 93% for CS; p=0.27). 40% of CS families indicated that they would have preferred SVS, whereas no SVS families indicated preference for the CS option (p<0.001). Distance from the hospital did not correlate with satisfaction. Estimated cost savings for an SVS family was $188. Reimbursement, hospital and physician charges, and day-of-surgery cancellation rates were similar. SVS provides substantial cost savings to families while maintaining patient satisfaction and equivalent institutional reimbursement. SVS is an effective approach to low-risk ambulatory surgical procedures that is less disruptive to families, facilitates access to pediatric surgical care, and reduces resource utilization. Cost Effectiveness Study. Level II. Copyright © 2017 Elsevier Inc. All rights reserved.

Two synaptobrevin molecules are sufficient for vesicle fusion in central nervous system synapses

PubMed Central

Sinha, Raunak; Ahmed, Saheeb; Jahn, Reinhard; Klingauf, Jurgen

2011-01-01

Exocytosis of synaptic vesicles (SVs) during fast synaptic transmission is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly formed by the coil-coiling of three members of this protein family: vesicle SNARE protein, synaptobrevin 2 (syb2), and the presynaptic membrane SNAREs syntaxin-1A and SNAP-25. However, it is controversially debated how many SNARE complexes are minimally needed for SV priming and fusion. To quantify this effective number, we measured the fluorescence responses from single fusing vesicles expressing pHluorin (pHl), a pH-sensitive variant of GFP, fused to the luminal domain of the vesicular SNARE syb2 (spH) in cultured hippocampal neurons lacking endogenous syb2. Fluorescence responses were quantal, with the unitary signals precisely corresponding to single pHluorin molecules. Using this approach we found that two copies of spH per SV fully rescued evoked fusion whereas SVs expressing only one spH were unable to rapidly fuse upon stimulation. Thus, two syb2 molecules and likely two SNARE complexes are necessary and sufficient for SV fusion during fast synaptic transmission. PMID:21844343

The neuroimaging of sacred values.

PubMed

Vilarroya, Oscar; Hilferty, Joseph

2013-09-01

Sacred (or protected) values (SVs) constitute core beliefs that define primary reference groups. There is significant research on SVs at a behavioral level, but their neural underpinnings are just beginning to be discovered. In this paper, we highlight the current state of neuroimaging research concerning SVs. Given that SVs are considered to be strongly motivated by moral principles, we first provide an outline of the neural circuits that have been found to be involved in moral cognition. We then review various neuroimaging studies that have explored the notion of SVs. Specifically, we concentrate on neuroimaging studies dealing with intergroup bias and those that focus on social norms, since these are two basic dimensions of SVs that have been studied with neuroimaging techniques. Finally, we review two studies that have directly addressed SVs with neuroimaging techniques, and we offer suggestions for further avenues of study. © 2013 New York Academy of Sciences.

Structural variation discovery in the cancer genome using next generation sequencing: Computational solutions and perspectives

PubMed Central

Liu, Biao; Conroy, Jeffrey M.; Morrison, Carl D.; Odunsi, Adekunle O.; Qin, Maochun; Wei, Lei; Trump, Donald L.; Johnson, Candace S.; Liu, Song; Wang, Jianmin

2015-01-01

Somatic Structural Variations (SVs) are a complex collection of chromosomal mutations that could directly contribute to carcinogenesis. Next Generation Sequencing (NGS) technology has emerged as the primary means of interrogating the SVs of the cancer genome in recent investigations. Sophisticated computational methods are required to accurately identify the SV events and delineate their breakpoints from the massive amounts of reads generated by a NGS experiment. In this review, we provide an overview of current analytic tools used for SV detection in NGS-based cancer studies. We summarize the features of common SV groups and the primary types of NGS signatures that can be used in SV detection methods. We discuss the principles and key similarities and differences of existing computational programs and comment on unresolved issues related to this research field. The aim of this article is to provide a practical guide of relevant concepts, computational methods, software tools and important factors for analyzing and interpreting NGS data for the detection of SVs in the cancer genome. PMID:25849937

COSMOS: accurate detection of somatic structural variations through asymmetric comparison between tumor and normal samples.

PubMed

Yamagata, Koichi; Yamanishi, Ayako; Kokubu, Chikara; Takeda, Junji; Sese, Jun

2016-05-05

An important challenge in cancer genomics is precise detection of structural variations (SVs) by high-throughput short-read sequencing, which is hampered by the high false discovery rates of existing analysis tools. Here, we propose an accurate SV detection method named COSMOS, which compares the statistics of the mapped read pairs in tumor samples with isogenic normal control samples in a distinct asymmetric manner. COSMOS also prioritizes the candidate SVs using strand-specific read-depth information. Performance tests on modeled tumor genomes revealed that COSMOS outperformed existing methods in terms of F-measure. We also applied COSMOS to an experimental mouse cell-based model, in which SVs were induced by genome engineering and gamma-ray irradiation, followed by polymerase chain reaction-based confirmation. The precision of COSMOS was 84.5%, while the next best existing method was 70.4%. Moreover, the sensitivity of COSMOS was the highest, indicating that COSMOS has great potential for cancer genome analysis. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading.

PubMed

Egashira, Yoshihiro; Takase, Miki; Watanabe, Shoji; Ishida, Junji; Fukamizu, Akiyoshi; Kaneko, Ryosuke; Yanagawa, Yuchio; Takamori, Shigeo

2016-09-20

GABA acts as the major inhibitory neurotransmitter in the mammalian brain, shaping neuronal and circuit activity. For sustained synaptic transmission, synaptic vesicles (SVs) are required to be recycled and refilled with neurotransmitters using an H(+) electrochemical gradient. However, neither the mechanism underlying vesicular GABA uptake nor the kinetics of GABA loading in living neurons have been fully elucidated. To characterize the process of GABA uptake into SVs in functional synapses, we monitored luminal pH of GABAergic SVs separately from that of excitatory glutamatergic SVs in cultured hippocampal neurons. By using a pH sensor optimal for the SV lumen, we found that GABAergic SVs exhibited an unexpectedly higher resting pH (∼6.4) than glutamatergic SVs (pH ∼5.8). Moreover, unlike glutamatergic SVs, GABAergic SVs displayed unique pH dynamics after endocytosis that involved initial overacidification and subsequent alkalization that restored their resting pH. GABAergic SVs that lacked the vesicular GABA transporter (VGAT) did not show the pH overshoot and acidified further to ∼6.0. Comparison of luminal pH dynamics in the presence or absence of VGAT showed that VGAT operates as a GABA/H(+) exchanger, which is continuously required to offset GABA leakage. Furthermore, the kinetics of GABA transport was slower (τ > 20 s at physiological temperature) than that of glutamate uptake and may exceed the time required for reuse of exocytosed SVs, allowing reuse of incompletely filled vesicles in the presence of high demand for inhibitory transmission.

Dynamics of Multiple Trafficking Behaviors of Individual Synaptic Vesicles Revealed by Quantum-Dot Based Presynaptic Probe

PubMed Central

Lee, Suho; Jung, Kyung Jin; Jung, Hyun Suk; Chang, Sunghoe

2012-01-01

Although quantum dots (QDs) have provided invaluable information regarding the diffusive behaviors of postsynaptic receptors, their application in presynaptic terminals has been rather limited. In addition, the diffraction-limited nature of the presynaptic bouton has hampered detailed analyses of the behaviors of synaptic vesicles (SVs) at synapses. Here, we created a quantum-dot based presynaptic probe and characterized the dynamic behaviors of individual SVs. As previously reported, the SVs exhibited multiple exchanges between neighboring boutons. Actin disruption induced a dramatic decrease in the diffusive behaviors of SVs at synapses while microtubule disruption only reduced extrasynaptic mobility. Glycine-induced synaptic potentiation produced significant increases in synaptic and inter-boutonal trafficking of SVs, which were NMDA receptor- and actin-dependent while NMDA-induced synaptic depression decreased the mobility of the SVs at synapses. Together, our results show that sPH-AP-QD revealed previously unobserved trafficking properties of SVs around synapses, and the dynamic modulation of SV mobility could regulate presynaptic efficacy during synaptic activity. PMID:22666444

Plant acoustics: in the search of a sound mechanism for sound signaling in plants.

PubMed

Mishra, Ratnesh Chandra; Ghosh, Ritesh; Bae, Hanhong

2016-08-01

Being sessile, plants continuously deal with their dynamic and complex surroundings, identifying important cues and reacting with appropriate responses. Consequently, the sensitivity of plants has evolved to perceive a myriad of external stimuli, which ultimately ensures their successful survival. Research over past centuries has established that plants respond to environmental factors such as light, temperature, moisture, and mechanical perturbations (e.g. wind, rain, touch, etc.) by suitably modulating their growth and development. However, sound vibrations (SVs) as a stimulus have only started receiving attention relatively recently. SVs have been shown to increase the yields of several crops and strengthen plant immunity against pathogens. These vibrations can also prime the plants so as to make them more tolerant to impending drought. Plants can recognize the chewing sounds of insect larvae and the buzz of a pollinating bee, and respond accordingly. It is thus plausible that SVs may serve as a long-range stimulus that evokes ecologically relevant signaling mechanisms in plants. Studies have suggested that SVs increase the transcription of certain genes, soluble protein content, and support enhanced growth and development in plants. At the cellular level, SVs can change the secondary structure of plasma membrane proteins, affect microfilament rearrangements, produce Ca(2+) signatures, cause increases in protein kinases, protective enzymes, peroxidases, antioxidant enzymes, amylase, H(+)-ATPase / K(+) channel activities, and enhance levels of polyamines, soluble sugars and auxin. In this paper, we propose a signaling model to account for the molecular episodes that SVs induce within the cell, and in so doing we uncover a number of interesting questions that need to be addressed by future research in plant acoustics. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Concept of Operations for Commercial and Business Aircraft Synthetic Vision Systems. 1.0

NASA Technical Reports Server (NTRS)

Williams Daniel M.; Waller, Marvin C.; Koelling, John H.; Burdette, Daniel W.; Capron, William R.; Barry, John S.; Gifford, Richard B.; Doyle, Thomas M.

2001-01-01

A concept of operations (CONOPS) for the Commercial and Business (CaB) aircraft synthetic vision systems (SVS) is described. The CaB SVS is expected to provide increased safety and operational benefits in normal and low visibility conditions. Providing operational benefits will promote SVS implementation in the Net, improve aviation safety, and assist in meeting the national aviation safety goal. SVS will enhance safety and enable consistent gate-to-gate aircraft operations in normal and low visibility conditions. The goal for developing SVS is to support operational minima as low as Category 3b in a variety of environments. For departure and ground operations, the SVS goal is to enable operations with a runway visual range of 300 feet. The system is an integrated display concept that provides a virtual visual environment. The SVS virtual visual environment is composed of three components: an enhanced intuitive view of the flight environment, hazard and obstacle defection and display, and precision navigation guidance. The virtual visual environment will support enhanced operations procedures during all phases of flight - ground operations, departure, en route, and arrival. The applications selected for emphasis in this document include low visibility departures and arrivals including parallel runway operations, and low visibility airport surface operations. These particular applications were selected because of significant potential benefits afforded by SVS.

Exhibition of Stochastic Resonance in Vestibular Perception

NASA Technical Reports Server (NTRS)

Galvan-Garza, R. C.; Clark, T. K.; Merfeld, D. M.; Bloomberg, J. J.; Oman, C. M.; Mulavara, A. P.

2016-01-01

Astronauts experience sensorimotor changes during spaceflight, particularly during G-transitions. Post flight sensorimotor changes include spatial disorientation, along with postural and gait instability that may degrade operational capabilities of the astronauts and endanger the crew. A sensorimotor countermeasure that mitigates these effects would improve crewmember safety and decrease risk. The goal of this research is to investigate the potential use of stochastic vestibular stimulation (SVS) as a technology to improve sensorimotor function. We hypothesize that low levels of SVS will improve sensorimotor perception through the phenomenon of stochastic resonance (SR), when the response of a nonlinear system to a weak input signal is enhanced by the application of a particular nonzero level of noise. This study aims to advance the development of SVS as a potential countermeasure by 1) demonstrating the exhibition of stochastic resonance in vestibular perception, a vital component of sensorimotor function, 2) investigating the repeatability of SR exhibition, and 3) determining the relative contribution of the semicircular canals (SCC) and otolith (OTO) organs to vestibular perceptual SR. A constant current stimulator was used to deliver bilateral bipolar SVS via electrodes placed on each of the mastoid processes, as previously done. Vestibular perceptual motion recognition thresholds were measured using a 6-degree of freedom MOOG platform and a 150 trial 3-down/1-up staircase procedure. In the first test session, we measured vestibular perceptual thresholds in upright roll-tilt at 0.2 Hz (SCC+OTO) with SVS ranging from 0-700 µA. In a second test session a week later, we re-measured roll-tilt thresholds with 0, optimal (from test session 1), and 1500 µA SVS levels. A subset of these subjects, plus naive subjects, participated in two additional test sessions in which we measured thresholds in supine roll-rotation at 0.2 Hz (SCC) and upright y-translation at 1 Hz (OTO) with SVS up to 700 µA. A sinusoidal galvanic vestibular stimulation (GVS) perceptual threshold was also measured on each test day and used to normalize the SVS levels across subjects. In roll-tilt thresholds with SVS, the characteristic SR curve was qualitatively exhibited in 10 of 12 subjects, and the improvement in motion threshold was significant in 6 subjects, indicating that optimal SVS improved passive body motion perception in a way that is consistent with classical SR theory. A probabilistic comparison to numeric simulations further validated these experimental results. On the second test session, 4 out of the 10 SR exhibitors showed repeated improvement with SVS compared to the no SVS condition. Data collection is ongoing for the last two test sessions in which SCC and OTO only perceptual motion recognition thresholds are being measured with SVS. The final results of these test sessions will give insight into whether vestibular perceptual SR can occur when only one type of vestibular sensor is sensing motion or if it is more evident when sensory integration between the SCC and OTO is occurring during the motion. The overall purpose of this research is to further quantify the effects of SVS on various sensorimotor tasks and to gain a more fundamental understanding of how SVS causes SR in the vestibular system. In the context of human space flight, results from this research will help in understanding how SVS may be practically implemented in the future as a component of a comprehensive countermeasure plan for G-transition adaptation.

Initial Development of a Metric to Describe the Level of Safety Associated with Piloting an Aircraft with Synthetic Vision Systems (SVS) Displays

NASA Technical Reports Server (NTRS)

Bartolone, Anthony P.; Glabb, Louis J.; Hughes, Monica F.; Parrish, Russell V.

2005-01-01

Synthetic Vision Systems (SVS) displays provide pilots with a continuous view of terrain combined with integrated guidance symbology in an effort to increase situation awareness (SA) and decrease workload during operations in Instrument Meteorological Conditions (IMC). It is hypothesized that SVS displays can replicate the safety and operational flexibility of flight in Visual Meteorological Conditions (VMC), regardless of actual out-the-window (OTW) visibility or time of day. Significant progress has been made towards evolving SVS displays as well as demonstrating their ability to increase SA compared to conventional avionics in a variety of conditions. While a substantial amount of data has been accumulated demonstrating the capabilities of SVS displays, the ability of SVS to replicate the safety and operational flexibility of VMC flight performance in all visibility conditions is unknown to any specific degree. In order to more fully quantify the relationship of flight operations in IMC with SVS displays to conventional operations conducted in VMC, a fundamental comparison to current day general aviation (GA) flight instruments was warranted. Such a comparison could begin to establish the extent to which SVS display concepts are capable of maintaining an "equivalent level of safety" with the round dials they could one day replace, for both current and future operations. A combination of subjective and objective data measures were used to quantify the relationship between selected components of safety that are associated with flying an approach. Four information display methods ranging from a "round dials" baseline through a fully integrated SVS package that includes terrain, pathway based guidance, and a strategic navigation display, were investigated in this high fidelity simulation experiment. In addition, a broad spectrum of pilots, representative of the GA population, were employed for testing in an attempt to enable greater application of the results and determine if "equivalent levels of safety" are achievable through the incorporation of SVS technology regardless of a pilot's flight experience.

Age-related variations of varicose veins anatomy.

PubMed

Caggiati, Alberto; Rosi, Caterina; Heyn, Rosemarie; Franceschini, Marco; Acconcia, Maria Cristina

2006-12-01

Primary varicose veins are commonly considered a progressive disease starting from the saphenous junctions and extending to tributaries in a retrograde fashion along the saphenous trunks. This theory has been criticized by studies indicating different patterns of development and progression of varicose veins. To contribute to the understanding of the pathogenesis of the disease, the anatomy of the venous bed was comparatively evaluated by duplex sonography in patients with varicose veins with a marked difference in age. The study included 100 varicose limbs in 82 patients aged < 30 years and 238 limbs in 183 patients aged > 60 years. Veins were designated as saphenous veins (SVs), tributaries of the SVs (STVs), and veins not connected with the SVs (NSVs). Four main anatomic patterns were comparatively evaluated: (1) varicose changes only along SVs, (2) varicose changes along SVs and STVs, (3) varicose changes only in STVs, and (4) varicose changes only in NSVs. SVs were normal in 44% of varicose limbs. In most limbs from young subjects, varicose changes afflicted only SVTs (25%) and NSVs (36%). Varicose SVs were more frequent in the older group (62%) than in younger one (39%) owing to a higher prevalence of limbs with combined SV and STV varicosities (respectively, 59% and 37%). In the older group, varicosities in the STVs were more frequently observed in association with incompetence of the SV trunks. The frequent occurrence of normal SVs in varicose limbs of all patients does not support the crucial role commonly credited to SVs in the pathogenesis of primary varicosities. Moreover, the SV trunks were normal in most varicose limbs from young patients. These findings suggest that varicose disease may progressively extend in an antegrade fashion, spreading from the STVs to the SVs. This hypothesis suggests that the saphenous trunks could be spared in the treatment of a relevant number of varicose legs. Prospective longitudinal studies with serial duplex evaluations of large series of extremities are necessary to confirm this hypothesis.

Prevention of symptomatic vasospasm by continuous cisternal irrigation with mock-CSF containing ascorbic acid and Mg(2+).

PubMed

Satoh, Akira; Sugiyama, Tatsuya; Ooigawa, Hidetoshi; Nakajima, Hiroyuki; Ogura, Takeshi; Neki, Hiroaki; Morikawa, Eiharu

2010-01-01

Symptomatic vasospasm (SVS) is still a major cause of poor outcome in cases undergoing early surgical intervention for ruptured intracranial aneurysm. Among the numbers of therapeutic trials to prevent and ameliorate neurological deterioration due to SVS, removal or quenching of oxy-hemoglobin (OxyHb) from subarachnoid colts and administration of Mg(2+) (Mg) have especially been expected to be effective. In this report the authors investigated the effect of continuous cisternal irrigation (CCI) with mock CSF containing ascorbic acid (ASA) and Mg, performed after early surgery for ruptured aneurysm. Sixty-three cases which had received CCI were retrospectively compared with 40 control cases as to the incidence of SVS and outcome. Incidence of SVS was significantly less frequent (P < 0.05) in the CCI group (11%) than in the control group (25%). Severe and definitive SVS requiring additional specific treatment occurred only in 3.2% of the CCI group, while 22.5% in the control (P < 0.01). Overall outcome at discharge was significantly better in the CCI group than in the control (P < 0.01). Postoperative CCI with ASA and Mg was definitively effective in preventing SVS and in lessening severity of SVS if it occurs.

Clathrin coat controls synaptic vesicle acidification by blocking vacuolar ATPase activity

PubMed Central

Farsi, Zohreh; Rammner, Burkhard; Woehler, Andrew; Lafer, Eileen M; Mim, Carsten; Jahn, Reinhard

2018-01-01

Newly-formed synaptic vesicles (SVs) are rapidly acidified by vacuolar adenosine triphosphatases (vATPases), generating a proton electrochemical gradient that drives neurotransmitter loading. Clathrin-mediated endocytosis is needed for the formation of new SVs, yet it is unclear when endocytosed vesicles acidify and refill at the synapse. Here, we isolated clathrin-coated vesicles (CCVs) from mouse brain to measure their acidification directly at the single vesicle level. We observed that the ATP-induced acidification of CCVs was strikingly reduced in comparison to SVs. Remarkably, when the coat was removed from CCVs, uncoated vesicles regained ATP-dependent acidification, demonstrating that CCVs contain the functional vATPase, yet its function is inhibited by the clathrin coat. Considering the known structures of the vATPase and clathrin coat, we propose a model in which the formation of the coat surrounds the vATPase and blocks its activity. Such inhibition is likely fundamental for the proper timing of SV refilling. PMID:29652249

The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer.

PubMed

Ng, Charlotte K Y; Cooke, Susanna L; Howe, Kevin; Newman, Scott; Xian, Jian; Temple, Jillian; Batty, Elizabeth M; Pole, Jessica C M; Langdon, Simon P; Edwards, Paul A W; Brenton, James D

2012-04-01

High-grade serous ovarian carcinoma (HGSOC) is characterized by genomic instability, ubiquitous TP53 loss, and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOCs and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole-genome paired-end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SVs) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small deletions through its early evolution, but a revertant BRCA2 mutation restoring HR function in the resistant lineage re-stabilized its genome and reduced platinum sensitivity. The second case (PEO14/PEO23) had 216 tandem duplications and did not show evidence of HR or mismatch repair deficiency. By comparing the cell lines to the tissues from which they originated, we showed that the tandem duplicator mutator phenotype arose early in progression in vivo and persisted throughout evolution in vivo and in vitro, which may have enabled continual evolution. From the analysis of SNP array data from 454 HGSOC cases in The Cancer Genome Atlas series, we estimate that 12.8% of cases show patterns of aberrations similar to the tandem duplicator, and this phenotype is mutually exclusive with BRCA1/2 carrier mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Aspects of Synthetic Vision Display Systems and the Best Practices of the NASA's SVS Project

NASA Technical Reports Server (NTRS)

Bailey, Randall E.; Kramer, Lynda J.; Jones, Denise R.; Young, Steven D.; Arthur, Jarvis J.; Prinzel, Lawrence J.; Glaab, Louis J.; Harrah, Steven D.; Parrish, Russell V.

2008-01-01

NASA s Synthetic Vision Systems (SVS) Project conducted research aimed at eliminating visibility-induced errors and low visibility conditions as causal factors in civil aircraft accidents while enabling the operational benefits of clear day flight operations regardless of actual outside visibility. SVS takes advantage of many enabling technologies to achieve this capability including, for example, the Global Positioning System (GPS), data links, radar, imaging sensors, geospatial databases, advanced display media and three dimensional video graphics processors. Integration of these technologies to achieve the SVS concept provides pilots with high-integrity information that improves situational awareness with respect to terrain, obstacles, traffic, and flight path. This paper attempts to emphasize the system aspects of SVS - true systems, rather than just terrain on a flight display - and to document from an historical viewpoint many of the best practices that evolved during the SVS Project from the perspective of some of the NASA researchers most heavily involved in its execution. The Integrated SVS Concepts are envisagements of what production-grade Synthetic Vision systems might, or perhaps should, be in order to provide the desired functional capabilities that eliminate low visibility as a causal factor to accidents and enable clear-day operational benefits regardless of visibility conditions.

Validation of the Society for Vascular Surgery's objective performance goals for critical limb ischemia in everyday vascular surgery practice.

PubMed

Goodney, Philip P; Schanzer, Andres; Demartino, Randall R; Nolan, Brian W; Hevelone, Nathanael D; Conte, Michael S; Powell, Richard J; Cronenwett, Jack L

2011-07-01

To develop standardized metrics for expected outcomes in lower extremity revascularization for critical limb ischemia (CLI), the Society for Vascular Surgery (SVS) has developed objective performance goals (OPGs) based on aggregate data from randomized trials of lower extremity bypass (LEB). It remains unknown, however, if these targets can be achieved in everyday vascular surgery practice. We applied SVS OPG criteria to 1039 patients undergoing 1039 LEB operations for CLI with autogenous vein (excluding patients on dialysis) within the Vascular Study Group of New England (VSGNE). Each of the individual OPGs was calculated within the VSGNE dataset, along with its surrounding 95% confidence intervals (CIs) and compared to published SVS OPGs using χ(2) comparisons and survival analysis. Across most risk strata, patients in the VSGNE and SVS OPG cohorts were similar (clinical high-risk [age >80 years and tissue loss]: 15.3% VSGNE; 16.2% SVS OPG; P = .58; anatomic high risk [infrapopliteal target artery]: 57.8% VSGNE; 60.2% SVS OPG; P = .32). However, the proportion of VSGNE patients designated as conduit high-risk (lack of single-segment great saphenous vein) was lower (10.2% VSGNE; 26.9% SVS OPG;P < .001). The primary safety endpoint, major adverse limb events (MALE) at 30 days, was lower in the VSGNE cohort (3.2%; 95% CI, 2.3-4.6) than the SVS OPG cohort (6.2%; 95% CI, 4.2-8.1; P = .05). The primary efficacy OPG endpoint, freedom from any MALE or postoperative death within the first year (MALE + postoperative death [POD]), was similar between VSGNE and SVS OPG cohorts (77%; 95% CI, 74%-80%) SVS OPG, 74% (95% CI, 71%-77%) VSGNE, P = .58). In the remaining safety and efficacy OPGs, the VSGNE cohort met or exceeded the benchmarks established by the SVS OPG cohort. Community and academic centers in everyday vascular surgery practice can meet OPGs derived from centers of excellence in LEB. Quality improvement initiatives, as well as clinical trials, should incorporate OPGs in their outcome measures to facilitate communication and comparison of risk-adjusted outcomes in the treatment of CLI. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Overestimation of Susceptibility Vessel Sign: A Predictive Marker of Stroke Cause.

PubMed

Zhang, Ruiting; Zhou, Ying; Liu, Chang; Zhang, Meixia; Yan, Shenqiang; Liebeskind, David S; Lou, Min

2017-07-01

The extent of blooming artifact may reflect the amount of paramagnetic material. We thus assessed the overestimation ratio of susceptibility vessel sign (SVS) on susceptibility-weighted imaging, defined as the extent of SVS width beyond the lumen and examined its value for predicting the stroke cause in acute ischemic stroke patients. We included consecutive acute ischemic stroke patients with proximal large artery occlusion who underwent both susceptibility-weighted imaging and time-of-flight magnetic resonance angiography within 8 hours poststroke onset. We calculated the length, width, and overestimation ratio of SVS on susceptibility-weighted imaging and then investigated their values for predicting the stroke cause, respectively. One-hundred eleven consecutive patients (72 female; mean age, 66.6±13.4 years) were enrolled, among whom 39 (35.1%) were diagnosed with cardiogenic embolism, 43 (38.7%) with large artery atherosclerosis, and 29 (26.1%) with undetermined cause. The presence, length, width, and overestimation ratio of SVS were all independently associated with the cause of cardiogenic embolism after adjusting for baseline National Institute of Health Stroke Scale and infarct volume. After excluded patients with undetermined cause, the sensitivity and specificity of overestimation ratio of SVS for cardiogenic embolism were 0.971 and 0.913; for the length of SVS, they were 0.629 and 0.739; for the width of SVS, they were 0.829 and 0.826, respectively. The overestimation ratio of SVS can predict cardiogenic embolism, with both high sensitivity and specificity, which can be helpful for the management of acute ischemic stroke patients in hyperacute stage. © 2017 American Heart Association, Inc.

Improving Sensorimotor Function and Adaptation using Stochastic Vestibular Stimulation

NASA Technical Reports Server (NTRS)

Galvan, R. C.; Bloomberg, J. J.; Mulavara, A. P.; Clark, T. K.; Merfeld, D. M.; Oman, C. M.

2014-01-01

Astronauts experience sensorimotor changes during adaption to G-transitions that occur when entering and exiting microgravity. Post space flight, these sensorimotor disturbances can include postural and gait instability, visual performance changes, manual control disruptions, spatial disorientation, and motion sickness, all of which can hinder the operational capabilities of the astronauts. Crewmember safety would be significantly increased if sensorimotor changes brought on by gravitational changes could be mitigated and adaptation could be facilitated. The goal of this research is to investigate and develop the use of electrical stochastic vestibular stimulation (SVS) as a countermeasure to augment sensorimotor function and facilitate adaptation. For this project, SVS will be applied via electrodes on the mastoid processes at imperceptible amplitude levels. We hypothesize that SVS will improve sensorimotor performance through the phenomena of stochastic resonance, which occurs when the response of a nonlinear system to a weak input signal is optimized by the application of a particular nonzero level of noise. In line with the theory of stochastic resonance, a specific optimal level of SVS will be found and tested for each subject [1]. Three experiments are planned to investigate the use of SVS in sensory-dependent tasks and performance. The first experiment will aim to demonstrate stochastic resonance in the vestibular system through perception based motion recognition thresholds obtained using a 6-degree of freedom Stewart platform in the Jenks Vestibular Laboratory at Massachusetts Eye and Ear Infirmary. A range of SVS amplitudes will be applied to each subject and the subjectspecific optimal SVS level will be identified as that which results in the lowest motion recognition threshold, through previously established, well developed methods [2,3,4]. The second experiment will investigate the use of optimal SVS in facilitating sensorimotor adaptation to system disturbances. Subjects will adapt to wearing minifying glasses, resulting in decreased vestibular ocular reflex (VOR) gain. The VOR gain will then be intermittently measured while the subject readapts to normal vision, with and without optimal SVS. We expect that optimal SVS will cause a steepening of the adaptation curve. The third experiment will test the use of optimal SVS in an operationally relevant aerospace task, using the tilt translation sled at NASA Johnson Space Center, a test platform capable of recreating the tilt-gain and tilt-translation illusions associated with landing of a spacecraft post-space flight. In this experiment, a perception based manual control measure will be used to compare performance with and without optimal SVS. We expect performance to improve in this task when optimal SVS is applied. The ultimate goal of this work is to systematically investigate and further understand the potential benefits of stochastic vestibular stimulation in the context of human space flight so that it may be used in the future as a component of a comprehensive countermeasure plan for adaptation to G-transitions.

78 FR 16756 - Twenty-Second Meeting: RTCA Special Committee 213, Enhanced Flight Vision Systems/Synthetic...

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Fast Query-Optimized Kernel-Machine Classification

NASA Technical Reports Server (NTRS)

Mazzoni, Dominic; DeCoste, Dennis

2004-01-01

A recently developed algorithm performs kernel-machine classification via incremental approximate nearest support vectors. The algorithm implements support-vector machines (SVMs) at speeds 10 to 100 times those attainable by use of conventional SVM algorithms. The algorithm offers potential benefits for classification of images, recognition of speech, recognition of handwriting, and diverse other applications in which there are requirements to discern patterns in large sets of data. SVMs constitute a subset of kernel machines (KMs), which have become popular as models for machine learning and, more specifically, for automated classification of input data on the basis of labeled training data. While similar in many ways to k-nearest-neighbors (k-NN) models and artificial neural networks (ANNs), SVMs tend to be more accurate. Using representations that scale only linearly in the numbers of training examples, while exploring nonlinear (kernelized) feature spaces that are exponentially larger than the original input dimensionality, KMs elegantly and practically overcome the classic curse of dimensionality. However, the price that one must pay for the power of KMs is that query-time complexity scales linearly with the number of training examples, making KMs often orders of magnitude more computationally expensive than are ANNs, decision trees, and other popular machine learning alternatives. The present algorithm treats an SVM classifier as a special form of a k-NN. The algorithm is based partly on an empirical observation that one can often achieve the same classification as that of an exact KM by using only small fraction of the nearest support vectors (SVs) of a query. The exact KM output is a weighted sum over the kernel values between the query and the SVs. In this algorithm, the KM output is approximated with a k-NN classifier, the output of which is a weighted sum only over the kernel values involving k selected SVs. Before query time, there are gathered statistics about how misleading the output of the k-NN model can be, relative to the outputs of the exact KM for a representative set of examples, for each possible k from 1 to the total number of SVs. From these statistics, there are derived upper and lower thresholds for each step k. These thresholds identify output levels for which the particular variant of the k-NN model already leans so strongly positively or negatively that a reversal in sign is unlikely, given the weaker SV neighbors still remaining. At query time, the partial output of each query is incrementally updated, stopping as soon as it exceeds the predetermined statistical thresholds of the current step. For an easy query, stopping can occur as early as step k = 1. For more difficult queries, stopping might not occur until nearly all SVs are touched. A key empirical observation is that this approach can tolerate very approximate nearest-neighbor orderings. In experiments, SVs and queries were projected to a subspace comprising the top few principal- component dimensions and neighbor orderings were computed in that subspace. This approach ensured that the overhead of the nearest-neighbor computations was insignificant, relative to that of the exact KM computation.

Improving Sensorimotor Function Using Stochastic Vestibular Stimulation

NASA Technical Reports Server (NTRS)

Galvan, R. C.; Clark, T. K.; Merfeld, D. M.; Bloomberg, J. J.; Mulavara, A. P.; Oman, C. M.

2014-01-01

Astronauts experience sensorimotor changes during spaceflight, particularly during G-transition phases. Post flight sensorimotor changes may include postural and gait instability, spatial disorientation, and visual performance decrements, all of which can degrade operational capabilities of the astronauts and endanger the crew. Crewmember safety would be improved if these detrimental effects of spaceflight could be mitigated by a sensorimotor countermeasure and even further if adaptation to baseline could be facilitated. The goal of this research is to investigate the potential use of stochastic vestibular stimulation (SVS) as a technology to improve sensorimotor function. We hypothesize that low levels of SVS will improve sensorimotor performance through stochastic resonance (SR). The SR phenomenon occurs when the response of a nonlinear system to a weak input signal is optimized by the application of a particular nonzero level of noise. Two studies have been initiated to investigate the beneficial effects and potential practical usage of SVS. In both studies, electrical vestibular stimulation is applied via electrodes on the mastoid processes using a constant current stimulator. The first study aims to determine the repeatability of the effect of vestibular stimulation on sensorimotor performance and perception in order to better understand the practical use of SVS. The beneficial effect of low levels of SVS on balance performance has been shown in the past. This research uses the same balance task repeated multiple times within a day and across days to study the repeatability of the stimulation effects. The balance test consists of 50 sec trials in which the subject stands with his or her feet together, arms crossed, and eyes closed on compliant foam. Varying levels of SVS, ranging from 0-700 micro A, are applied across different trials. The subject-specific optimal SVS level is that which results in the best balance performance as measured by inertial measurement units placed on the upper and lower torso of the subjects. Additionally, each individual’s threshold for illusory motion perception of suprasensory electrical vestibular stimulation is measured multiple times within and across days to better understand how multiple SVS test methods compare. The second study aims to demonstrate stochastic resonance in the vestibular system using a perception based motion recognition task. This task measures an individual’s velocity threshold of motion recognition using a 6-degree of freedom Stewart platform and a 3-down/1-up staircase procedure. For this study, thresholds are determined using 150 trials in the upright, head-centered roll tilt motion direction at a 0.2 Hz frequency. We aim to demonstrate the characteristic bell shaped curve associated with stochastic resonance with each subject’s motion recognition thresholds at varying SVS levels ranging from 0 to 1500 micro A. The curve includes the individual’s baseline threshold with no SVS, optimal or minimal threshold at some mid-level of SVS, and finally degraded or increased threshold at a high SVS level. An additional aim is to formally retest each subject at his or her individual optimal SVS level on a different day than the original testing for additional validity. The overall purpose of this research is to further quantify the effects of SVS on various sensorimotor tasks and investigate the practical implications of its use in the context of human space flight so that it may be implemented in the future as a component of a comprehensive countermeasure plan for adaptation to G-transitions.

Stevioside improves pancreatic beta-cell function during glucotoxicity via regulation of acetyl-CoA carboxylase.

PubMed

Chen, Jianguo; Jeppesen, Per Bendix; Nordentoft, Iver; Hermansen, Kjeld

2007-06-01

Chronic hyperglycemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and beta-cell turnover. The characteristic secretory defects are increased basal insulin secretion (BIS) and a selective loss of glucose-stimulated insulin secretion (GSIS). Several recent studies support the view that the acetyl-CoA carboxylase (ACC) plays a pivotal role for GSIS. We have shown that stevioside (SVS) enhances insulin secretion and ACC gene expression. Whether glucotoxicity influences ACC and whether this action can be counteracted by SVS are not known. To investigate this, we exposed isolated mouse islets as well as clonal INS-1E beta-cells for 48 h to 27 or 16.7 mM glucose, respectively. We found that 48-h exposure to high glucose impairs GSIS from mouse islets and INS-1E cells, an effect that is partly counteracted by SVS. The ACC dephosphorylation inhibitor okadaic acid (OKA, 10(-8) M), and 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR, 10(-4) M), an activator of 5'-AMP protein kinase that phosphorylates ACC, eliminated the beneficial effect of SVS. 5-Tetrade-cyloxy-2-furancarboxylic acid (TOFA), the specific ACC inhibitor, blocked the effect of SVS as well. During glucotoxity, ACC gene expression, ACC protein, and phosphorylated ACC protein were increased in INS-1E beta-cells. SVS pretreatment further increased ACC gene expression with strikingly elevated ACC activity and increased glucose uptake accompanied by enhanced GSIS. Our studies show that glucose is a potent stimulator of ACC and that SVS to some extent counteracts glucotoxicity via increased ACC activity. SVS possesses the potential to alleviate negative effects of glucotoxicity in beta-cells via a unique mechanism of action.

Transport of fungal RAB11 secretory vesicles involves myosin-5, dynein/dynactin/p25, and kinesin-1 and is independent of kinesin-3

PubMed Central

Peñalva, Miguel A.; Zhang, Jun; Xiang, Xin; Pantazopoulou, Areti

2017-01-01

Hyphal tip cells of the fungus Aspergillus nidulans are useful for studying long-range intracellular traffic. Post-Golgi secretory vesicles (SVs) containing the RAB11 orthologue RabE engage myosin-5 as well as plus end– and minus end–directed microtubule motors, providing an experimental system with which to investigate the interplay between microtubule and actin motors acting on the same cargo. By exploiting the fact that depolymerization of F-actin unleashes SVs focused at the apex by myosin-5 to microtubule-dependent motors, we establish that the minus end–directed transport of SVs requires the dynein/dynactin supercomplex. This minus end–directed transport is largely unaffected by genetic ablation of the Hook complex adapting early endosomes (EEs) to dynein but absolutely requires p25 in dynactin. Thus dynein recruitment to two different membranous cargoes, namely EEs and SVs, requires p25, highlighting the importance of the dynactin pointed-end complex to scaffold cargoes. Finally, by studying the behavior of SVs and EEs in null and rigor mutants of kinesin-3 and kinesin-1 (UncA and KinA, respectively), we demonstrate that KinA is the major kinesin mediating the anterograde transport of SVs. Therefore SVs arrive at the apex of A. nidulans by anterograde transport involving cooperation of kinesin-1 with myosin-5 and can move away from the apex powered by dynein. PMID:28209731

Estimation of Optimum Stimulus Amplitude for Balance Training using Electrical Stimulation of the Vestibular System

NASA Technical Reports Server (NTRS)

Goel, R.; Rosenberg, M. J.; De Dios, Y. E.; Cohen, H. S.; Bloomberg, J. J.; Mulavara, A. P.

2016-01-01

Sensorimotor changes such as posture and gait instabilities can affect the functional performance of astronauts after gravitational transitions. Sensorimotor Adaptability (SA) training can help alleviate decrements on exposure to novel sensorimotor environments based on the concept of 'learning to learn' by exposure to varying sensory challenges during posture and locomotion tasks (Bloomberg 2015). Supra-threshold Stochastic Vestibular Stimulation (SVS) can be used to provide one of many challenges by disrupting vestibular inputs. In this scenario, the central nervous system can be trained to utilize veridical information from other sensory inputs, such as vision and somatosensory inputs, for posture and locomotion control. The minimum amplitude of SVS to simulate the effect of deterioration in vestibular inputs for preflight training or for evaluating vestibular contribution in functional tests in general, however, has not yet been identified. Few studies (MacDougall 2006; Dilda 2014) have used arbitrary but fixed maximum current amplitudes from 3 to 5 mA in the medio-lateral (ML) direction to disrupt balance function in healthy adults. Giving this high level of current amplitude to all the individuals has a risk of invoking side effects such as nausea and discomfort. The goal of this study was to determine the minimum SVS level that yields an equivalently degraded balance performance. Thirteen subjects stood on a compliant foam surface with their eyes closed and were instructed to maintain a stable upright stance. Measures of stability of the head, trunk, and whole body were quantified in the ML direction. Duration of time they could stand on the foam surface was also measured. The minimum SVS dosage was defined to be that level which significantly degraded balance performance such that any further increase in stimulation level did not lead to further balance degradation. The minimum SVS level was determined by performing linear fits on the performance variable at different stimulation levels. Results from the balance task suggest that there are inter-individual differences and the minimum SVS amplitude was found to be in the range of 1 mA to 2.5 mA across subjects. SVS resulted in an average decrement of balance task performance in the range of 62%-73% across different measured variables at the minimum SVS amplitude in comparison to the control trial (no stimulus). Training using supra-threshold SVS stimulation is one of the sensory challenges used for preflight SA training designed to improve adaptability to novel gravitational environments. Inter-individual differences in response to SVS can help customize the SA training paradigms using minimal dosage required. Another application of using SVS is to simulate acute deterioration of vestibular sensory inputs in the evaluation of tests for assessing vestibular function.

Flight Test Evaluation of Synthetic Vision Concepts at a Terrain Challenged Airport

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Prince, Lawrence J., III; Bailey, Randell E.; Arthur, Jarvis J., III; Parrish, Russell V.

2004-01-01

NASA's Synthetic Vision Systems (SVS) Project is striving to eliminate poor visibility as a causal factor in aircraft accidents as well as enhance operational capabilities of all aircraft through the display of computer generated imagery derived from an onboard database of terrain, obstacle, and airport information. To achieve these objectives, NASA 757 flight test research was conducted at the Eagle-Vail, Colorado airport to evaluate three SVS display types (Head-up Display, Head-Down Size A, Head-Down Size X) and two terrain texture methods (photo-realistic, generic) in comparison to the simulated Baseline Boeing-757 Electronic Attitude Direction Indicator and Navigation/Terrain Awareness and Warning System displays. The results of the experiment showed significantly improved situation awareness, performance, and workload for SVS concepts compared to the Baseline displays and confirmed the retrofit capability of the Head-Up Display and Size A SVS concepts. The research also demonstrated that the tunnel guidance display concept used within the SVS concepts achieved required navigation performance (RNP) criteria.

Human factors flight trial analysis for 3D SVS: part II

NASA Astrophysics Data System (ADS)

Schiefele, Jens; Howland, Duncan; Maris, John; Pschierer, Christian; Wipplinger, Patrick; Meuter, Michael

2005-05-01

This paper describes flight trials performed in Centennial, CO using a Piper Cheyenne owned and operated by Marinvent. The goal of the flight trial was to evaluate the objective performance of pilots using conventional paper charts or a 3D SVS display. Six pilots flew thirty-six approaches to the Colorado Springs airport to accomplish this goal. As dependent variables, positional accuracy and situational awareness probe (SAP) statistics were measured while analysis was conducted by an ANOVA test. In parallel, all pilots answered subjective Cooper-Harper, NASA TLX, situation awareness rating technique (SART), Display Readability Rating, Display Flyability Rating and debriefing questionnaires. Three different settings (paper chart, electronic navigation chart, 3D SVS display) were evaluated in a totally randomized manner. This paper describes the comparison between the conventional paper chart and the 3D SVS display. The 3D SVS primary flight display provides a depiction of primary flight data as well as a 3D depiction of airports, terrain and obstacles. In addition, a 3D dynamic channel visualizing the selected approach procedure can be displayed. The result shows that pilots flying the 3D SVS display perform no worse than pilots with the conventional paper chart. Flight technical error and workload are lower, situational awareness is equivalent with conventional paper charts.

Adding Biotin to Parenteral Nutrition Solutions Without Lipid Accelerates the Growth of Candida albicans.

PubMed

Kuwahara, Takashi; Kaneda, Shinya; Shimono, Kazuyuki

2016-01-01

We have previously demonstrated that Candida albicans requires multivitamins (MVs) or lipid to increase rapidly in parenteral nutrition (PN) solutions. In this study, in detail, the effects of vitamins on the growth of C. albicans in PN solutions without lipid were investigated. In the 1st experiment, a commercial PN solution without lipid was supplemented with water-soluble vitamins (SVs: vitamins B1, B2, B6, B12 and C, folic acid, nicotinamide, biotin and panthenol), water-insoluble vitamins (IVs: vitamins A, D, E and K) or both (MVs). In the 2nd experiment, the test solutions were prepared by supplementing the PN solution with one of each or all of the SVs. In the 3rd experiment, another commercial peripheral PN (PPN) solution without lipid was supplemented with SVs, nicotinic acid, biotin or both nicotinic acid and biotin. In each of the experiments, a specified number of C. albicans organisms was added to each test solution, and all of the test solutions were allowed to stand at room temperature (23-26ºC). The number of C. albicans was counted at 0, 24, 48 and 72 hours after the addition of the organism. In the 1st experiment, the C. albicans increased rapidly in the PN solution supplemented with the SVs, but increased slowly without the SVs, regardless of the addition of the IVs. In the 2nd experiment, the C. albicans increased rapidly in the PN solution supplemented with the SVs or biotin, but increased slowly with each of the other water-soluble vitamins. In the 3rd experiment, the C. albicans increased rapidly in the PPN solution supplemented with the SVs or biotin, but increased slowly with the addition of nicotinic acid. These results suggested that adding MVs or SVs to PN solutions without lipid promotes the growth of C. albicans, and that this effect is mostly attributable to biotin.

Transition of Attention in Terminal Area NextGen Operations Using Synthetic Vision Systems

NASA Technical Reports Server (NTRS)

Ellis, Kyle K. E.; Kramer, Lynda J.; Shelton, Kevin J.; Arthur, Shelton, J. J., III; Prinzel, Lance J., III; Norman, Robert M.

2011-01-01

This experiment investigates the capability of Synthetic Vision Systems (SVS) to provide significant situation awareness in terminal area operations, specifically in low visibility conditions. The use of a Head-Up Display (HUD) and Head-Down Displays (HDD) with SVS is contrasted to baseline standard head down displays in terms of induced workload and pilot behavior in 1400 RVR visibility levels. Variances across performance and pilot behavior were reviewed for acceptability when using HUD or HDD with SVS under reduced minimums to acquire the necessary visual components to continue to land. The data suggest superior performance for HUD implementations. Improved attentional behavior is also suggested for HDD implementations of SVS for low-visibility approach and landing operations.

Anticancer β-hairpin peptides: membrane-induced folding triggers activity

PubMed Central

Sinthuvanich, Chomdao; Veiga, Ana Salomé; Gupta, Kshitij; Gaspar, Diana; Blumenthal, Robert; Schneider, Joel P.

2012-01-01

Several cationic antimicrobial peptides (AMPs) have recently been shown to display anticancer activity via a mechanism that usually entails the disruption of cancer cell membranes. In this work, we designed an 18-residue anticancer peptide, SVS-1, whose mechanism of action is designed to take advantage of the aberrant lipid composition presented on the outer leaflet of cancer cell membranes, which makes the surface of these cells relatively electronegative relative to non-cancerous cells. SVS-1 is designed to remain unfolded and inactive in aqueous solution but preferentially fold at the surface of cancer cells, adopting an amphiphilic β-hairpin structure capable of membrane disruption. Membrane-induced folding is driven by electrostatic interaction between the peptide and the negatively charge membrane surface of cancer cells. SVS-1 is active against a variety of cancer cell lines such as A549 (lung carcinoma), KB (epidermal carcinoma), MCF-7 (breast carcinoma) and MDA-MB-436 (breast carcinoma). However, the cytotoxicity towards non-cancerous cells having typical membrane compositions, such as HUVEC and erythrocytes, is low. CD spectroscopy, appropriately designed peptide controls, cell-based studies, liposome leakage assays and electron microscopy support the intended mechanism of action, which leads to preferential killing of cancerous cells. PMID:22413859

Influence of Pig Farming on the Human Nasal Microbiota: Key Role of Airborne Microbial Communities

PubMed Central

Kraemer, Julia G.; Ramette, Alban; Aebi, Suzanne; Oppliger, Anne

2018-01-01

ABSTRACT It has been hypothesized that the environment can influence the composition of the nasal microbiota. However, the direct influence of pig farming on the anterior and posterior nasal microbiota is unknown. Using a cross-sectional design, pig farms (n = 28) were visited in 2014 to 2015, and nasal swabs from 43 pig farmers and 56 pigs, as well as 27 air samples taken in the vicinity of the pig enclosures, were collected. As controls, nasal swabs from 17 cow farmers and 26 non-animal-exposed individuals were also included. Analyses of the microbiota were performed based on 16S rRNA amplicon sequencing and the DADA2 pipeline to define sequence variants (SVs). We found that pig farming is strongly associated with specific microbial signatures (including alpha- and beta-diversity), which are reflected in the microbiota of the human nose. Furthermore, the microbial communities were more similar within the same farm compared to between the different farms, indicating a specific microbiota pattern for each pig farm. In total, there were 82 SVs that occurred significantly more abundantly in samples from pig farms than from cow farmers and nonexposed individuals (i.e., the core pig farm microbiota). Of these, nine SVs were significantly associated with the posterior part of the human nose. The results strongly indicate that pig farming is associated with a distinct human nose microbiota. Finally, the community structures derived by the DADA2 pipeline showed an excellent agreement with the outputs of the mothur pipeline which was revealed by procrustes analyses. IMPORTANCE The knowledge about the influence of animal keeping on the human microbiome is important. Previous research has shown that pets significantly affect the microbial communities of humans. However, the effect of animal farming on the human microbiota is less clear, although it is known that the air at farms and, in particular, at pig farms is charged with large amounts of dust, bacteria, and fungi. In this study, we simultaneously investigated the nasal microbiota of pigs, humans, and the environment at pig farms. We reveal an enormous impact of pig farming on the human nasal microbiota which is far more pronounced compared to cow farming. In addition, we analyzed the airborne microbiota and found significant associations suggesting an animal-human transmission of the microbiota within pig farms. We also reveal that microbial patterns are farm specific, suggesting that the environment influences animals and humans in a similar manner. PMID:29330190

Novel pH-Sensitive Lipid Based Exo-Endocytosis Tracers Reveal Fast Intermixing of Synaptic Vesicle Pools

PubMed Central

Kahms, Martin; Klingauf, Jürgen

2018-01-01

Styryl dyes and genetically encoded pH-sensitive fluorescent proteins like pHluorin are well-established tools for the optical analysis of synaptic vesicle (SV) recycling at presynaptic boutons. Here, we describe the development of a new class of fluorescent probes based on pH-sensitive organic dyes covalently bound to lipids, providing a promising complementary assay to genetically encoded fluorescent probes. These new optical tracers allow a pure read out of membrane turnover during synaptic activity and visualization of multiple rounds of stimulation-dependent SV recycling without genetic perturbation. Measuring the incorporation efficacy of different dye-labeled lipids into budding SVs, we did not observe an enrichment of lipids with affinity for liquid ordered membrane domains. But most importantly, we found no evidence for a static segregation of SVs into recycling and resting pools. A small but significant fraction of SVs that is reluctant to release during a first round of evoked activity can be exocytosed during a second bout of stimulation, showing fast intermixing of SV pools within seconds. Furthermore, we found that SVs recycling spontaneously have a higher chance to re-occupy release sites than SVs recycling during high-frequency evoked activity. In summary, our data provide strong evidence for a highly dynamic and use-dependent control of the fractions of releasable or resting SVs. PMID:29456492

Certifiable database generation for SVS

NASA Astrophysics Data System (ADS)

Schiefele, Jens; Damjanovic, Dejan; Kubbat, Wolfgang

2000-06-01

In future aircraft cockpits SVS will be used to display 3D physical and virtual information to pilots. A review of prototype and production Synthetic Vision Displays (SVD) from Euro Telematic, UPS Advanced Technologies, Universal Avionics, VDO-Luftfahrtgeratewerk, and NASA, are discussed. As data sources terrain, obstacle, navigation, and airport data is needed, Jeppesen-Sanderson, Inc. and Darmstadt Univ. of Technology currently develop certifiable methods for acquisition, validation, and processing methods for terrain, obstacle, and airport databases. The acquired data will be integrated into a High-Quality Database (HQ-DB). This database is the master repository. It contains all information relevant for all types of aviation applications. From the HQ-DB SVS relevant data is retried, converted, decimated, and adapted into a SVS Real-Time Onboard Database (RTO-DB). The process of data acquisition, verification, and data processing will be defined in a way that allows certication within DO-200a and new RTCA/EUROCAE standards for airport and terrain data. The open formats proposed will be established and evaluated for industrial usability. Finally, a NASA-industry cooperation to develop industrial SVS products under the umbrella of the NASA Aviation Safety Program (ASP) is introduced. A key element of the SVS NASA-ASP is the Jeppesen lead task to develop methods for world-wide database generation and certification. Jeppesen will build three airport databases that will be used in flight trials with NASA aircraft.

Chemical properties and GMR improvement of specular spin valves with nano-oxide layers, formed in ambient mixed gases

NASA Astrophysics Data System (ADS)

Quang, H. D.; Hien, N. T.; Oh, S. K.; Sinh, N. H.; Yu, S. C.

2004-12-01

Specular spin valves (SVs) containing nano-oxide layers (NOLs) structured as substrate/seed/AF/P1/NOL/P2/Cu/F/NOL, have been fabricated. The NOLs were formed by natural oxidation in different ambient atmospheres of pure oxygen, oxygen/nitrogen and oxygen/argon gas mixtures. The fabrication conditions were optimized to enhance the magnetoresistance (MR) ratio, to suppress the interlayer coupling fields (Hf) between the free and pinned layers, to suppress the high interface density of the NOL, to ease the control of the NOL thickness and to form a smooth NOL/P2 interface for promoting specular electron scattering. The characteristics of our specular SVs are the MR ratio of 14.1%, the exchange bias field of 44-45 mT, and Hf weaker than 1.0 mT. The optimal conditions for oxidation time, total oxidation pressure and the annealing temperature were found to be 300 s, 0.14 Pa (oxygen/argon = 80/20) and 250°C, respectively. Also, the origin of thermal stability of MMn-based (M = Fe, Pt, Ir, etc) specular SVs has been explained in detail by chemical properties of NOL using secondary-ion mass spectroscopy and x-ray photoelectron spectroscopy depth profile analyses. Thermal stability turns out to be caused by a decrease in MR ratios at high temperatures (>250°C), which is a serious problem for device applications using the SV structure as a high density read head device.

How neurosecretory vesicles release their cargo.

PubMed

Scalettar, Bethe A

2006-04-01

Neurons and related cell types often contain two major classes of neurosecretory vesicles, synaptic vesicles (SVs) and dense-core granules (DCGs), which store and release distinct cargo. SVs store and release classic neurotransmitters, which facilitate propagation of action potentials across the synaptic cleft, whereas DCGs transport, store, and release hormones, proteins, and neuropeptides, which facilitate neuronal survival, synaptic transmission, and learning. Over the past few years, there has been a major surge in our understanding of many of the key molecular mechanisms underlying cargo release from SVs and DCGs. This surge has been driven largely by the use of fluorescence microscopy (especially total internal reflection fluorescence microscopy) to visualize SVs or DCGs in living cells. This review highlights some of the recent insights into cargo release from neurosecretory vesicles provided by fluorescence microscopy, with emphasis on DCGs.

Bioinformatic analysis of meningococcal Msf and Opc to inform vaccine antigen design

PubMed Central

Andreae, Clio A.; Sessions, Richard B.; Virji, Mumtaz

2018-01-01

Neisseria meningitidis is an antigenically and genetically variable Gram-negative bacterium and a causative agent of meningococcal meningitis and septicaemia. Meningococci encode many outer membrane proteins, including Opa, Opc, Msf, fHbp and NadA, identified as being involved in colonisation of the host and evasion of the immune response. Although vaccines are available for the prevention of some types of meningococcal disease, none currently offer universal protection. We have used sequences within the Neisseria PubMLST database to determine the variability of msf and opc in 6,500 isolates. In-silico analysis revealed that although opc is highly conserved, it is not present in all isolates, with most isolates in clonal complex ST-11 lacking a functional opc. In comparison, msf is found in all meningococcal isolates, and displays diversity in the N-terminal domain. We identified 20 distinct Msf sequence variants (Msf SV), associated with differences in number of residues within the putative Vn binding motifs. Moreover, we showed distinct correlations with certain Msf SVs and isolates associated with either hyperinvasive lineages or those clonal complexes associated with a carriage state. We have demonstrated differences in Vn binding between three Msf SVs and generated a cross reactive Msf polyclonal antibody. Our study has highlighted the importance of using large datasets to inform vaccine development and provide further information on the antigenic diversity exhibited by N. meningitidis. PMID:29547646

Bioinformatic analysis of meningococcal Msf and Opc to inform vaccine antigen design.

PubMed

Andreae, Clio A; Sessions, Richard B; Virji, Mumtaz; Hill, Darryl J

2018-01-01

Neisseria meningitidis is an antigenically and genetically variable Gram-negative bacterium and a causative agent of meningococcal meningitis and septicaemia. Meningococci encode many outer membrane proteins, including Opa, Opc, Msf, fHbp and NadA, identified as being involved in colonisation of the host and evasion of the immune response. Although vaccines are available for the prevention of some types of meningococcal disease, none currently offer universal protection. We have used sequences within the Neisseria PubMLST database to determine the variability of msf and opc in 6,500 isolates. In-silico analysis revealed that although opc is highly conserved, it is not present in all isolates, with most isolates in clonal complex ST-11 lacking a functional opc. In comparison, msf is found in all meningococcal isolates, and displays diversity in the N-terminal domain. We identified 20 distinct Msf sequence variants (Msf SV), associated with differences in number of residues within the putative Vn binding motifs. Moreover, we showed distinct correlations with certain Msf SVs and isolates associated with either hyperinvasive lineages or those clonal complexes associated with a carriage state. We have demonstrated differences in Vn binding between three Msf SVs and generated a cross reactive Msf polyclonal antibody. Our study has highlighted the importance of using large datasets to inform vaccine development and provide further information on the antigenic diversity exhibited by N. meningitidis.

MOSAIK: a hash-based algorithm for accurate next-generation sequencing short-read mapping.

PubMed

Lee, Wan-Ping; Stromberg, Michael P; Ward, Alistair; Stewart, Chip; Garrison, Erik P; Marth, Gabor T

2014-01-01

MOSAIK is a stable, sensitive and open-source program for mapping second and third-generation sequencing reads to a reference genome. Uniquely among current mapping tools, MOSAIK can align reads generated by all the major sequencing technologies, including Illumina, Applied Biosystems SOLiD, Roche 454, Ion Torrent and Pacific BioSciences SMRT. Indeed, MOSAIK was the only aligner to provide consistent mappings for all the generated data (sequencing technologies, low-coverage and exome) in the 1000 Genomes Project. To provide highly accurate alignments, MOSAIK employs a hash clustering strategy coupled with the Smith-Waterman algorithm. This method is well-suited to capture mismatches as well as short insertions and deletions. To support the growing interest in larger structural variant (SV) discovery, MOSAIK provides explicit support for handling known-sequence SVs, e.g. mobile element insertions (MEIs) as well as generating outputs tailored to aid in SV discovery. All variant discovery benefits from an accurate description of the read placement confidence. To this end, MOSAIK uses a neural-network based training scheme to provide well-calibrated mapping quality scores, demonstrated by a correlation coefficient between MOSAIK assigned and actual mapping qualities greater than 0.98. In order to ensure that studies of any genome are supported, a training pipeline is provided to ensure optimal mapping quality scores for the genome under investigation. MOSAIK is multi-threaded, open source, and incorporated into our command and pipeline launcher system GKNO (http://gkno.me).

MOSAIK: A Hash-Based Algorithm for Accurate Next-Generation Sequencing Short-Read Mapping

PubMed Central

Lee, Wan-Ping; Stromberg, Michael P.; Ward, Alistair; Stewart, Chip; Garrison, Erik P.; Marth, Gabor T.

2014-01-01

MOSAIK is a stable, sensitive and open-source program for mapping second and third-generation sequencing reads to a reference genome. Uniquely among current mapping tools, MOSAIK can align reads generated by all the major sequencing technologies, including Illumina, Applied Biosystems SOLiD, Roche 454, Ion Torrent and Pacific BioSciences SMRT. Indeed, MOSAIK was the only aligner to provide consistent mappings for all the generated data (sequencing technologies, low-coverage and exome) in the 1000 Genomes Project. To provide highly accurate alignments, MOSAIK employs a hash clustering strategy coupled with the Smith-Waterman algorithm. This method is well-suited to capture mismatches as well as short insertions and deletions. To support the growing interest in larger structural variant (SV) discovery, MOSAIK provides explicit support for handling known-sequence SVs, e.g. mobile element insertions (MEIs) as well as generating outputs tailored to aid in SV discovery. All variant discovery benefits from an accurate description of the read placement confidence. To this end, MOSAIK uses a neural-network based training scheme to provide well-calibrated mapping quality scores, demonstrated by a correlation coefficient between MOSAIK assigned and actual mapping qualities greater than 0.98. In order to ensure that studies of any genome are supported, a training pipeline is provided to ensure optimal mapping quality scores for the genome under investigation. MOSAIK is multi-threaded, open source, and incorporated into our command and pipeline launcher system GKNO (http://gkno.me). PMID:24599324

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

PubMed Central

Morrison, Carl D.; Liu, Pengyuan; Woloszynska-Read, Anna; Zhang, Jianmin; Luo, Wei; Qin, Maochun; Bshara, Wiam; Conroy, Jeffrey M.; Sabatini, Linda; Vedell, Peter; Xiong, Donghai; Liu, Song; Wang, Jianmin; Shen, He; Li, Yinwei; Omilian, Angela R.; Hill, Annette; Head, Karen; Guru, Khurshid; Kunnev, Dimiter; Leach, Robert; Eng, Kevin H.; Darlak, Christopher; Hoeflich, Christopher; Veeranki, Srividya; Glenn, Sean; You, Ming; Pruitt, Steven C.; Johnson, Candace S.; Trump, Donald L.

2014-01-01

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as “stitchers,” to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication–licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer. PMID:24469795

Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals

PubMed Central

Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

2016-01-01

The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission. PMID:27242505

Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals.

PubMed

Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

2016-01-01

The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.

Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-{kappa}B pathway

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

Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui

Highlights: Black-Right-Pointing-Pointer Stevioside ameliorates high-fat diet-induced insulin resistance. Black-Right-Pointing-Pointer Stevioside alleviates the adipose tissue inflammation. Black-Right-Pointing-Pointer Stevioside reduces macrophages infiltration into the adipose tissue. Black-Right-Pointing-Pointer Stevioside suppresses the activation of NF-{kappa}B in the adipose tissue. -- Abstract: Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration ofmore » SVS for 1 month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-{alpha}, IL6, IL10, IL1{beta}, KC, MIP-1{alpha}, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-{kappa}B) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-{kappa}B pathway.« less

Precise detection of chromosomal translocation or inversion breakpoints by whole-genome sequencing.

PubMed

Suzuki, Toshifumi; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Saitsu, Hirotomo; Takeda, Satoru; Matsumoto, Naomichi

2014-12-01

Structural variations (SVs), including translocations, inversions, deletions and duplications, are potentially associated with Mendelian diseases and contiguous gene syndromes. Determination of SV-related breakpoints at the nucleotide level is important to reveal the genetic causes for diseases. Whole-genome sequencing (WGS) by next-generation sequencers is expected to determine structural abnormalities more directly and efficiently than conventional methods. In this study, 14 SVs (9 balanced translocations, 1 inversion and 4 microdeletions) in 9 patients were analyzed by WGS with a shallow (5 × ) to moderate read coverage (20 × ). Among 28 breakpoints (as each SV has two breakpoints), 19 SV breakpoints had been determined previously at the nucleotide level by any other methods and 9 were uncharacterized. BreakDancer and Integrative Genomics Viewer determined 20 breakpoints (16 translocation, 2 inversion and 2 deletion breakpoints), but did not detect 8 breakpoints (2 translocation and 6 deletion breakpoints). These data indicate the efficacy of WGS for the precise determination of translocation and inversion breakpoints.

A new approach on JPSS VIIRS BCS and SVS PRT calibration

NASA Astrophysics Data System (ADS)

Wang, Tung R.; Marschke, Steve; Borroto, Michael; Jones, Christopher M.; Chovit, Christopher

2015-05-01

A set of calibrated platinum resistance thermometers (PRT's) was used to monitor the temperature of a Blackbody Calibration Source (BCS) and Space View Source (SVS). BCS is Ground Support Equipment (GSE) used to validate the emissive band calibration of Visible Infrared Imaging Radiometer Suite (VIIRS) of the Joint Polar Satellite System (JPSS). Another GSE, the SVS was used as an optical simulator to provide zero radiance sources for all VIIRS bands. The required PRT temperature 1 uncertainty is less than 0.030K. A process was developed to calibrate the PRTs in its thermal block by selecting a single thermal bath fluid that is compatible with spaceflight, is easy to clean and supported the entire temperature range. The process involves thermal cycling the PRTs that are installed in an aluminum housing using RTV566A prior to calibration. The PRTs were calibrated thermal cycled again and then calibrated once more to verify repeatability. Once completed these PRTs were installed on both the BCS and SVS. The PRT calibration uncertainty was estimated and deemed sufficient to support the effective temperature requirements for the operating temperature range of the BCS and SVS.

Nonmedical Use of Cough Syrup Among Secondary Vocational School Students

PubMed Central

Wu, Qingfeng; Yu, Jincong; Yang, Chengwu; Chen, Jiayan; Yang, Longyu; Zhang, Hui; Teng, Shiwei; Li, Jiang; Yan, Dong; Cao, Jiepin; Zhao, Yanting; Wang, Zengzhen

2016-01-01

Abstract Nonmedical use of cough syrup (NUCS) among secondary vocational school (SVS) students has been an increasing concern for public health in China, but no data were available. This cross-sectional study aimed to investigate the epidemiological characters of NUCS as well as its risk factors among SVS students in China. From September 2013 to December 2014, a total of 13,614 SVS students were purposively selected through multistage sampling in 6 cities of China. Information on NUCS, demographics, family background, smoking and alcohol consumption, impulsiveness, sensation seeking, and parental monitoring were collected. Logistic regression was used to explore factors related to NUCS. The 12,923 (94.9%) valid responses (16.3 ± 1.0 years old, and 52.6% men) reported 3.47% (95% confidence interval: 3.15–3.79%) lifetime NUCS. Logistic regression indicated that smoking, part-time job experience, high level of impulsiveness, and sensation seeking were risk factors for NUCS, whereas urban living and high parental monitoring were protective ones. NUCS was prevalent among SVS students. Interventions that target on smoking, impulsiveness and sensation seeking control, improvement on parental monitoring may have considerable impact on NUCS among SVS students. PMID:26962800

Nonmedical Use of Cough Syrup Among Secondary Vocational School Students: A National Survey in China.

PubMed

Wu, Qingfeng; Yu, Jincong; Yang, Chengwu; Chen, Jiayan; Yang, Longyu; Zhang, Hui; Teng, Shiwei; Li, Jiang; Yan, Dong; Cao, Jiepin; Zhao, Yanting; Wang, Zengzhen

2016-03-01

Nonmedical use of cough syrup (NUCS) among secondary vocational school (SVS) students has been an increasing concern for public health in China, but no data were available. This cross-sectional study aimed to investigate the epidemiological characters of NUCS as well as its risk factors among SVS students in China.From September 2013 to December 2014, a total of 13,614 SVS students were purposively selected through multistage sampling in 6 cities of China. Information on NUCS, demographics, family background, smoking and alcohol consumption, impulsiveness, sensation seeking, and parental monitoring were collected. Logistic regression was used to explore factors related to NUCS.The 12,923 (94.9%) valid responses (16.3 ± 1.0 years old, and 52.6% men) reported 3.47% (95% confidence interval: 3.15-3.79%) lifetime NUCS. Logistic regression indicated that smoking, part-time job experience, high level of impulsiveness, and sensation seeking were risk factors for NUCS, whereas urban living and high parental monitoring were protective ones.NUCS was prevalent among SVS students. Interventions that target on smoking, impulsiveness and sensation seeking control, improvement on parental monitoring may have considerable impact on NUCS among SVS students.

Synthetic Vision Enhances Situation Awareness and RNP Capabilities for Terrain-Challenged Approaches

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Prinzel, Lawrence J., III; Bailey, Randall E.; Arthur, Jarvis J., III

2003-01-01

The Synthetic Vision Systems (SVS) Project of Aviation Safety Program is striving to eliminate poor visibility as a causal factor in aircraft accidents as well as enhance operational capabilities of all aircraft through the display of computer generated imagery derived from an onboard database of terrain, obstacle, and airport information. To achieve these objectives, NASA 757 flight test research was conducted at the Eagle-Vail, Colorado airport to evaluate three SVS display types (Head-Up Display, Head-Down Size A, Head-Down Size X) and two terrain texture methods (photo-realistic, generic) in comparison to the simulated Baseline Boeing-757 Electronic Attitude Direction Indicator and Navigation / Terrain Awareness and Warning System displays. These independent variables were evaluated for situation awareness, path error, and workload while making approaches to Runway 25 and 07 and during simulated engine-out Cottonwood 2 and KREMM departures. The results of the experiment showed significantly improved situation awareness, performance, and workload for SVS concepts compared to the Baseline displays and confirmed the retrofit capability of the Head-Up Display and Size A SVS concepts. The research also demonstrated that the pathway and pursuit guidance used within the SVS concepts achieved required navigation performance (RNP) criteria.

Social vulnerability and bullying in children with Asperger syndrome.

PubMed

Sofronoff, Kate; Dark, Elizabeth; Stone, Valerie

2011-05-01

Children with Asperger syndrome (AS) have IQ within the normal range but specific impairments in theory of mind, social interaction and communication skills. The majority receive education in mainstream schools and research suggests they are bullied more than typically developing peers. The current study aimed to evaluate factors that predict bullying for such children and also to examine a new measure, the Social Vulnerability Scale (SVS). One hundred and thirty three parents of children with AS completed the SVS and of these 92 parents completed both the SVS and questionnaires measuring anxiety, anger, behaviour problems, social skills and bullying. Regression analyses revealed that these variables together strongly predicted bullying, but that social vulnerability was the strongest predictor. Test-re-test and internal consistency analyses of the SVS demonstrated sound psychometric properties and factor analyses revealed two sub-scales: gullibility and credulity. Limitations of the study are acknowledged and suggestions for future research discussed.

Awareness and Detection of Traffic and Obstacles Using Synthetic and Enhanced Vision Systems

NASA Technical Reports Server (NTRS)

Bailey, Randall E.

2012-01-01

Research literature are reviewed and summarized to evaluate the awareness and detection of traffic and obstacles when using Synthetic Vision Systems (SVS) and Enhanced Vision Systems (EVS). The study identifies the critical issues influencing the time required, accuracy, and pilot workload associated with recognizing and reacting to potential collisions or conflicts with other aircraft, vehicles and obstructions during approach, landing, and surface operations. This work considers the effect of head-down display and head-up display implementations of SVS and EVS as well as the influence of single and dual pilot operations. The influences and strategies of adding traffic information and cockpit alerting with SVS and EVS were also included. Based on this review, a knowledge gap assessment was made with recommendations for ground and flight testing to fill these gaps and hence, promote the safe and effective implementation of SVS/EVS technologies for the Next Generation Air Transportation System

Intraoperative transit-time flow measurement is not altered in venous bypass grafts covered by the eSVS mesh.

PubMed

Emery, Robert W; Solien, Eric

2013-01-01

The aim of this study was to determine whether the eSVS Mesh interferes with transit-time flow measurement (TTFM) assessing intraoperative coronary vein graft patency. In four swine undergoing off-pump bypass grafting to the anterior descending coronary artery, five TTFMs were sequentially obtained on meshed and bare grafts at baseline and under Dobutamine stress at five separate locations on the graft in each animal. The Medistim VeriQ was used for TTFM. The grafts were examined for patency after the swine were killed. There was no difference in hemodynamics or TTFM either at baseline or under Dobutamine stress between the eSVS Mesh covered and uncovered grafts. Dobutamine, however, significantly increased hemodynamics and graft flow parameters measured from baseline. The eSVS Mesh does not interfere with Doppler flow measurement in covered coronary vein grafts.

MRI Interscanner Agreement of the Association between the Susceptibility Vessel Sign and Histologic Composition of Thrombi.

PubMed

Bourcier, Romain; Détraz, Lili; Serfaty, Jean Michel; Delasalle, Beatrice Guyomarch; Mirza, Mahmood; Derraz, Imad; Toulgoat, Frédérique; Naggara, Olivier; Toquet, Claire; Desal, Hubert

2017-11-01

The susceptibility vessel sign (SVS) on magnetic resonance imaging (MRI) is related to thrombus location, composition, and size in acute stroke. No previous study has determined its inter-MRI scanner variability. We aimed to compare the diagnostic accuracy in-vitro of four different MRI scanners for the characterization of histologic thrombus composition. Thirty-five manufactured thrombi analogs of different composition that were histologically categorized as fibrin-dominant, mixed, or red blood cell (RBC)-dominant were scanned on four different MRI units with T2* sequence. Nine radiologists, blinded to thrombus composition and MRI scanner model, classified twice, in a 2-week interval, the SVS of each thrombus as absent, questionable, or present. We calculated the weighted kappa with 95% confidence interval (CI), sensitivity, specificity and accuracy of the SVS on each MRI scanner to detect RBC-dominant thrombi. The SVS was present in 42%, absent in 33%, and questionable in 25% of thrombi. The interscanner agreement was moderate to good, ranging from .45 (CI: .37-.52) to .67 (CI: .61-.74). The correlation between the SVS and the thrombus composition was moderate (κ: .50 [CI: .44-.55]) to good κ: .76 ([CI: .72-.80]). Sensitivity, specificity, and accuracy to identify RBC-dominant clots were significantly different between MRI scanners (P < .001). The diagnostic accuracy of SVS to determine thrombus composition varies significantly among MRI scanners. Normalization of T2*sequences between scanners may be needed to better predict thrombus composition in multicenter studies. Copyright © 2017 by the American Society of Neuroimaging.

A Hybrid Synthetic Vision System for the Tele-operation of Unmanned Vehicles

NASA Technical Reports Server (NTRS)

Delgado, Frank; Abernathy, Mike

2004-01-01

A system called SmartCam3D (SC3D) has been developed to provide enhanced situational awareness for operators of a remotely piloted vehicle. SC3D is a Hybrid Synthetic Vision System (HSVS) that combines live sensor data with information from a Synthetic Vision System (SVS). By combining the dual information sources, the operators are afforded the advantages of each approach. The live sensor system provides real-time information for the region of interest. The SVS provides information rich visuals that will function under all weather and visibility conditions. Additionally, the combination of technologies allows the system to circumvent some of the limitations from each approach. Video sensor systems are not very useful when visibility conditions are hampered by rain, snow, sand, fog, and smoke, while a SVS can suffer from data freshness problems. Typically, an aircraft or satellite flying overhead collects the data used to create the SVS visuals. The SVS data could have been collected weeks, months, or even years ago. To that extent, the information from an SVS visual could be outdated and possibly inaccurate. SC3D was used in the remote cockpit during flight tests of the X-38 132 and 131R vehicles at the NASA Dryden Flight Research Center. SC3D was also used during the operation of military Unmanned Aerial Vehicles. This presentation will provide an overview of the system, the evolution of the system, the results of flight tests, and future plans. Furthermore, the safety benefits of the SC3D over traditional and pure synthetic vision systems will be discussed.

Using large-scale genome variation cohorts to decipher the molecular mechanism of cancer.

PubMed

Habermann, Nina; Mardin, Balca R; Yakneen, Sergei; Korbel, Jan O

2016-01-01

Characterizing genomic structural variations (SVs) in the human genome remains challenging, and there is a growing interest to understand somatic SVs occurring in cancer, a disease of the genome. A havoc-causing SV process known as chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe. Recent efforts led to the development of a set of conceptual criteria for the inference of chromothripsis events in cancer genomes and to the development of experimental model systems for studying this striking DNA alteration process in vitro. We discuss these approaches, and additionally touch upon current "Big Data" efforts that employ hybrid cloud computing to enable studies of numerous cancer genomes in an effort to search for commonalities and differences in molecular DNA alteration processes in cancer. Copyright © 2016. Published by Elsevier SAS.

Using Vision System Technologies for Offset Approaches in Low Visibility Operations

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Bailey, Randall E.; Ellis, Kyle K.

2015-01-01

Flight deck-based vision systems, such as Synthetic Vision Systems (SVS) and Enhanced Flight Vision Systems (EFVS), have the potential to provide additional margins of safety for aircrew performance and enable the implementation of operational improvements for low visibility surface, arrival, and departure operations in the terminal environment with equivalent efficiency to visual operations. Twelve air transport-rated crews participated in a motion-base simulation experiment to evaluate the use of SVS/EFVS in Next Generation Air Transportation System low visibility approach and landing operations at Chicago O'Hare airport. Three monochromatic, collimated head-up display (HUD) concepts (conventional HUD, SVS HUD, and EFVS HUD) and three instrument approach types (straight-in, 3-degree offset, 15-degree offset) were experimentally varied to test the efficacy of the SVS/EFVS HUD concepts for offset approach operations. The findings suggest making offset approaches in low visibility conditions with an EFVS HUD or SVS HUD appear feasible. Regardless of offset approach angle or HUD concept being flown, all approaches had comparable ILS tracking during the instrument segment and were within the lateral confines of the runway with acceptable sink rates during the visual segment of the approach. Keywords: Enhanced Flight Vision Systems; Synthetic Vision Systems; Head-up Display; NextGen

Synthetic Vision Enhanced Surface Operations and Flight Procedures Rehearsal Tool

NASA Technical Reports Server (NTRS)

Arthur, Jarvis J., III; Prinzel, Lawrence J., III; Williams, Steven P.; Kramer, Lynda J.

2006-01-01

Limited visibility has been cited as predominant causal factor for both Controlled-Flight-Into-Terrain (CFIT) and runway incursion accidents. NASA is conducting research and development of Synthetic Vision Systems (SVS) technologies which may potentially mitigate low visibility conditions as a causal factor to these accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. Two experimental evaluation studies were performed to determine the efficacy of two concepts: 1) head-worn display application of SVS technology to enhance transport aircraft surface operations, and 2) three-dimensional SVS electronic flight bag display concept for flight plan preview, mission rehearsal and controller-pilot data link communications interface of flight procedures. In the surface operation study, pilots evaluated two display devices and four display modes during taxi under unlimited and CAT II visibility conditions. In the mission rehearsal study, pilots flew approaches and departures in an operationally-challenged airport environment, including CFIT scenarios. Performance using the SVS concepts was compared to traditional baseline displays with paper charts only or EFB information. In general, the studies evince the significant situation awareness and enhanced operational capabilities afforded from these advanced SVS display concepts. The experimental results and conclusions from these studies are discussed along with future directions.

Secular Variation in Slip (Invited)

NASA Astrophysics Data System (ADS)

Cowgill, E.; Gold, R. D.

2010-12-01

Faults show temporal variations in slip rate at time scales ranging from the hours following a major rupture to the millions of years over which plate boundaries reorganize. One such behavior is secular variation in slip (SVS), which we define as a pulse of accelerated strain release along a single fault that occurs at a frequency that is > 1 order of magnitude longer than the recurrence interval of earthquakes within the pulse. Although numerous mechanical models have been proposed to explain SVS, it has proven much harder to measure long (5-500 kyr) records of fault displacement as a function of time. Such fault-slip histories may be obtained from morphochronologic data, which are measurements of offset and age obtained from faulted landforms. Here we describe slip-history modeling of morphochronologic data and show how this method holds promise for obtaining long records of fault slip. In detail we place SVS in the context of other types of time-varying fault-slip phenomena, explain the importance of measuring fault-slip histories, summarize models proposed to explain SVS, review current approaches for measuring SVS in the geologic record, and illustrate the slip-history modeling approach we advocate here using data from the active, left-slip Altyn Tagh fault in NW Tibet. In addition to SVS, other types of temporal variation in fault slip include post-seismic transients, discrepancies between geologic slip rates and those derived from geodetic and/or paleoseismic data, and single changes in slip rate resulting from plate reorganization. Investigating secular variation in slip is important for advancing understanding of long-term continental deformation, fault mechanics, and seismic risk. Mechanical models producing such behavior include self-driven mode switching, changes in pore-fluid pressure, viscoelasticity, postseismic reloading, and changes in local surface loads (e.g., ice sheets, large lakes, etc.) among others. However, a key problem in testing these models is the paucity of long records of fault slip. Paleoseismic data are unlikely to yield such histories because measurements of the slip associated with each event are generally unavailable and long records require large accumulated offsets, which can result in structural duplication or omission of the stratigraphic records of events. In contrast, morphochronologic data capture both the age and offset of individual piercing points, although this approach generally does not resolve individual earthquake events. Because the uncertainties in both age and offset are generally large (5-15%) for individual markers, SVS is best resolved by obtaining suites of such measurements, in which case the errors can be used to reduce the range of slip histories common to all such data points. A suite of such data from the central Altyn Tagh fault reveals a pulse of accelerated strain release in the mid Holocene, with ~20 m of slip being released from ~6.7 to ~5.9 ka at a short-term rate (~28 mm/yr) that is 3 times greater than the average rate (~9 mm/yr). We interpret this pulse to represent a cluster of two to six, Mw > 7.2 earthquakes. To our knowledge, this is the first possible earthquake cluster detected using morphochronologic techniques.

Improving Early Adaptation Following Long Duration Spaceflight by Enhancing Vestibular Information

NASA Technical Reports Server (NTRS)

Mulavara, Ajitkumar; Kofman, Igor; DeDios, Yiri E.; Galvan, Raquel; Miller, Chris; Peters, Brian; Cohen, Helen; Jeevarajan, Jerome; Reschke, Millard; Wood, Scott;

75 FR 38863 - Tenth Meeting: Joint RTCA Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-06

... Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS) AGENCY...-79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS). SUMMARY: The FAA is issuing...: Enhanced Flight [[Page 38864

YAHA: fast and flexible long-read alignment with optimal breakpoint detection.

PubMed

Faust, Gregory G; Hall, Ira M

2012-10-01

With improved short-read assembly algorithms and the recent development of long-read sequencers, split mapping will soon be the preferred method for structural variant (SV) detection. Yet, current alignment tools are not well suited for this. We present YAHA, a fast and flexible hash-based aligner. YAHA is as fast and accurate as BWA-SW at finding the single best alignment per query and is dramatically faster and more sensitive than both SSAHA2 and MegaBLAST at finding all possible alignments. Unlike other aligners that report all, or one, alignment per query, or that use simple heuristics to select alignments, YAHA uses a directed acyclic graph to find the optimal set of alignments that cover a query using a biologically relevant breakpoint penalty. YAHA can also report multiple mappings per defined segment of the query. We show that YAHA detects more breakpoints in less time than BWA-SW across all SV classes, and especially excels at complex SVs comprising multiple breakpoints. YAHA is currently supported on 64-bit Linux systems. Binaries and sample data are freely available for download from http://faculty.virginia.edu/irahall/YAHA. imh4y@virginia.edu.

Exhibition of stochastic resonance in vestibular tilt motion perception.

PubMed

Galvan-Garza, R C; Clark, T K; Mulavara, A P; Oman, C M

2018-04-03

Stochastic Resonance (SR) is a phenomenon broadly described as "noise benefit". The application of subsensory electrical Stochastic Vestibular Stimulation (SVS) via electrodes behind each ear has been used to improve human balance and gait, but its effect on motion perception thresholds has not been examined. This study investigated the capability of subsensory SVS to reduce vestibular motion perception thresholds in a manner consistent with a characteristic bell-shaped SR curve. We measured upright, head-centered, roll tilt Direction Recognition (DR) thresholds in the dark in 12 human subjects with the application of wideband 0-30 Hz SVS ranging from ±0-700 μA. To conservatively assess if SR was exhibited, we compared the proportions of both subjective and statistical SR exhibition in our experimental data to proportions of SR exhibition in multiple simulation cases with varying underlying SR behavior. Analysis included individual and group statistics. As there is not an established mathematical definition, three humans subjectively judged that SR was exhibited in 78% of subjects. "Statistically significant SR exhibition", which additionally required that a subject's DR threshold with SVS be significantly lower than baseline (no SVS), was present in 50% of subjects. Both percentages were higher than simulations suggested could occur simply by chance. For SR exhibitors, defined by subjective or statistically significant criteria, the mean DR threshold improved by -30% and -39%, respectively. The largest individual improvement was -47%. At least half of the subjects were better able to perceive passive body motion with the application of subsensory SVS. This study presents the first conclusive demonstration of SR in vestibular motion perception. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthetic Vision Systems - Operational Considerations Simulation Experiment

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Williams, Steven P.; Bailey, Randall E.; Glaab, Louis J.

2007-01-01

Synthetic vision is a computer-generated image of the external scene topography that is generated from aircraft attitude, high-precision navigation information, and data of the terrain, obstacles, cultural features, and other required flight information. A synthetic vision system (SVS) enhances this basic functionality with real-time integrity to ensure the validity of the databases, perform obstacle detection and independent navigation accuracy verification, and provide traffic surveillance. Over the last five years, NASA and its industry partners have developed and deployed SVS technologies for commercial, business, and general aviation aircraft which have been shown to provide significant improvements in terrain awareness and reductions in the potential for Controlled-Flight-Into-Terrain incidents/accidents compared to current generation cockpit technologies. It has been hypothesized that SVS displays can greatly improve the safety and operational flexibility of flight in Instrument Meteorological Conditions (IMC) to a level comparable to clear-day Visual Meteorological Conditions (VMC), regardless of actual weather conditions or time of day. An experiment was conducted to evaluate SVS and SVS-related technologies as well as the influence of where the information is provided to the pilot (e.g., on a Head-Up or Head-Down Display) for consideration in defining landing minima based upon aircraft and airport equipage. The "operational considerations" evaluated under this effort included reduced visibility, decision altitudes, and airport equipage requirements, such as approach lighting systems, for SVS-equipped aircraft. Subjective results from the present study suggest that synthetic vision imagery on both head-up and head-down displays may offer benefits in situation awareness; workload; and approach and landing performance in the visibility levels, approach lighting systems, and decision altitudes tested.

Using Low Levels of Stochastic Vestibular Stimulation to Improve Balance Function

PubMed Central

Goel, Rahul; Kofman, Igor; Jeevarajan, Jerome; De Dios, Yiri; Cohen, Helen S.; Bloomberg, Jacob J.; Mulavara, Ajitkumar P.

2015-01-01

Low-level stochastic vestibular stimulation (SVS) has been associated with improved postural responses in the medio-lateral (ML) direction, but its effect in improving balance function in both the ML and anterior-posterior (AP) directions has not been studied. In this series of studies, the efficacy of applying low amplitude SVS in 0–30 Hz range between the mastoids in the ML direction on improving cross-planar balance function was investigated. Forty-five (45) subjects stood on a compliant surface with their eyes closed and were instructed to maintain a stable upright stance. Measures of stability of the head, trunk, and whole body were quantified in ML, AP and combined APML directions. Results show that binaural bipolar SVS given in the ML direction significantly improved balance performance with the peak of optimal stimulus amplitude predominantly in the range of 100–500 μA for all the three directions, exhibiting stochastic resonance (SR) phenomenon. Objective perceptual and body motion thresholds as estimates of internal noise while subjects sat on a chair with their eyes closed and were given 1 Hz bipolar binaural sinusoidal electrical stimuli were also measured. In general, there was no significant difference between estimates of perceptual and body motion thresholds. The average optimal SVS amplitude that improved balance performance (peak SVS amplitude normalized to perceptual threshold) was estimated to be 46% in ML, 53% in AP, and 50% in APML directions. A miniature patch-type SVS device may be useful to improve balance function in people with disabilities due to aging, Parkinson’s disease or in astronauts returning from long-duration space flight. PMID:26295807

Multimedia applications in nursing curriculum: the process of producing streaming videos for medication administration skills.

PubMed

Sowan, Azizeh K

2014-07-01

Streaming videos (SVs) are commonly used multimedia applications in clinical health education. However, there are several negative aspects related to the production and delivery of SVs. Only a few published studies have included sufficient descriptions of the videos and the production process and design innovations. This paper describes the production of innovative SVs for medication administration skills for undergraduate nursing students at a public university in Jordan and focuses on the ethical and cultural issues in producing this type of learning resource. The curriculum development committee approved the modification of educational techniques for medication administration procedures to include SVs within an interactive web-based learning environment. The production process of the videos adhered to established principles for "protecting patients' rights when filming and recording" and included: preproduction, production and postproduction phases. Medication administration skills were videotaped in a skills laboratory where they are usually taught to students and also in a hospital setting with real patients. The lab videos included critical points and Do's and Don'ts and the hospital videos fostered real-world practices. The range of time of the videos was reasonable to eliminate technical difficulty in access. Eight SVs were produced that covered different types of the medication administration skills. The production of SVs required the collaborative efforts of experts in IT, multimedia, nursing and informatics educators, and nursing care providers. Results showed that the videos were well-perceived by students, and the instructors who taught the course. The process of producing the videos in this project can be used as a valuable framework for schools considering utilizing multimedia applications in teaching. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of accelerated 3-D spiral chemical shift imaging and single-voxel spectroscopy at 3T in the pediatric age group.

PubMed

Yazbek, Sandrine; Prabhu, Sanjay P; Connaughton, Pauline; Grant, Patricia E; Gagoski, Borjan

2015-08-01

Single-voxel spectroscopy (SVS) is usually used in the pediatric population when a short acquisition time is crucial. To overcome the long acquisition time of 3-D phase-encoded chemical shift imaging (CSI) and lack of spatial coverage of single-voxel spectroscopy, efficient encoding schemes using spiral k-space trajectories have been successfully deployed, enabling acquisition of volumetric CSI in <5 min. We assessed feasibility of using 3-D spiral CSI sequence routinely in pediatric clinical settings by comparing its reconstructed spectra against SVS spectra. Volumetric spiral CSI obtained spectra from 2-cc isotropic voxels over a 16×16×10-cm region. SVS acquisition encoded a 3.4-cc (1.5-mm) isotropic voxel. Acquisition time was 3 min for every technique. Data were gathered prospectively from 11 random pediatric patients. Spectra from left basal ganglia were obtained using both techniques and were processed with post-processing software. The following metabolite ratios were calculated: N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), lactate/creatine (Lac/Cr) and N-acetylapartate/choline (NAA/Cho). We collected data on 11 children ages 4 days to 10 years. In 10/11 cases, spectral quality of both methods was acceptable. Considering 10/11 cases, we found a statistically significant difference between SVS and 3-D spiral CSI for all three ratios. However, this difference was fixed and was probably caused by a fixed bias. This means that 3-D spiral CSI can be used instead of SVS by removing the mean difference between the methods for each ratio. Accelerated 3-D CSI is feasible in pediatric patients and can potentially substitute for SVS.

Synthetic vision systems: operational considerations simulation experiment

NASA Astrophysics Data System (ADS)

Kramer, Lynda J.; Williams, Steven P.; Bailey, Randall E.; Glaab, Louis J.

2007-04-01

Synthetic vision is a computer-generated image of the external scene topography that is generated from aircraft attitude, high-precision navigation information, and data of the terrain, obstacles, cultural features, and other required flight information. A synthetic vision system (SVS) enhances this basic functionality with real-time integrity to ensure the validity of the databases, perform obstacle detection and independent navigation accuracy verification, and provide traffic surveillance. Over the last five years, NASA and its industry partners have developed and deployed SVS technologies for commercial, business, and general aviation aircraft which have been shown to provide significant improvements in terrain awareness and reductions in the potential for Controlled-Flight-Into-Terrain incidents / accidents compared to current generation cockpit technologies. It has been hypothesized that SVS displays can greatly improve the safety and operational flexibility of flight in Instrument Meteorological Conditions (IMC) to a level comparable to clear-day Visual Meteorological Conditions (VMC), regardless of actual weather conditions or time of day. An experiment was conducted to evaluate SVS and SVS-related technologies as well as the influence of where the information is provided to the pilot (e.g., on a Head-Up or Head-Down Display) for consideration in defining landing minima based upon aircraft and airport equipage. The "operational considerations" evaluated under this effort included reduced visibility, decision altitudes, and airport equipage requirements, such as approach lighting systems, for SVS-equipped aircraft. Subjective results from the present study suggest that synthetic vision imagery on both head-up and head-down displays may offer benefits in situation awareness; workload; and approach and landing performance in the visibility levels, approach lighting systems, and decision altitudes tested.

Flight Simulator Evaluation of Display Media Devices for Synthetic Vision Concepts

NASA Technical Reports Server (NTRS)

Arthur, J. J., III; Williams, Steven P.; Prinzel, Lawrence J., III; Kramer, Lynda J.; Bailey, Randall E.

2004-01-01

The Synthetic Vision Systems (SVS) Project of the National Aeronautics and Space Administration's (NASA) Aviation Safety Program (AvSP) is striving to eliminate poor visibility as a causal factor in aircraft accidents as well as enhance operational capabilities of all aircraft. To accomplish these safety and capacity improvements, the SVS concept is designed to provide a clear view of the world around the aircraft through the display of computer-generated imagery derived from an onboard database of terrain, obstacle, and airport information. Display media devices with which to implement SVS technology that have been evaluated so far within the Project include fixed field of view head up displays and head down Primary Flight Displays with pilot-selectable field of view. A simulation experiment was conducted comparing these display devices to a fixed field of view, unlimited field of regard, full color Helmet-Mounted Display system. Subject pilots flew a visual circling maneuver in IMC at a terrain-challenged airport. The data collected for this experiment is compared to past SVS research studies.

Lacrimal gland uptake of (67)Ga-gallium citrate correlates with biopsy results in patients with suspected sarcoidosis.

PubMed

Tannen, Bradford L; Kolomeyer, Anton M; Turbin, Roger E; Frohman, Larry; Langer, Paul D; Oh, Cheongeun; Ghesani, Nasrin V; Zuckier, Lionel S; Chu, David S

2014-02-01

To investigate whether lacrimal gland uptake on (67)Ga-gallium citrate scintigraphy correlates with histopathologic evidence of sarcoidosis. A retrospective, pilot study of 31 patients with suspected sarcoidosis who underwent gallium scintigraphy and lacrimal gland biopsy. Lacrimal gland gallium uptake was assessed by subjective visual scoring (SVS) and lacrimal uptake ratio (LUR). Eleven (36%) patients had lacrimal gland biopsies containing noncaseating granulomas. A statistically significant correlation was found between lacrimal gland gallium uptake and biopsy positivity using SVS (p = 0.03) or LUR (p = 0.01). Using SVS, biopsy positivity rate increased from 0 to 50% in patients with mild to intense uptake. Using LUR, biopsy positivity rate increased linearly as the ratio increased from 13% (LUR < 4) to 100% (LUR > 8). Lacrimal biopsy positivity rate significantly correlated with gallium uptake on scintigraphy. Both SVS and LUR methods appear to correlate with histologic results and may potentially aid in patient selection for biopsy.

Synaptic Vesicle Endocytosis Occurs on Multiple Timescales and Is Mediated by Formin-Dependent Actin Assembly.

PubMed

Soykan, Tolga; Kaempf, Natalie; Sakaba, Takeshi; Vollweiter, Dennis; Goerdeler, Felix; Puchkov, Dmytro; Kononenko, Natalia L; Haucke, Volker

2017-02-22

Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Recent data suggest that at physiological temperature SVs are internalized via clathrin-independent ultrafast endocytosis (UFE) within hundreds of milliseconds, while other studies have postulated a key role for clathrin-mediated endocytosis (CME) of SV proteins on a timescale of seconds to tens of seconds. Here we demonstrate using cultured hippocampal neurons as a model that at physiological temperature SV endocytosis occurs on several timescales from less than a second to several seconds, yet, is largely independent of clathrin. Clathrin-independent endocytosis (CIE) of SV membranes is mediated by actin-nucleating formins such as mDia1, which are required for the formation of presynaptic endosome-like vacuoles from which SVs reform. Our results resolve previous discrepancies in the field and suggest that SV membranes are predominantly retrieved via CIE mediated by formin-dependent actin assembly. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of step-synchronized vibration stimulation of soles on gait in Parkinson's disease: a pilot study.

PubMed

Novak, Peter; Novak, Vera

2006-05-04

Previous studies have suggested that impaired proprioceptive processing in the striatum may contribute to abnormal gait in Parkinson's disease (PD). This pilot study assessed the effects of enhanced proprioceptive feedback using step-synchronized vibration stimulation of the soles (S-VS) on gait in PD. S-VS was used in 8 PD subjects (3 women and 5 men, age range 44-79 years, on medication) and 8 age-matched healthy subjects (5 women and 3 men). PD subjects had mild or moderate gait impairment associated with abnormal balance, but they did not have gait freezing. Three vibratory devices (VDs) were embedded in elastic insoles (one below the heel and two below the forefoot areas) inserted into the shoes. Each VD operates independently and has a pressure switch that activates the underlying vibratory actuator. The VD delivered the 70-Hz suprathreshold vibration pulse upon touch by the heel or forefoot, and the vibration pulse was deactivated upon respective push-offs. Six-minute hallway walking was studied with and without S-VS. Gait characteristics were measured using the force-sensitive foot switches. The primary outcome was the stride variability expressed as a coefficient of variation (CV), a measure of gait steadiness. Secondary outcome measures were walking distance and speed, stride length and duration, cadence, stance, swing and double support duration, and respective CVs (if applicable). The walking speed (p < 0.04) and the CV of the stride interval (p < 0.02) differed between the groups and S-VS conditions. In the PD group, S-VS decreased stride variability (p < 0.002), increased walking speed (p < 0.0001), stride duration (p < 0.01), stride length (p < 0.0002), and cadence (p < 0.03). In the control group, S-VS decreased stride variability (p < 0.006) and increased gait speed (p < 0.03), but other locomotion parameters were not significantly altered. Augmented sensory feedback improves parkinsonian gait steadiness in the short-term setting. Because the suprathreshold stimulation prevented blinding of subjects, the learning effect and increased attention can be a confounding factor underlying results. Long-term studies are needed to establish the clinical value of the S-VS.

Coarse Graining to Investigate Membrane Induced Peptide Folding of Anticancer Peptides

NASA Astrophysics Data System (ADS)

Ganesan, Sai; Xu, Hongcheng; Matysiak, Silvina

Information about membrane induced peptide folding mechanisms using all-atom molecular dynamics simulations is a challenge due to time and length scale issues.We recently developed a low resolution Water Explicit Polarizable PROtein coarse-grained Model by adding oppositely charged dummy particles inside protein backbone beads.These two dummy particles represent a fluctuating dipole,thus introducing structural polarization into the coarse-grained model.With this model,we were able to achieve significant α- β secondary structure content de novo,without any added bias.We extended the model to zwitterionic and anionic lipids,by adding oppositely charged dummy particles inside polar beads, to capture the ability of the head group region to form hydrogen bonds.We use zwitterionic POPC and anionic POPS as our model lipids, and a cationic anticancer peptide,SVS1,as our model peptide.We have characterized the driving forces for SVS1 folding on lipid bilayers with varying anionic and zwitterionic lipid compositions.Based on our results, dipolar interactions between peptide backbone and lipid head groups contribute to stabilize folded conformations.Cooperativity in folding is induced by both intra peptide and membrane-peptide interaction.

Molecular Mechanisms for the Coupling of Endocytosis to Exocytosis in Neurons

PubMed Central

Xie, Zhenli; Long, Jiangang; Liu, Jiankang; Chai, Zuying; Kang, Xinjiang; Wang, Changhe

2017-01-01

Neuronal communication and brain function mainly depend on the fundamental biological events of neurotransmission, including the exocytosis of presynaptic vesicles (SVs) for neurotransmitter release and the subsequent endocytosis for SV retrieval. Neurotransmitters are released through the Ca2+- and SNARE-dependent fusion of SVs with the presynaptic plasma membrane. Following exocytosis, endocytosis occurs immediately to retrieve SV membrane and fusion machinery for local recycling and thus maintain the homeostasis of synaptic structure and sustained neurotransmission. Apart from the general endocytic machinery, recent studies have also revealed the involvement of SNARE proteins (synaptobrevin, SNAP25 and syntaxin), synaptophysin, Ca2+/calmodulin, and members of the synaptotagmin protein family (Syt1, Syt4, Syt7 and Syt11) in the balance and tight coupling of exo-endocytosis in neurons. Here, we provide an overview of recent progress in understanding how these neuron-specific adaptors coordinate to ensure precise and efficient endocytosis during neurotransmission. PMID:28348516

[Trust in organizations concerned with risks of the Great East Japan Earthquake].

PubMed

Nakayachi, Kazuya; Kudo, Daisuke; Ozaki, Taku

2014-06-01

This study investigated the levels of public trust in organizations associated with the Great East Japan Earthquake. In Study 1 (N = 639), the levels of trust in eight organizations as well as the determinants of trust--perceived salient value similarity (SVS), ability, and motivation--were measured twice, first immediately after the earthquake and then a year later. The results indicated that the trust levels for six of the eight organizations had been preserved, supporting the double asymmetric effect of trust. The results of structural equation modeling (SEM) revealed that SVS explained trust more when the organization had been less trusted. Trust in the organization explains well the perceived reduction of the target risk. The results of SEM in Study 2 (N = 1,030) replicated those of Study 1, suggesting the stability of the explanatory power of the determinants of trust. Implications of the study for risk management practices are discussed.

77 FR 2342 - Seventeenth Meeting: RTCA Special Committee 213, Enhanced Flight Vision/Synthetic Vision Systems...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-17

... Committee 213, Enhanced Flight Vision/Synthetic Vision Systems (EFVS/SVS) AGENCY: Federal Aviation..., Enhanced Flight Vision/ Synthetic Vision Systems (EFVS/SVS). SUMMARY: The FAA is issuing this notice to advise the public of the seventeenth meeting of RTCA Special Committee 213, Enhanced Flight Vision...

Effect of the nano-oxide layer as a Mn diffusion barrier in specular spin valves

NASA Astrophysics Data System (ADS)

Jang, S. H.; Kang, T.; Kim, H. J.; Kim, K. Y.

2002-07-01

In previous work an enhanced giant magnetoresistance (GMR) effect in spin valves (SVs) with a nano-oxide layer (NOL) after annealing at about 250-300 degC has been reported. We have shown that SVs with a NOL also have higher thermal stability of the MR ratio at 300 degC. From secondary-ion-mass spectroscopy and x-ray photoelectron spectroscopy depth profile analysis, the mechanism of the improved thermal stability of the SVs with a NOL is shown to be related to MnO formation within the NOL. Thus, Mn atoms from the FeMn layer are trapped, and Mn diffusion is inhibited by the NOL during annealing.

Effectively Transforming IMC Flight into VMC Flight: An SVS Case Study

NASA Technical Reports Server (NTRS)

Glaab, Louis J.; Hughes, Monic F.; Parrish, Russell V.; Takallu, Mohammad A.

2006-01-01

A flight-test experiment was conducted using the NASA LaRC Cessna 206 aircraft. Four primary flight and navigation display concepts, including baseline and Synthetic Vision System (SVS) concepts, were evaluated in the local area of Roanoke Virginia Airport, flying visual and instrument approach procedures. A total of 19 pilots, from 3 pilot groups reflecting the diverse piloting skills of the GA population, served as evaluation pilots. Multi-variable Discriminant Analysis was applied to three carefully selected and markedly different operating conditions with conventional instrumentation to provide an extension of traditional analysis methods as well as provide an assessment of the effectiveness of SVS displays to effectively transform IMC flight into VMC flight.

76 FR 11847 - Thirteenth Meeting: Joint RTCA Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision...

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2011-03-03

... Special Committee 213: EUROCAE WG- 79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS... Joint RTCA Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems/Synthetic Vision Systems... Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS...

76 FR 20437 - Fourteenth Meeting: Joint RTCA Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision...

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2011-04-12

... Special Committee 213: EUROCAE WG- 79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS... Joint RTCA Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems/Synthetic Vision Systems... Special Committee 213: EUROCAE WG-79: Enhanced Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS...

Support vector machine incremental learning triggered by wrongly predicted samples

NASA Astrophysics Data System (ADS)

Tang, Ting-long; Guan, Qiu; Wu, Yi-rong

2018-05-01

According to the classic Karush-Kuhn-Tucker (KKT) theorem, at every step of incremental support vector machine (SVM) learning, the newly adding sample which violates the KKT conditions will be a new support vector (SV) and migrate the old samples between SV set and non-support vector (NSV) set, and at the same time the learning model should be updated based on the SVs. However, it is not exactly clear at this moment that which of the old samples would change between SVs and NSVs. Additionally, the learning model will be unnecessarily updated, which will not greatly increase its accuracy but decrease the training speed. Therefore, how to choose the new SVs from old sets during the incremental stages and when to process incremental steps will greatly influence the accuracy and efficiency of incremental SVM learning. In this work, a new algorithm is proposed to select candidate SVs and use the wrongly predicted sample to trigger the incremental processing simultaneously. Experimental results show that the proposed algorithm can achieve good performance with high efficiency, high speed and good accuracy.

Enhanced and Synthetic Vision for Terminal Maneuvering Area NextGen Operations

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Bailey, Randall E.; Ellis, Kyle K. E.; Norman, R. Michael; Williams, Steven P.; Arthur, Jarvis J., III; Shelton, Kevin J.; Prinzel, Lawrence J., III

2011-01-01

Synthetic Vision Systems and Enhanced Flight Vision System (SVS/EFVS) technologies have the potential to provide additional margins of safety for aircrew performance and enable operational improvements for low visibility operations in the terminal area environment with equivalent efficiency as visual operations. To meet this potential, research is needed for effective technology development and implementation of regulatory and design guidance to support introduction and use of SVS/EFVS advanced cockpit vision technologies in Next Generation Air Transportation System (NextGen) operations. A fixed-base pilot-in-the-loop simulation test was conducted at NASA Langley Research Center that evaluated the use of SVS/EFVS in NextGen low visibility ground (taxi) operations and approach/landing operations. Twelve crews flew approach and landing operations in a simulated NextGen Chicago O Hare environment. Various scenarios tested the potential for EFVS for operations in visibility as low as 1000 ft runway visibility range (RVR) and SVS to enable lower decision heights (DH) than can currently be flown today. Expanding the EFVS visual segment from DH to the runway in visibilities as low as 1000 RVR appears to be viable as touchdown performance was excellent without any workload penalties noted for the EFVS concept tested. A lower DH to 150 ft and/or possibly reduced visibility minima by virtue of SVS equipage appears to be viable when implemented on a Head-Up Display, but the landing data suggests further study for head-down implementations.

Safeguards of Neurotransmission: Endocytic Adaptors as Regulators of Synaptic Vesicle Composition and Function

PubMed Central

Kaempf, Natalie; Maritzen, Tanja

2017-01-01

Communication between neurons relies on neurotransmitters which are released from synaptic vesicles (SVs) upon Ca2+ stimuli. To efficiently load neurotransmitters, sense the rise in intracellular Ca2+ and fuse with the presynaptic membrane, SVs need to be equipped with a stringently controlled set of transmembrane proteins. In fact, changes in SV protein composition quickly compromise neurotransmission and most prominently give rise to epileptic seizures. During exocytosis SVs fully collapse into the presynaptic membrane and consequently have to be replenished to sustain neurotransmission. Therefore, surface-stranded SV proteins have to be efficiently retrieved post-fusion to be used for the generation of a new set of fully functional SVs, a process in which dedicated endocytic sorting adaptors play a crucial role. The question of how the precise reformation of SVs is achieved is intimately linked to how SV membranes are retrieved. For a long time both processes were believed to be two sides of the same coin since Clathrin-mediated endocytosis (CME), the proposed predominant SV recycling mode, will jointly retrieve SV membranes and proteins. However, with the recent proposal of Clathrin-independent SV recycling pathways SV membrane retrieval and SV reformation turn into separable events. This review highlights the progress made in unraveling the molecular mechanisms mediating the high-fidelity retrieval of SV proteins and discusses how the gathered knowledge about SV protein recycling fits in with the new notions of SV membrane endocytosis. PMID:29085282

Effect of step-synchronized vibration stimulation of soles on gait in Parkinson's disease: a pilot study

PubMed Central

Novak, Peter; Novak, Vera

2006-01-01

Background Previous studies have suggested that impaired proprioceptive processing in the striatum may contribute to abnormal gait in Parkinson's disease (PD). Methods This pilot study assessed the effects of enhanced proprioceptive feedback using step-synchronized vibration stimulation of the soles (S-VS) on gait in PD. S-VS was used in 8 PD subjects (3 women and 5 men, age range 44–79 years, on medication) and 8 age-matched healthy subjects (5 women and 3 men). PD subjects had mild or moderate gait impairment associated with abnormal balance, but they did not have gait freezing. Three vibratory devices (VDs) were embedded in elastic insoles (one below the heel and two below the forefoot areas) inserted into the shoes. Each VD operates independently and has a pressure switch that activates the underlying vibratory actuator. The VD delivered the 70-Hz suprathreshold vibration pulse upon touch by the heel or forefoot, and the vibration pulse was deactivated upon respective push-offs. Six-minute hallway walking was studied with and without S-VS. Gait characteristics were measured using the force-sensitive foot switches. The primary outcome was the stride variability expressed as a coefficient of variation (CV), a measure of gait steadiness. Secondary outcome measures were walking distance and speed, stride length and duration, cadence, stance, swing and double support duration, and respective CVs (if applicable). Results The walking speed (p < 0.04) and the CV of the stride interval (p < 0.02) differed between the groups and S-VS conditions. In the PD group, S-VS decreased stride variability (p < 0.002), increased walking speed (p < 0.0001), stride duration (p < 0.01), stride length (p < 0.0002), and cadence (p < 0.03). In the control group, S-VS decreased stride variability (p < 0.006) and increased gait speed (p < 0.03), but other locomotion parameters were not significantly altered. Conclusion Augmented sensory feedback improves parkinsonian gait steadiness in the short-term setting. Because the suprathreshold stimulation prevented blinding of subjects, the learning effect and increased attention can be a confounding factor underlying results. Long-term studies are needed to establish the clinical value of the S-VS. PMID:16674823

Terrain Portrayal for Head-Down Displays Experiment

NASA Technical Reports Server (NTRS)

Hughes, Monica F.; Takallu, M. A.

2002-01-01

The General Aviation Element of the Aviation Safety Program's Synthetic Vision Systems (SVS) Project is developing technology to eliminate low visibility induced General Aviation (GA) accidents. SVS displays present computer generated 3-dimensional imagery of the surrounding terrain on the Primary Flight Display (PFD) to greatly enhance pilot's situation awareness (SA), reducing or eliminating Controlled Flight into Terrain, as well as Low-Visibility Loss of Control accidents. SVS-conducted research is facilitating development of display concepts that provide the pilot with an unobstructed view of the outside terrain, regardless of weather conditions and time of day. A critical component of SVS displays is the appropriate presentation of terrain to the pilot. An experimental study has been conducted at NASA Langley Research Center (LaRC) to explore and quantify the relationship between the realism of the terrain presentation and resulting enhancements of pilot SA and pilot performance. Composed of complementary simulation and flight test efforts, Terrain Portrayal for Head-Down Displays (TP-HDD) experiments will help researchers evaluate critical terrain portrayal concepts. The experimental effort is to provide data to enable design trades that optimize SVS applications, as well as develop requirements and recommendations to facilitate the certification process. This paper focuses on the experimental set-up and preliminary qualitative results of the TP-HDD simulation experiment. In this experiment a fixed based flight simulator was equipped with various types of Head Down flight displays, ranging from conventional round dials (typical of most GA aircraft) to glass cockpit style PFD's. The variations of the PFD included an assortment of texturing and Digital Elevation Model (DEM) resolution combinations. A test matrix of 10 terrain display configurations (in addition to the baseline displays) were evaluated by 27 pilots of various backgrounds and experience levels. Qualitative (questionnaires) and quantitative (pilot performance and physiological) data were collected during the experimental runs. Preliminary results indicate that all of the evaluation pilots favored SVS displays over standard gauges, in terms of terrain awareness, SA, and perceived pilot performance. Among the terrain portrayal concepts tested, most pilots preferred the higher-resolution DEM. In addition, with minimal training, low-hour VFR evaluation pilots were able to negotiate a precision approach using SVS displays with a tunnel in the sky guidance concept.

Terrain Portrayal for Head-Down Displays Flight Test

NASA Technical Reports Server (NTRS)

Hughes, Monica F.; Glaab, Louis J.

2003-01-01

The Synthetic Vision Systems General Aviation (SVS-GA) element of NASA's Aviation Safety Program is developing technology to eliminate low visibility induced General Aviation (GA) accidents through the application of synthetic vision techniques. SVS displays present computer generated 3-dimensional imagery of the surrounding terrain to greatly enhance pilot's situation awareness (SA), reducing or eliminating Controlled Flight into Terrain (CFIT), as well as Low-Visibility Loss of Control (LVLOC) accidents. In addition to substantial safety benefits, SVS displays have many potential operational benefits that can lead to flight in instrument meteorological conditions (IMC) resembling those conducted in visual meteorological conditions (VMC). Potential benefits could include lower landing minimums, more approach options, reduced training time, etc. SVS conducted research will develop display concepts providing the pilot with an unobstructed view of the outside terrain, regardless of weather conditions and time of day. A critical component of SVS displays is the appropriate presentation of terrain to the pilot. The relationship between the realism of the terrain presentation and resulting enhancements of pilot SA and pilot performance has been largely undefined. Comprised of coordinated simulation and flight test efforts, the terrain portrayal for head-down displays (TP-HDD) test series examined the effects of two primary elements of terrain portrayal: variations of digital elevation model (DEM) resolution and terrain texturing. Variations in DEM resolution ranged from sparsely spaced (30 arc-sec/2,953ft) to very closely spaced data (1 arc-sec/98 ft). Variations in texture involved three primary methods: constant color, elevation-based generic, and photo-realistic, along with a secondary depth cue enhancer in the form of a fishnet grid overlay. The TP-HDD test series was designed to provide comprehensive data to enable design trades to optimize all SVS applications, as well as develop requirements and recommendations to facilitate the implementation and certification of SVS displays. The TP-HDD flight experiment utilized the NASA LaRC Cessna 206 Stationaire and evaluated eight terrain portrayal concepts in an effort to confirm and extend results from the previously conducted TP-HDD simulation experiment. A total of 15 evaluation pilots, of various qualifications, accumulated over 75 hours of dedicated research flight time at Newport News (PHF) and Roanoke (ROA), VA, airports from August through October, 2002. This report will present results from the portion of testing conducted at Roanoke, VA.

The Society for Vascular Surgery's objective performance goals for lower extremity revascularization are not generalizable to many open surgical bypass patients encountered in contemporary surgical practice.

PubMed

Saraidaridis, Julia T; Ergul, Emel; Patel, Virendra I; Stone, David H; Cambria, Richard P; Conrad, Mark F

2015-08-01

In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPG) for lower extremity bypass (LEB) in patients with critical limb ischemia (CLI) based on pooled data from previously performed prospective studies in an effort to provide a benchmark and historical control for future trials. However, patients with a prosthetic conduit and end-stage renal disease were excluded from this cohort. In contemporary practice, many patients do not meet the criteria for SVS OPG inclusion, making generalization of the SVS OPG difficult. The goal of this study was to establish safety and efficacy measures for patients who were excluded from the original SVS OPG analysis. All patients who underwent LEB for CLI in the Vascular Study Group of New England (VSGNE) from 2003 to 2013 were identified. Patients were stratified into OPG-eligible and non-OPG-eligible cohorts. Outcomes included 30-day major adverse limb events, 30-day major adverse cardiovascular events, 1-year survival, and 1-year freedom from amputation. The SVS OPG methodology was used to create new performance goals for the non-OPG-eligible patients. We identified 3609 patients: 2360 OPG (65%) vs 1249 non-OPG (35%), and overall results were stratified as a function of OPG status. The 30-day major adverse limb event rate was 5.0% (5.5% non-OPG vs 4.4% OPG; P = .34), and the 30-day major adverse cardiovascular event rate was 7.3% (9.2% non-OPG vs 6.2% OPG; P = .001). At 1 year, survival was 84% (75.9% non-OPG vs 88.3% OPG; P < .001), and freedom from amputation was 86.9% (80.9% non-OPG vs 90.1% OPG; P < .001). The SVS OPG were attainable in New England for the population of patients who would have met SVS OPG study cohort inclusion criteria. However, 35% of the patients who underwent LEB for CLI in the last 10 years fell outside of these criteria by having end-stage renal disease or requiring a prosthetic conduit. We therefore suggest new benchmarks for these high-risk populations. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Setting high-impact clinical research priorities for the Society for Vascular Surgery.

PubMed

Kraiss, Larry W; Conte, Michael S; Geary, Randolph L; Kibbe, Melina; Ozaki, C Keith

2013-02-01

With the overall goal of enhancing the effectiveness and efficiency of vascular care, the Society for Vascular Surgery (SVS) recently completed a process by which it identified its top clinical research priorities to address critical gaps in knowledge guiding practitioners in prevention and treatment of vascular disease. After a survey of the SVS membership, a panel of SVS committee members and opinion leaders considered 53 distinct research questions through a structured process that resulted in identification of nine clinical issues that were felt to merit immediate attention by vascular investigators and external funding agencies. These are, in order of priority: (1) define optimal management of asymptomatic carotid stenosis, (2) compare the effectiveness of medical vs invasive treatment (open or endovascular) of vasculogenic claudication, (3) compare effectiveness of open vs endovascular infrainguinal revascularization as initial treatment of critical limb ischemia, (4) develop and compare the effectiveness of clinical strategies to reduce cardiovascular and other perioperative complications (eg, wound) after vascular intervention, (5) compare the effectiveness of strategies to enhance arteriovenous fistula maturation and durability, (6) develop best practices for management of chronic venous ulcer, (7) define optimal adjunctive medical therapy to enhance the success of lower extremity revascularization, (8) identify and evaluate medical therapy to prevent abdominal aortic aneurysm growth, and (9) evaluate ultrasound vs computed tomographic angiography surveillance after endovascular aneurysm repair. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Salient value similarity, social trust, and attitudes toward wildland fire management strategies

Treesearch

Jerry J. Vaske; James D. Absher; Alan D. Bright

2007-01-01

Using the salient value similarity (SVS) model, we predicted that social trust mediated the relationship between SVS and attitudes toward prescribed burns and mechanical thinning. Data were obtained from a mail survey (n = 532) of Colorado residents living in the wildland-urban interface. Results indicated that respondents shared the same values as U...

Salient value similarity, social trust and attitudes toward wildland fire management strategies

Treesearch

J.J. Vaske; J.D. Absher; A.D. Bright

2007-01-01

We predicted that social trust in the USDA Forest Service would mediate the relationship between shared value similarity (SVS) and attitudes toward prescribed burning and mechanical thinning. Data were obtained from a mail survey (n = 532) of rural Colorado residents living in the wildland urban interface (WUI). A structural equation analysis was used to assess the...

Using Vision System Technologies to Enable Operational Improvements for Low Visibility Approach and Landing Operations

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Ellis, Kyle K. E.; Bailey, Randall E.; Williams, Steven P.; Severance, Kurt; Le Vie, Lisa R.; Comstock, James R.

2014-01-01

Flight deck-based vision systems, such as Synthetic and Enhanced Vision System (SEVS) technologies, have the potential to provide additional margins of safety for aircrew performance and enable the implementation of operational improvements for low visibility surface, arrival, and departure operations in the terminal environment with equivalent efficiency to visual operations. To achieve this potential, research is required for effective technology development and implementation based upon human factors design and regulatory guidance. This research supports the introduction and use of Synthetic Vision Systems and Enhanced Flight Vision Systems (SVS/EFVS) as advanced cockpit vision technologies in Next Generation Air Transportation System (NextGen) operations. Twelve air transport-rated crews participated in a motion-base simulation experiment to evaluate the use of SVS/EFVS in NextGen low visibility approach and landing operations. Three monochromatic, collimated head-up display (HUD) concepts (conventional HUD, SVS HUD, and EFVS HUD) and two color head-down primary flight display (PFD) concepts (conventional PFD, SVS PFD) were evaluated in a simulated NextGen Chicago O'Hare terminal environment. Additionally, the instrument approach type (no offset, 3 degree offset, 15 degree offset) was experimentally varied to test the efficacy of the HUD concepts for offset approach operations. The data showed that touchdown landing performance were excellent regardless of SEVS concept or type of offset instrument approach being flown. Subjective assessments of mental workload and situation awareness indicated that making offset approaches in low visibility conditions with an EFVS HUD or SVS HUD may be feasible.

Characteristics of successful and unsuccessful completers of 3 postacute brain injury rehabilitation pathways.

PubMed

Malec, James F; Degiorgio, Lisa

2002-12-01

To determine whether successful participants along different postacute brain injury rehabilitation pathways differ on demographic, injury-related, disability, and outcome variables. Secondary analysis of pre- and posttreatment, and 1-year follow-up data obtained in a previous study of specialized vocational services (SVS) for persons with brain injury. Outpatient brain injury rehabilitation clinic. One hundred fourteen persons with acquired brain injury. Participants in 3 distinct rehabilitation pathways were studied: SVS only; SVS and a 3-h/wk community reintegration outpatient group; and SVS and 6-h/d comprehensive day treatment (CDT). Mayo-Portland Adaptability Inventory (MPAI); Vocational Independence Scale; and "success," as defined by community-based employment (CBE) at 1-year follow-up. The percentage (77%-85%) of participants in CBE at 1-year follow-up did not differ among the 3 pathways. CDT participants had more limited educational backgrounds, were less recently injured, and showed greater disability and more impaired self-awareness than those receiving limited intervention (ie, SVS or community reintegration outpatient group). MPAI scores for limited-intervention participants who were unsuccessful were similar in level to successful participants in CDT. Logistic regression models were developed to predict the probability of success with limited intervention and CDT. Different rehabilitation pathways result in CBE for a large percentage of persons with brain injury if the intensity of service is appropriately matched to the severity of the disability, the time since injury, and other participant characteristics. Copyright 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Using Relative Position and Temporal Judgments to Assess the Effects of Texture and Field of View on Spatial Awareness for Synthetic Vision Systems Displays

NASA Technical Reports Server (NTRS)

Bolton, Matthew L.; Bass, Ellen J.; Comstock, James R., Jr.

2006-01-01

Synthetic Vision Systems (SVS) depict computer generated views of terrain surrounding an aircraft. In the assessment of textures and field of view (FOV) for SVS, no studies have directly measured the 3 levels of spatial awareness: identification of terrain, its relative spatial location, and its relative temporal location. This work introduced spatial awareness measures and used them to evaluate texture and FOV in SVS displays. Eighteen pilots made 4 judgments (relative angle, distance, height, and abeam time) regarding the location of terrain points displayed in 112 5-second, non-interactive simulations of a SVS heads down display. Texture produced significant main effects and trends for the magnitude of error in the relative distance, angle, and abeam time judgments. FOV was significant for the directional magnitude of error in the relative distance, angle, and height judgments. Pilots also provided subjective terrain awareness ratings that were compared with the judgment based measures. The study found that elevation fishnet, photo fishnet, and photo elevation fishnet textures best supported spatial awareness for both the judgments and the subjective awareness measures.

Flight Test Comparison of Synthetic Vision Display Concepts at Dallas/Fort Worth International Airport

NASA Technical Reports Server (NTRS)

Glaab, Louis J.; Kramer, Lynda J.; Arthur, Trey; Parrish, Russell V.; Barry, John S.

2003-01-01

Limited visibility is the single most critical factor affecting the safety and capacity of worldwide aviation operations. Synthetic Vision Systems (SVS) technology can solve this visibility problem with a visibility solution. These displays employ computer-generated terrain imagery to present 3D, perspective out-the-window scenes with sufficient information and realism to enable operations equivalent to those of a bright, clear day, regardless of weather conditions. To introduce SVS display technology into as many existing aircraft as possible, a retrofit approach was defined that employs existing HDD display capabilities for glass cockpits and HUD capabilities for the other aircraft. This retrofit approach was evaluated for typical nighttime airline operations at a major international airport. Overall, 6 evaluation pilots performed 75 research approaches, accumulating 18 hours flight time evaluating SVS display concepts that used the NASA LaRC's Boeing B-757-200 aircraft at Dallas/Fort Worth International Airport. Results from this flight test establish the SVS retrofit concept, regardless of display size, as viable for tested conditions. Future assessments need to extend evaluation of the approach to operations in an appropriate, terrain-challenged environment with daytime test conditions.

The influence of nano-oxide layer on magnetostriction of sensing layer in bottom spin valves

NASA Astrophysics Data System (ADS)

Qiu, J. J.; Han, G. C.; Li, K. B.; Liu, Z. Y.; Zong, B. Y.; Wu, Y. H.

2006-05-01

The magnetostriction coefficient (λs) of ultrathin sputtered polycrystalline as-deposited and annealed Ta/Ni81Fe19(t)/Ta films was studied as a function of the thickness. λs and magnetoresistance (MR) of bottom-type spin valves (SVs) with nano-oxide layer (NOL) added in the pinned layer were investigated by using NiFe, Co90Fe10, and CoFe/NiFe/CoFe layers as free layer (FL), respectively. λs of SV with NOL increased slightly except that of CoFe FL. NOLs were added at different positions to study the effects of NOL on λs of CoFe FL. All λs of CoFe FL change from negative to positive and its absolute value also increases significantly with CoFeOx related NOL added below. Our λs and surface roughness results indicated that the structure of the film not the roughness dominates λs of ultrathin FL in SVs.

[Regulatory Mechanisms of PD-L1 Expression and Its Role in Immune Evasion].

PubMed

Kataoka, Keisuke

2017-11-01

Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption.

MS Non-Pharmacological Countermeasure to Decrease Landing Sickness and Improve Functional Performance While Disorientad

NASA Technical Reports Server (NTRS)

Rosenberg, M. J. F.; Kreutzberg, G. A.; Galvan-Garza, R. C.; Mulavara, A. P.; Reschke, M. F.

2017-01-01

Upon return from spaceflight, a majority of crewmembers experience motion sickness (MS) symptoms. The interactions between crewmembers' adaptation to a gravitational transition, the performance decrements resulting from MS and/or use of promethazine (PMZ), and the constraints imposed by mission task demands could significantly challenge and limit an astronaut's ability to perform functional tasks during gravitational transitions. No operational countermeasure currently exists to mitigate the risks associated with these sensorimotor disturbances. Stochastic resonance (SR) can be thought of simply as "noise benefit" or an increase in information transfer by a system when in the presence of a non-zero level of noise. We have shown that low levels of stochastic vestibular stimulation (SVS) improve balance and locomotor performance due to SR (Goel et al. 2015, Mulavara et al. 2011, 2015). Additionally, a study in a 6-hydroxydopamine (6-OHDA) hemi-lesioned rat model of Parkinson's disease demonstrated improvements in locomotor activity after low-level SVS delivery possibly due to an increase in nigral gamma-aminobutyric acid (GABA) release in a dopamine independent way (Samoudi et al. 2012). SVS specifically increased GABA release on the lesioned, but not the intact side. These results suggest that SVS can cause targeted alterations of GABA release to affect performance of functional tasks. Activation of the GABA pathway is important in modulating MS and promoting adaptability (Cohen 2008). Magnusson et al. (2000) supported this finding by showing that the administration of a GABAB agonist caused a reversal of the symptoms that is normally seen after unilateral labyrinthectomy. Thus, GABA could play a significant role in reducing MS and promoting adaptability. We have taken advantage of the SR mechanism as a modulator of neurotransmitters to develop a unique SVS countermeasure system to mitigate MS symptoms and improve functional performance after landing. Healthy subjects (n=20) participated in two test sessions, one in which they received +/-400 microA of SVS and one where they received no stimulation (0 microA); the study design was counterbalanced. Subjects began by performing a series of four functional tasks 3-5 times as baseline measurements of task performance. Then, to induce MS, subjects walked an obstacle course with up-down reversing prisms. If they completed the course before achieving our pre-determined level of MS, they were asked to read a poster while making large up-down head movements to a metronome while still wearing the reversing prism goggles. Subjects were stopped every two minutes and asked to report their MS symptoms. Using the Pensacola Scale for motion sickness, test operators evaluated the level of MS of each subject. Once a subject reached an 8 on this scale, which is equivalent to mild malaise, or 30 minutes had passed since the start of the MS induction, this protocol was stopped. Finally, immediately after MS induction, subjects were asked to complete the four functional tasks again. Although, 100% of our subjects experienced at least one MS symptom, only 55% of our subjects experienced stomach awareness to any degree. Without SVS, only 40% of subjects lasted the full 30-minute MS induction protocol, while 65% of subjects lasted the full 30 minutes with SVS, which is nearly a significant increase (p=0.056). In addition, subjects showed significant improvement from baseline when performing a tandem walk and a prone-to-stand test immediately after the MS induction protocol was stopped but the stimulation level was continued. The results are promising and future work includes comparing MS progression between PMZ and SVS directly in subjects that are provoked to a minimum of nausea. Low levels of SVS stimulation may serve as a non-pharmacological countermeasure to replace or reduce the PMZ dosage requirements and concurrently improve functional performance during transitions to new gravitational environments after spaceflight.

Assessment of PaO2/FiO2 for stratification of patients with moderate and severe acute respiratory distress syndrome

PubMed Central

Villar, Jesús; Blanco, Jesús; del Campo, Rafael; Andaluz-Ojeda, David; Díaz-Domínguez, Francisco J; Muriel, Arturo; Córcoles, Virgilio; Suárez-Sipmann, Fernando; Tarancón, Concepción; González-Higueras, Elena; López, Julia; Blanch, Lluis; Pérez-Méndez, Lina; Fernández, Rosa Lidia; Kacmarek, Robert M

2015-01-01

Objectives A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at ARDS onset. Since the proposal did not mandate PaO2/FiO2 calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO2/FiO2 would not provide accurate assessment of lung injury severity. Design A prospective, multicentre, observational study. Setting A network of teaching hospitals. Participants 478 patients with eligible criteria for moderate (100300). Primary and secondary outcomes Group severity and hospital mortality. Results At ARDS onset, 173 patients had a PaO2/FiO2≤100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO2/FiO2 category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO2/FiO2 and non-standardised PaO2/FiO2 at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). Conclusions Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. Trial registration numbers NCT00435110 and NCT00736892. PMID:25818272

Assessment of PaO₂/FiO₂ for stratification of patients with moderate and severe acute respiratory distress syndrome.

PubMed

Villar, Jesús; Blanco, Jesús; del Campo, Rafael; Andaluz-Ojeda, David; Díaz-Domínguez, Francisco J; Muriel, Arturo; Córcoles, Virgilio; Suárez-Sipmann, Fernando; Tarancón, Concepción; González-Higueras, Elena; López, Julia; Blanch, Lluis; Pérez-Méndez, Lina; Fernández, Rosa Lidia; Kacmarek, Robert M

2015-03-27

A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) at ARDS onset. Since the proposal did not mandate PaO₂/FiO₂ calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO₂/FiOv would not provide accurate assessment of lung injury severity. A prospective, multicentre, observational study. A network of teaching hospitals. 478 patients with eligible criteria for moderate (100300). Group severity and hospital mortality. At ARDS onset, 173 patients had a PaO₂/FiO₂≤100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO₂/FiO₂ category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO₂/FiO₂ and non-standardised PaO₂/FiO₂ at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. NCT00435110 and NCT00736892. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Do not hesitate to use Tversky-and other hints for successful active analogue searches with feature count descriptors.

PubMed

Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre

2013-07-22

This study is an exhaustive analysis of the neighborhood behavior over a large coherent data set (ChEMBL target/ligand pairs of known Ki, for 165 targets with >50 associated ligands each). It focuses on similarity-based virtual screening (SVS) success defined by the ascertained optimality index. This is a weighted compromise between purity and retrieval rate of active hits in the neighborhood of an active query. One key issue addressed here is the impact of Tversky asymmetric weighing of query vs candidate features (represented as integer-value ISIDA colored fragment/pharmacophore triplet count descriptor vectors). The nearly a 3/4 million independent SVS runs showed that Tversky scores with a strong bias in favor of query-specific features are, by far, the most successful and the least failure-prone out of a set of nine other dissimilarity scores. These include classical Tanimoto, which failed to defend its privileged status in practical SVS applications. Tversky performance is not significantly conditioned by tuning of its bias parameter α. Both initial "guesses" of α = 0.9 and 0.7 were more successful than Tanimoto (at its turn, better than Euclid). Tversky was eventually tested in exhaustive similarity searching within the library of 1.6 M commercial + bioactive molecules at http://infochim.u-strasbg.fr/webserv/VSEngine.html , comparing favorably to Tanimoto in terms of "scaffold hopping" propensity. Therefore, it should be used at least as often as, perhaps in parallel to Tanimoto in SVS. Analysis with respect to query subclasses highlighted relationships of query complexity (simply expressed in terms of pharmacophore pattern counts) and/or target nature vs SVS success likelihood. SVS using more complex queries are more robust with respect to the choice of their operational premises (descriptors, metric). Yet, they are best handled by "pro-query" Tversky scores at α > 0.5. Among simpler queries, one may distinguish between "growable" (allowing for active analogs with additional features), and a few "conservative" queries not allowing any growth. These (typically bioactive amine transporter ligands) form the specific application domain of "pro-candidate" biased Tversky scores at α < 0.5.

Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle.

PubMed

Li, Yin; Hamilton, Katherine J; Lai, Anne Y; Burns, Katherine A; Li, Leping; Wade, Paul A; Korach, Kenneth S

2014-03-01

Diethylstilbestrol (DES) is a synthetic estrogen associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by estrogen receptor α (ERα), which alters expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in SVs of wild-type (WT) and ERα-knockout (αERKO) mice. The DNA methylation status at four specific CpGs (-160, -237, -306, and -367) in the Svs4 gene promoter changed during mouse development from methylated to unmethylated, and DES prevented this change at 10 weeks of age in WT SV. At two specific CpGs (-449 and -459) of the Ltf gene promoter, DES altered the methylation status from methylated to unmethylated. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SVs, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status was associated with the level of gene expression. In addition, gene expression of three epigenetic modifiers-DNMT3A, MBD2, and HDAC2-increased in the SV of DES-exposed WT mice. DES-induced hormonal toxicity resulted from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that were mediated by ERα. Alterations in gene expression of DNMT3A, MBD2, and HDAC2 in DES-exposed male mice may be involved in mediating the changes in methylation status in the SV. Li Y, Hamilton KJ, Lai AY, Burns KA, Li L, Wade PA, Korach KS. 2014. Diethylstilbestrol (DES)-stimulated hormonal toxicity is mediated by ERα alteration of target gene methylation patterns and epigenetic modifiers (DNMT3A, MBD2, and HDAC2) in the mouse seminal vesicle. Environ Health Perspect 122:262-268; http://dx.doi.org/10.1289/ehp.1307351.

Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers.

PubMed

Kataoka, Keisuke; Shiraishi, Yuichi; Takeda, Yohei; Sakata, Seiji; Matsumoto, Misako; Nagano, Seiji; Maeda, Takuya; Nagata, Yasunobu; Kitanaka, Akira; Mizuno, Seiya; Tanaka, Hiroko; Chiba, Kenichi; Ito, Satoshi; Watatani, Yosaku; Kakiuchi, Nobuyuki; Suzuki, Hiromichi; Yoshizato, Tetsuichi; Yoshida, Kenichi; Sanada, Masashi; Itonaga, Hidehiro; Imaizumi, Yoshitaka; Totoki, Yasushi; Munakata, Wataru; Nakamura, Hiromi; Hama, Natsuko; Shide, Kotaro; Kubuki, Yoko; Hidaka, Tomonori; Kameda, Takuro; Masuda, Kyoko; Minato, Nagahiro; Kashiwase, Koichi; Izutsu, Koji; Takaori-Kondo, Akifumi; Miyazaki, Yasushi; Takahashi, Satoru; Shibata, Tatsuhiro; Kawamoto, Hiroshi; Akatsuka, Yoshiki; Shimoda, Kazuya; Takeuchi, Kengo; Seya, Tsukasa; Miyano, Satoru; Ogawa, Seishi

2016-06-16

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.

A Probabilistic Mass Estimation Algorithm for a Novel 7- Channel Capacitive Sample Verification Sensor

NASA Technical Reports Server (NTRS)

Wolf, Michael

2012-01-01

A document describes an algorithm created to estimate the mass placed on a sample verification sensor (SVS) designed for lunar or planetary robotic sample return missions. A novel SVS measures the capacitance between a rigid bottom plate and an elastic top membrane in seven locations. As additional sample material (soil and/or small rocks) is placed on the top membrane, the deformation of the membrane increases the capacitance. The mass estimation algorithm addresses both the calibration of each SVS channel, and also addresses how to combine the capacitances read from each of the seven channels into a single mass estimate. The probabilistic approach combines the channels according to the variance observed during the training phase, and provides not only the mass estimate, but also a value for the certainty of the estimate. SVS capacitance data is collected for known masses under a wide variety of possible loading scenarios, though in all cases, the distribution of sample within the canister is expected to be approximately uniform. A capacitance-vs-mass curve is fitted to this data, and is subsequently used to determine the mass estimate for the single channel s capacitance reading during the measurement phase. This results in seven different mass estimates, one for each SVS channel. Moreover, the variance of the calibration data is used to place a Gaussian probability distribution function (pdf) around this mass estimate. To blend these seven estimates, the seven pdfs are combined into a single Gaussian distribution function, providing the final mean and variance of the estimate. This blending technique essentially takes the final estimate as an average of the estimates of the seven channels, weighted by the inverse of the channel s variance.

The use of tracheostomy speaking valves in mechanically ventilated patients results in improved communication and does not prolong ventilation time in cardiothoracic intensive care unit patients.

PubMed

Sutt, Anna-Liisa; Cornwell, Petrea; Mullany, Daniel; Kinneally, Toni; Fraser, John F

2015-06-01

The aim of this study was to assess the effect of the introduction of in-line tracheostomy speaking valves (SVs) on duration of mechanical ventilation and time to verbal communication in patients requiring tracheostomy for prolonged mechanical ventilation in a predominantly cardiothoracic intensive care unit (ICU). We performed a retrospective preobservational-postobservational study using data from the ICU clinical information system and medical record. Extracted data included demographics, diagnoses and disease severity, mechanical ventilation requirements, and details on verbal communication and oral intake. Data were collected on 129 patients. Mean age was 59 ± 16 years, with 75% male. Demographics, case mix, and median time from intubation to tracheostomy (6 days preimplementation-postimplementation) were unchanged between timepoints. A significant decrease in time from tracheostomy to establishing verbal communication was observed (18 days preimplementation and 9 days postimplementation, P <.05). There was no difference in length of mechanical ventilation (20 days preimplementation-post) or time to decannulation (14 days preimplementation-postimplementation). No adverse events were documented in relation to the introduction of in-line SVs. In-line SVs were successfully implemented in mechanically ventilated tracheostomized patient population. This resulted in earlier verbal communication, no detrimental effect on ventilator weaning times, and no change in decannulation times. The purpose of the study was to compare tracheostomy outcomes in mechanically ventilated patients in a cardiothoracic ICU preintroduction and postintroduction of in-line SVs. It was hypothesized that in-line SVs would improve communication and swallowing specific outcomes with no increase in average time to decannulation or the number of adverse events. Copyright © 2015 Elsevier Inc. All rights reserved.

Binding, folding and insertion of a β-hairpin peptide at a lipid bilayer surface: Influence of electrostatics and lipid tail packing.

PubMed

Reid, Keon A; Davis, Caitlin M; Dyer, R Brian; Kindt, James T

2018-03-01

Antimicrobial peptides (AMPs) act as host defenses against microbial pathogens. Here we investigate the interactions of SVS-1 (KVKVKVKV d P l PTKVKVKVK), an engineered AMP and anti-cancer β-hairpin peptide, with lipid bilayers using spectroscopic studies and atomistic molecular dynamics simulations. In agreement with literature reports, simulation and experiment show preferential binding of SVS-1 peptides to anionic over neutral bilayers. Fluorescence and circular dichroism studies of a Trp-substituted SVS-1 analogue indicate, however, that it will bind to a zwitterionic DPPC bilayer under high-curvature conditions and folds into a hairpin. In bilayers formed from a 1:1 mixture of DPPC and anionic DPPG lipids, curvature and lipid fluidity are also observed to promote deeper insertion of the fluorescent peptide. Simulations using the CHARMM C36m force field offer complementary insight into timescales and mechanisms of folding and insertion. SVS-1 simulated at an anionic mixed POPC/POPG bilayer folded into a hairpin over a microsecond, the final stage in folding coinciding with the establishment of contact between the peptide's valine sidechains and the lipid tails through a "flip and dip" mechanism. Partial, transient folding and superficial bilayer contact are seen in simulation of the peptide at a zwitterionic POPC bilayer. Only when external surface tension is applied does the peptide establish lasting contact with the POPC bilayer. Our findings reveal the influence of disruption to lipid headgroup packing (via curvature or surface tension) on the pathway of binding and insertion, highlighting the collaborative effort of electrostatic and hydrophobic interactions on interaction of SVS-1 with lipid bilayers. Copyright © 2017 Elsevier B.V. All rights reserved.

Semiquantitative visual approach to scoring lung cancer treatment response using computed tomography: a pilot study.

PubMed

Gottlieb, Ronald H; Kumar, Prasanna; Loud, Peter; Klippenstein, Donald; Raczyk, Cheryl; Tan, Wei; Lu, Jenny; Ramnath, Nithya

2009-01-01

Our objective was to compare a newly developed semiquantitative visual scoring (SVS) method with the current standard, the Response Evaluation Criteria in Solid Tumors (RECIST) method, in the categorization of treatment response and reader agreement for patients with metastatic lung cancer followed by computed tomography. The 18 subjects (5 women and 13 men; mean age, 62.8 years) were from an institutional review board-approved phase 2 study that evaluated a second-line chemotherapy regimen for metastatic (stages III and IV) non-small cell lung cancer. Four radiologists, blinded to the patient outcome and each other's reads, evaluated the change in the patients' tumor burden from the baseline to the first restaging computed tomographic scan using either the RECIST or the SVS method. We compared the numbers of patients placed into the partial response, the stable disease (SD), and the progressive disease (PD) categories (Fisher exact test) and observer agreement (kappa statistic). Requiring the concordance of 3 of the 4 readers resulted in the RECIST placing 17 (100%) of 17 patients in the SD category compared with the SVS placing 9 (60%) of 15 patients in the partial response, 5 (33%) of the 15 patients in the SD, and 1 (6.7%) of the 15 patients in the PD categories (P < 0.0001). Interobserver agreement was higher among the readers using the SVS method (kappa, 0.54; P < 0.0001) compared with that of the readers using the RECIST method (kappa, -0.01; P = 0.5378). Using the SVS method, the readers more finely discriminated between the patient response categories with superior agreement compared with the RECIST method, which could potentially result in large differences in early treatment decisions for advanced lung cancer.

Enhanced Flight Vision Systems and Synthetic Vision Systems for NextGen Approach and Landing Operations

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Bailey, Randall E.; Ellis, Kyle K. E.; Williams, Steven P.; Arthur, Jarvis J., III; Prinzel, Lawrence J., III; Shelton, Kevin J.

2013-01-01

Synthetic Vision Systems and Enhanced Flight Vision System (SVS/EFVS) technologies have the potential to provide additional margins of safety for aircrew performance and enable operational improvements for low visibility operations in the terminal area environment with equivalent efficiency as visual operations. To meet this potential, research is needed for effective technology development and implementation of regulatory standards and design guidance to support introduction and use of SVS/EFVS advanced cockpit vision technologies in Next Generation Air Transportation System (NextGen) operations. A fixed-base pilot-in-the-loop simulation test was conducted at NASA Langley Research Center that evaluated the use of SVS/EFVS in NextGen low visibility approach and landing operations. Twelve crews flew approach and landing operations in a simulated NextGen Chicago O'Hare environment. Various scenarios tested the potential for using EFVS to conduct approach, landing, and roll-out operations in visibility as low as 1000 feet runway visual range (RVR). Also, SVS was tested to evaluate the potential for lowering decision heights (DH) on certain instrument approach procedures below what can be flown today. Expanding the portion of the visual segment in which EFVS can be used in lieu of natural vision from 100 feet above the touchdown zone elevation to touchdown and rollout in visibilities as low as 1000 feet RVR appears to be viable as touchdown performance was acceptable without any apparent workload penalties. A lower DH of 150 feet and/or possibly reduced visibility minima using SVS appears to be viable when implemented on a Head-Up Display, but the landing data suggests further study for head-down implementations.

Sildenafil vaginal suppositories: preparation, characterization, in vitro and in vivo evaluation.

PubMed

Shanmugam, Srinivasan; Kim, Young-Hun; Park, Jeong-Hee; Im, Ho Taek; Sohn, Young Taek; Kim, Kyeong Soo; Kim, Yong-Il; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon; Woo, Jong Soo

2014-06-01

The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS). Suppositories containing 25 mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated. The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127 ± 0.020 g, 98.25 ± 2.50%, 2.5 ± 0.08 kg and 9 ± 1.0 min, respectively. The release of sildenafil from the SVS was more than 90% at 30 min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n = 0.464). The plasma PK study demonstrated a significantly lower Cmax (∼10 times) and AUC0-24 h (∼13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher Cmax (∼40 times) and AUC0-24 h (∼20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution. This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.

Can Effective Synthetic Vision System Displays be Implemented on Limited Size Display Spaces?

NASA Technical Reports Server (NTRS)

Comstock, J. Raymond, Jr.; Glaab, Lou J.; Prinzel, Lance J.; Elliott, Dawn M.

2004-01-01

The Synthetic Vision Systems (SVS) element of the NASA Aviation Safety Program is striving to eliminate poor visibility as a causal factor in aircraft accidents, and to enhance operational capabilities of all types or aircraft. To accomplish these safety and situation awareness improvements, the SVS concepts are designed to provide a clear view of the world ahead through the display of computer generated imagery derived from an onboard database of terrain, obstacle and airport information. An important issue for the SVS concept is whether useful and effective Synthetic Vision System (SVS) displays can be implemented on limited size display spaces as would be required to implement this technology on older aircraft with physically smaller instrument spaces. In this study, prototype SVS displays were put on the following display sizes: (a) size "A' (e.g. 757 EADI), (b) form factor "D" (e.g. 777 PFD), and (c) new size "X" (Rectangular flat-panel, approximately 20 x 25 cm). Testing was conducted in a high-resolution graphics simulation facility at NASA Langley Research Center. Specific issues under test included the display size as noted above, the field-of-view (FOV) to be shown on the display and directly related to FOV is the degree of minification of the displayed image or picture. Using simulated approaches with display size and FOV conditions held constant no significant differences by these factors were found. Preferred FOV based on performance was determined by using approaches during which pilots could select FOV. Mean preference ratings for FOV were in the following order: (1) 30 deg., (2) Unity, (3) 60 deg., and (4) 90 deg., and held true for all display sizes tested. Limitations of the present study and future research directions are discussed.

Development of Sample Verification System for Sample Return Missions

NASA Technical Reports Server (NTRS)

Toda, Risaku; McKinney, Colin; Jackson, Shannon P.; Mojarradi, Mohammad; Trebi-Ollennu, Ashitey; Manohara, Harish

2011-01-01

This paper describes the development of a proof of-concept sample verification system (SVS) for in-situ mass measurement of planetary rock and soil sample in future robotic sample return missions. Our proof-of-concept SVS device contains a 10 cm diameter pressure sensitive elastic membrane placed at the bottom of a sample canister. The membrane deforms under the weight of accumulating planetary sample. The membrane is positioned in proximity to an opposing substrate with a narrow gap. The deformation of the membrane makes the gap to be narrower, resulting in increased capacitance between the two nearly parallel plates. Capacitance readout circuitry on a nearby printed circuit board (PCB) transmits data via a low-voltage differential signaling (LVDS) interface. The fabricated SVS proof-of-concept device has successfully demonstrated approximately 1pF/gram capacitance change

Symbology Development for General Aviation Synthetic Vision Primary Flight Displays for the Approach and Missed-Approach Modes of Flight

NASA Technical Reports Server (NTRS)

Bartolone, Anthony P.; Hughes, Monica F.; Wong, Douglas T.; Takallu, Mohammad A.

2004-01-01

Spatial disorientation induced by inadvertent flight into instrument meteorological conditions (IMC) continues to be a leading cause of fatal accidents in general aviation. The Synthetic Vision Systems General Aviation (SVS-GA) research element, an integral part of NASA s Aviation Safety and Security Program (AvSSP), is investigating a revolutionary display technology designed to mitigate low visibility events such as controlled flight into terrain (CFIT) and low-visibility loss of control (LVLoC). The integrated SVS Primary Flight Display (SVS-PFD) utilizes computer generated 3-dimensional imagery of the surrounding terrain augmented with flight path guidance symbology. This unique combination will provide GA pilots with an accurate representation of their environment and projection of their flight path, regardless of time of day or out-the-window (OTW) visibility. The initial Symbology Development for Head-Down Displays (SD-HDD) simulation experiment examined 16 display configurations on a centrally located high-resolution PFD installed in NASA s General Aviation Work Station (GAWS) flight simulator. The results of the experiment indicate that situation awareness (SA) can be enhanced without having a negative impact on flight technical error (FTE), by providing a general aviation pilot with an integrated SVS display to use when OTW visibility is obscured.

Radiolytic preparation and characterization of hydrophilic poly(acrylonitrile-co-vinylsulfonate)-grafted porous poly(tetrafluoroethylene) substrates

NASA Astrophysics Data System (ADS)

Park, Byeong-Hee; Sohn, Joon-Yong; Shin, Junhwa

2016-01-01

In this study, a hydrophilic copolymer of acrylonitrile (AN) and sodium vinylsulfonate (SVS) was grafted into a highly hydrophobic porous poly(tetrafluoroethylene) (PTFE) substrate using a gamma-ray irradiation method and the grafted substrate was used as a substrate for impregnating a hydrophilic ionomer, Nafion. The results of FT-IR and TGA analysis of the prepared substrate showed that the SVS/AN monomers were successfully grafted into the porous PTFE film. The results of degree of grafting, elemental analyzer, and contact angle analysis showed that the hydrophilicity of the prepared PTFE-g-P(AN-co-VS) substrate was increased with an increase in the amount of SVS/AN graft copolymers. Also, the results of FE-SEM and Gurley number measurement showed that the pores in the substrate were reduced as the amount of SVS/AN copolymers grafted into the substrate increased. The prepared porous PTFE-g-P(AN-co-VS) substrate at an irradiation dose of 70 kGy was found to impregnate Nafion ionomer effectively compared to the original porous PTFE substrate. These results suggest that the prepared PTFE-g-P(AN-co-VS) substrate can be effectively used for the impregnation of polymer electrolyte (Nafion) to prepare a reinforced composite membrane.

Structural changes in the nano-oxide layer with annealing in specular spin valves

NASA Astrophysics Data System (ADS)

Jang, S. H.; Kim, Y. W.; Kang, T.; Kim, H. J.; Kim, K. Y.

2003-05-01

We investigated microstructural changes in a nano-oxide layer (NOL) with annealing in specular spin valves (SVs) by cross-sectional transmission electron microscopy and x-ray photoelectron spectroscopy analysis. In the SV annealed at high temperature of 400 °C, an increase in thickness and a local breakdown of the NOL were observed. This local coarsening of the NOL is closely related to the formation of Mn oxides in the oxide-rich part of the NOL through Mn diffusion. Thus, the chemical structure of the NOL changes to the structure with Mn oxide-rich content after annealing.

The vascular surgeon-scientist: a 15-year report of the Society for Vascular Surgery Foundation/National Heart, Lung, and Blood Institute-mentored Career Development Award Program.

PubMed

Kibbe, Melina R; Dardik, Alan; Velazquez, Omaida C; Conte, Michael S

2015-04-01

The Society for Vascular Surgery (SVS) Foundation partnered with the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) in 1999 to initiate a competitive career development program that provides a financial supplement to surgeon-scientists receiving NIH K08 or K23 career development awards. Because the program has been in existence for 15 years, a review of the program's success has been performed. Between 1999 and 2013, 41 faculty members applied to the SVS Foundation program, and 29 from 21 different institutions were selected as awardees, resulting in a 71% success rate. Three women (10%) were among the 29 awardees. Nine awardees (31%) were supported by prior NIH F32 or T32 training grants. Awardees received their K award at an average of 3.5 years from the start of their faculty position, at the average age of 39.8 years. Thirteen awardees (45%) have subsequently received NIH R01 awards and five (17%) have received Veterans Affairs Merit Awards. Awardees received their first R01 at an average of 5.8 years after the start of their K award at the average age of 45.2 years. The SVS Foundation committed $9,350,000 to the Career Development Award Program. Awardees subsequently secured $45,108,174 in NIH and Veterans Affairs funds, resulting in a 4.8-fold financial return on investment for the SVS Foundation program. Overall, 23 awardees (79%) were promoted from assistant to associate professor in an average of 5.9 years, and 10 (34%) were promoted from associate professor to professor in an average of 5.2 years. Six awardees (21%) hold endowed professorships and four (14%) have secured tenure. Many of the awardees hold positions of leadership, including 12 (41%) as division chief and two (7%) as vice chair within a department of surgery. Eight (28%) awardees have served as president of a regional or national society. Lastly, 47 postdoctoral trainees have been mentored by recipients of the SVS Foundation Career Development Program on training grants or postdoctoral research fellowships. The SVS Foundation Career Development Program has been an effective vehicle to promote the development and independence of vascular surgeon-scientists in the field of academic vascular surgery. Published by Elsevier Inc.

Applying Novel Time-Frequency Moments Singular Value Decomposition Method and Artificial Neural Networks for Ballistocardiography

NASA Astrophysics Data System (ADS)

Akhbardeh, Alireza; Junnila, Sakari; Koivuluoma, Mikko; Koivistoinen, Teemu; Värri, Alpo

2006-12-01

As we know, singular value decomposition (SVD) is designed for computing singular values (SVs) of a matrix. Then, if it is used for finding SVs of an [InlineEquation not available: see fulltext.]-by-1 or 1-by- [InlineEquation not available: see fulltext.] array with elements representing samples of a signal, it will return only one singular value that is not enough to express the whole signal. To overcome this problem, we designed a new kind of the feature extraction method which we call ''time-frequency moments singular value decomposition (TFM-SVD).'' In this new method, we use statistical features of time series as well as frequency series (Fourier transform of the signal). This information is then extracted into a certain matrix with a fixed structure and the SVs of that matrix are sought. This transform can be used as a preprocessing stage in pattern clustering methods. The results in using it indicate that the performance of a combined system including this transform and classifiers is comparable with the performance of using other feature extraction methods such as wavelet transforms. To evaluate TFM-SVD, we applied this new method and artificial neural networks (ANNs) for ballistocardiogram (BCG) data clustering to look for probable heart disease of six test subjects. BCG from the test subjects was recorded using a chair-like ballistocardiograph, developed in our project. This kind of device combined with automated recording and analysis would be suitable for use in many places, such as home, office, and so forth. The results show that the method has high performance and it is almost insensitive to BCG waveform latency or nonlinear disturbance.

Budget Online Learning Algorithm for Least Squares SVM.

PubMed

Jian, Ling; Shen, Shuqian; Li, Jundong; Liang, Xijun; Li, Lei

2017-09-01

Batch-mode least squares support vector machine (LSSVM) is often associated with unbounded number of support vectors (SVs'), making it unsuitable for applications involving large-scale streaming data. Limited-scale LSSVM, which allows efficient updating, seems to be a good solution to tackle this issue. In this paper, to train the limited-scale LSSVM dynamically, we present a budget online LSSVM (BOLSSVM) algorithm. Methodologically, by setting a fixed budget for SVs', we are able to update the LSSVM model according to the updated SVs' set dynamically without retraining from scratch. In particular, when a new small chunk of SVs' substitute for the old ones, the proposed algorithm employs a low rank correction technology and the Sherman-Morrison-Woodbury formula to compute the inverse of saddle point matrix derived from the LSSVM's Karush-Kuhn-Tucker (KKT) system, which, in turn, updates the LSSVM model efficiently. In this way, the proposed BOLSSVM algorithm is especially useful for online prediction tasks. Another merit of the proposed BOLSSVM is that it can be used for k -fold cross validation. Specifically, compared with batch-mode learning methods, the computational complexity of the proposed BOLSSVM method is significantly reduced from O(n 4 ) to O(n 3 ) for leave-one-out cross validation with n training samples. The experimental results of classification and regression on benchmark data sets and real-world applications show the validity and effectiveness of the proposed BOLSSVM algorithm.

Flight Testing an Integrated Synthetic Vision System

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Arthur, Jarvis J., III; Bailey, Randall E.; Prinzel, Lawrence J., III

2005-01-01

NASA's Synthetic Vision Systems (SVS) project is developing technologies with practical applications to eliminate low visibility conditions as a causal factor to civil aircraft accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. A major thrust of the SVS project involves the development/demonstration of affordable, certifiable display configurations that provide intuitive out-the-window terrain and obstacle information with advanced pathway guidance for transport aircraft. The SVS concept being developed at NASA encompasses the integration of tactical and strategic Synthetic Vision Display Concepts (SVDC) with Runway Incursion Prevention System (RIPS) alerting and display concepts, real-time terrain database integrity monitoring equipment (DIME), and Enhanced Vision Systems (EVS) and/or improved Weather Radar for real-time object detection and database integrity monitoring. A flight test evaluation was jointly conducted (in July and August 2004) by NASA Langley Research Center and an industry partner team under NASA's Aviation Safety and Security, Synthetic Vision System project. A Gulfstream GV aircraft was flown over a 3-week period in the Reno/Tahoe International Airport (NV) local area and an additional 3-week period in the Wallops Flight Facility (VA) local area to evaluate integrated Synthetic Vision System concepts. The enabling technologies (RIPS, EVS and DIME) were integrated into the larger SVS concept design. This paper presents experimental methods and the high level results of this flight test.

Advancement of the Subjective Vitality Scale: examination of alternative measurement models for Japanese and Singaporeans.

PubMed

Kawabata, M; Yamazaki, F; Guo, D W; Chatzisarantis, N L D

2017-12-01

The Subjective Vitality Scale (SVS: Ryan & Frederick, 1997) is a 7-item self-report instrument to measure one's level of vitality and has been widely used in psychological studies. However, there have been discrepancies in which version of the SVS (7- or 6-item version) employed between as well as within researchers. Moreover, Item 5 seems not be a good indicator of vitality from a content validity perspective. Therefore, the present study aimed to evaluate the validity and reliability of the SVS for Japanese and Singaporeans rigorously by comparing 3 measurement models (5-, 6-, and 7-item models). To this end, the scale was first translated from English to Japanese and then the Japanese and English versions of the scale were administered to Japanese (n = 268) and Singaporean undergraduate students (n = 289), respectively. The factorial and concurrent validity of the three models were examined independently on each of the samples. Furthermore, the covariance stability of the vitality responses was assessed over a 4-week time period for another independent Japanese sample (n = 140). The findings from this study indicated that from methodological and content validity perspectives, the 5-item model is considered most preferable for both language versions of the SVS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Molecular Diversity of Plasmids Bearing Genes That Encode Toluene and Xylene Metabolism in Pseudomonas Strains Isolated from Different Contaminated Sites in Belarus

PubMed Central

Sentchilo, Vladimir S.; Perebituk, Alexander N.; Zehnder, Alexander J. B.; van der Meer, Jan Roelof

2000-01-01

Twenty different Pseudomonas strains utilizing m-toluate were isolated from oil-contaminated soil samples near Minsk, Belarus. Seventeen of these isolates carried plasmids ranging in size from 78 to about 200 kb (assigned pSVS plasmids) and encoding the meta cleavage pathway for toluene metabolism. Most plasmids were conjugative but of unknown incompatibility groups, except for one, which belonged to the IncP9 group. The organization of the genes for toluene catabolism was determined by restriction analysis and hybridization with xyl gene probes of pWW0. The majority of the plasmids carried xyl-type genes highly homologous to those of pWW53 and organized in a similar manner (M. T. Gallegos, P. A. Williams, and J. L. Ramos, J. Bacteriol. 179:5024–5029, 1997), with two distinguishable meta pathway operons, one upper pathway operon, and three xylS-homologous regions. All of these plasmids also possessed large areas of homologous DNA outside the catabolic genes, suggesting a common ancestry. Two other pSVS plasmids carried only one meta pathway operon, one upper pathway operon, and one copy each of xylS and xylR. The backbones of these two plasmids differed greatly from those of the others. Whereas these parts of the plasmids, carrying the xyl genes, were mostly conserved between plasmids of each group, the noncatabolic parts had undergone intensive DNA rearrangements. DNA sequencing of specific regions near and within the xylTE and xylA genes of the pSVS plasmids confirmed the strong homologies to the xyl genes of pWW53 and pWW0. However, several recombinations were discovered within the upper pathway operons of the pSVS plasmids and pWW0. The main genetic mechanisms which are thought to have resulted in the present-day configuration of the xyl operons are discussed in light of the diversity analysis carried out on the pSVS plasmids. PMID:10877777

The Society for Vascular Surgery lower extremity threatened limb classification system based on Wound, Ischemia, and foot Infection (WIfI) correlates with risk of major amputation and time to wound healing.

PubMed

Zhan, Luke X; Branco, Bernardino C; Armstrong, David G; Mills, Joseph L

2015-04-01

The purpose of this study was to evaluate whether the new Society for Vascular Surgery (SVS) Wound, Ischemia, and foot Infection (WIfI) classification system correlates with important clinical outcomes for limb salvage and wound healing. A total of 201 consecutive patients with threatened limbs treated from 2010 to 2011 in an academic medical center were analyzed. These patients were stratified into clinical stages 1 to 4 on the basis of the SVS WIfI classification. The SVS objective performance goals of major amputation, 1-year amputation-free survival (AFS) rate, and wound healing time (WHT) according to WIfI clinical stages were compared. The mean age was 58 years (79% male, 93% with diabetes). Forty-two patients required major amputation (21%); 159 (78%) had limb salvage. The amputation group had a significantly higher prevalence of advanced stage 4 patients (P < .001), whereas the limb salvage group presented predominantly as stages 1 to 3. Patients in clinical stages 3 and 4 had a significantly higher incidence of amputation (P < .001), decreased AFS (P < .001), and delayed WHT (P < .002) compared with those in stages 1 and 2. Among patients presenting with stage 3, primarily as a result of wound and ischemia grades, revascularization resulted in accelerated WHT (P = .008). These data support the underlying concept of the SVS WIfI, that an appropriate classification system correlates with important clinical outcomes for limb salvage and wound healing. As the clinical stage progresses, the risk of major amputation increases, 1-year AFS declines, and WHT is prolonged. We further demonstrated benefit of revascularization to improve WHT in selected patients, especially those in stage 3. Future efforts are warranted to incorporate the SVS WIfI classification into clinical decision-making algorithms in conjunction with a comorbidity index and anatomic classification. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Preliminary Effect of Synthetic Vision Systems Displays to Reduce Low-Visibility Loss of Control and Controlled Flight Into Terrain Accidents

NASA Technical Reports Server (NTRS)

Glaab, Louis J.; Takallu, Mohammad A.

2002-01-01

An experimental investigation was conducted to study the effectiveness of Synthetic Vision Systems (SVS) flight displays as a means of eliminating Low Visibility Loss of Control (LVLOC) and Controlled Flight Into Terrain (CFIT) accidents by low time general aviation (GA) pilots. A series of basic maneuvers were performed by 18 subject pilots during transition from Visual Meteorological Conditions (VMC) to Instrument Meteorological Conditions (IMC), with continued flight into IMC, employing a fixed-based flight simulator. A total of three display concepts were employed for this evaluation. One display concept, referred to as the Attitude Indicator (AI) replicated instrumentation common in today's General Aviation (GA) aircraft. The second display concept, referred to as the Electronic Attitude Indicator (EAI), featured an enlarged attitude indicator that was more representative of a glass display that also included advanced flight symbology, such as a velocity vector. The third concept, referred to as the SVS display, was identical to the EAI except that computer-generated terrain imagery replaced the conventional blue-sky/brown-ground of the EAI. Pilot performance parameters, pilot control inputs and physiological data were recorded for post-test analysis. Situation awareness (SA) and qualitative pilot comments were obtained through questionnaires and free-form interviews administered immediately after the experimental session. Initial pilot performance data were obtained by instructor pilot observations. Physiological data (skin temperature, heart rate, and muscle flexure) were also recorded. Preliminary results indicate that far less errors were committed when using the EAI and SVS displays than when using conventional instruments. The specific data example examined in this report illustrates the benefit from SVS displays to avoid massive loss of SA conditions. All pilots acknowledged the enhanced situation awareness provided by the SVS display concept. Levels of pilot stress appear to be correlated with skin temperature measurements.

Nitrogen oxide in protostellar envelopes and shocks: the ASAI survey

NASA Astrophysics Data System (ADS)

Codella, C.; Viti, S.; Lefloch, B.; Holdship, J.; Bachiller, R.; Bianchi, E.; Ceccarelli, C.; Favre, C.; Jiménez-Serra, I.; Podio, L.; Tafalla, M.

2018-03-01

The high sensitivity of the IRAM 30-m Astrochemical Surveys At IRAM (ASAI) unbiased spectral survey in the mm window allows us to detect NO emission towards both the Class I object SVS13-A and the protostellar outflow shock L1157-B1. We detect the hyperfine components of the 2Π1/2J = 3/2 → 1/2 (at 151 GHz) and the 2Π1/2J = 5/2 → 3/2 (at 250 GHz) spectral pattern. The two objects show different NO profiles: (i) SVS13-A emits through narrow (1.5 km s-1) lines at the systemic velocity, while (ii) L1157-B1 shows broad (˜5 km s-1) blueshifted emission. For SVS13-A, the analysis leads to Tex ≥ 4 K, N(NO) ≤ 3 × 1015 cm-2, and indicates the association of NO with the protostellar envelope. In L1157-B1, NO is tracing the extended outflow cavity: Tex ≃ 4-5 K, and N(NO) = 5.5 ± 1.5 × 1015 cm-2. Using C18O, 13C18O, C17O, and 13C17O ASAI observations, we derive an NO fractional abundance less than ˜10-7 for the SVS13-A envelope, in agreement with previous measurements towards extended photodissociation regions (PDRs) and prestellar objects. Conversely, a definite X(NO) enhancement is measured towards L1157-B1, ˜6 × 10-6, showing that the NO production increases in shocks. The public code UCLCHEM was used to interpret the NO observations, confirming that the abundance observed in SVS13-A can be attained in an envelope with a gas density of 105 cm-3 and a kinetic temperature of 40 K. The NO abundance in L1157-B1 is reproduced with pre-shock densities of 105 cm-3 subjected to a ˜45 km s-1 shock.

STS-52 CANEX-2 Canadian Target Assembly (CTA) held by RMS over OV-102's PLB

NASA Image and Video Library

1992-11-01

STS052-71-057 (22 Oct-1 Nov 1992) --- This 70mm frame, photographed with a handheld Hasselblad camera aimed through Columbia's aft flight deck windows, captures the operation of the Space Vision System (SVS) experiment above the cargo bay. Target dots have been placed on the Canadian Target Assembly (CTA), a small satellite, in the grasp of the Canadian-built remote manipulator system (RMS) arm. SVS utilized a Shuttle TV camera to monitor the dots strategically arranged on the satellite, to be tracked. As the satellite moved via the arm, the SVS computer measured the changing position of the dots and provided real-time television display of the location and orientation of the CTA. This type of displayed information is expected to help an operator guide the RMS or the Mobile Servicing System (MSS) of the future when berthing or deploying satellites. Also visible in the frame is the U.S. Microgravity Payload (USMP-01).

Eleven-Year Retrospective Report of Super-Selective Venous Sampling for the Evaluation of Recurrent or Persistent Hyperparathyroidism in 32 Patients.

PubMed

Habibollahi, Peiman; Shin, Benjamin; Shamchi, Sara P; Wachtel, Heather; Fraker, Douglas L; Trerotola, Scott O

2018-01-01

Parathyroid venous sampling (PAVS) is usually reserved for patients with persistent or recurrent hyperparathyroidism after parathyroidectomy with inconclusive noninvasive imaging studies. A retrospective study was performed to evaluate the diagnostic efficacy of super-selective PAVS (SSVS) in patients needing revision neck surgery with inconclusive imaging. Patients undergoing PAVS between 2005 and 2016 due to persistent or recurrent hyperparathyroidism following surgery were reviewed. PAVS was performed in all patients using super-selective technique. Single-value measurements within central neck veins performed as part of super-selective PAVS were used to simulate selective venous sampling (SVS) and allow for comparison to data, which might be obtained in a non-super-selective approach. 32 patients (mean age 51 ± 15 years; 8 men and 24 women) met inclusion and exclusion criteria. The sensitivity and positive predictive value (PPV) of SSVS for localizing the source of elevated PTH to a limited area in the neck or chest was 96 and 84%, respectively. Simulated SVS, on the other hand, had a sensitivity of 28% and a PPV of 89% based on the predefined gold standard. SSVS had a significantly higher sensitivity compared to simulated SVS (p < 0.001). SSVS is highly effective in localizing the source of hyperparathyroidism in patients undergoing revision surgery for hyperparathyroidism in whom noninvasive imaging studies are inconclusive. SSVS data had also markedly higher sensitivity for localizing disease in these patients compared to simulated SVS.

Free-breathing quantification of hepatic fat in healthy children and children with nonalcoholic fatty liver disease using a multi-echo 3-D stack-of-radial MRI technique.

PubMed

Armstrong, Tess; Ly, Karrie V; Murthy, Smruthi; Ghahremani, Shahnaz; Kim, Grace Hyun J; Calkins, Kara L; Wu, Holden H

2018-05-04

In adults, noninvasive chemical shift encoded Cartesian magnetic resonance imaging (MRI) and single-voxel magnetic resonance (MR) spectroscopy (SVS) accurately quantify hepatic steatosis but require breath-holding. In children, especially young and sick children, breath-holding is often limited or not feasible. Sedation can facilitate breath-holding but is highly undesirable. For these reasons, there is a need to develop free-breathing MRI technology that accurately quantifies steatosis in all children. This study aimed to compare non-sedated free-breathing multi-echo 3-D stack-of-radial (radial) MRI versus standard breath-holding MRI and SVS techniques in a group of children for fat quantification with respect to image quality, accuracy and repeatability. Healthy children (n=10, median age [±interquartile range]: 10.9 [±3.3] years) and overweight children with nonalcoholic fatty liver disease (NAFLD) (n=9, median age: 15.2 [±3.2] years) were imaged at 3 Tesla using free-breathing radial MRI, breath-holding Cartesian MRI and breath-holding SVS. Acquisitions were performed twice to assess repeatability (within-subject mean difference, MD within ). Images and hepatic proton-density fat fraction (PDFF) maps were scored for image quality. Free-breathing and breath-holding PDFF were compared using linear regression (correlation coefficient, r and concordance correlation coefficient, ρ c ) and Bland-Altman analysis (mean difference). P<0.05 was considered significant. In patients with NAFLD, free-breathing radial MRI demonstrated significantly less motion artifacts compared to breath-holding Cartesian (P<0.05). Free-breathing radial PDFF demonstrated a linear relationship (P<0.001) versus breath-holding SVS PDFF and breath-holding Cartesian PDFF with r=0.996 and ρ c =0.994, and r=0.997 and ρ c =0.995, respectively. The mean difference in PDFF between free-breathing radial MRI, breath-holding Cartesian MRI and breath-holding SVS was <0.7%. Repeated free-breathing radial MRI had MD within =0.25% for PDFF. In this pediatric study, non-sedated free-breathing radial MRI provided accurate and repeatable hepatic PDFF measurements and improved image quality, compared to standard breath-holding MR techniques.

Accuracy and Reproducibility of Strain by Speckle Tracking in Pediatric Subjects with Normal Heart and Single Ventricular Physiology: A 2D Speckle Tracking Echocardiography and Magnetic Resonance Imaging Correlative Study

PubMed Central

Singh, Gautam K.; Cupps, Brian; Pasque, Michael; Woodard, Pamela K.; Holland, Mark R.; Ludomirsky, Achiau

2013-01-01

Background Myocardial strain is a sensitive measure of ventricular systolic function. Two-dimensional speckle-tracking echocardiography (2DSE) is an angle-independent method for strain measurement but has not been validated in pediatric subjects. We evaluated the accuracy and reproducibility of 2DSE-measured strain against reference tagged MRI-measured strain in pediatric subjects with normal hearts and those with single ventricle (SV) of left ventricle (LV) morphology s/p Fontan procedure. Methods Peak systolic circumferential (CS) and longitudinal (LS) strains in segments (n = 16) of LVs in age and BSA matched 20 healthy and 12 pediatric subjects with tricuspid atresia s/p Fontan procedure were measured by 2DSE and tagged MRI. Average (global) and regional segmental strains measured by two methods were compared using Spearman and Bland-Altman analyses. Results 2DSE and tagged MRI measured global strains demonstrated close agreements, which were better for LS than CS and in normal LVs than in SVs (95% limits of agreement: +0.0% to +3.12%, −2.48 % to +1.08%, −4.6% to +1.8% and −3.6% to +1.8% respectively). There was variability in agreement between regional strains with wider limits in apical than in basal regions in normal LVs and heterogeneous in SVs. The strain values were significantly (p < 0.05) higher in normal LVs than in SVs except for basal LSs, which were similar in both cohorts. The regional strains in normal LVs demonstrated an apico-basal magnitude gradient whereas SVs showed heterogeneity. The reproducibility was the most robust for images obtained with frame rates between 60 and 90 frame/sec; global LS in both cohorts; and basal strains in normal LVs. Conclusions 2DSE-measured strains agree with MRI-measured strain globally but vary regionally particularly in SVs. Global strain may be more robust tool for the cardiac function evaluation than regional strain in SV physiology. The reliability of 2DSE measured strain is affected by the frame rate, nature of strain, and ventricular geometry. PMID:20850945

Visual Advantage of Enhanced Flight Vision System During NextGen Flight Test Evaluation

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Harrison, Stephanie J.; Bailey, Randall E.; Shelton, Kevin J.; Ellis, Kyle K.

2014-01-01

Synthetic Vision Systems and Enhanced Flight Vision System (SVS/EFVS) technologies have the potential to provide additional margins of safety for aircrew performance and enable operational improvements for low visibility operations in the terminal area environment. Simulation and flight tests were jointly sponsored by NASA's Aviation Safety Program, Vehicle Systems Safety Technology project and the Federal Aviation Administration (FAA) to evaluate potential safety and operational benefits of SVS/EFVS technologies in low visibility Next Generation Air Transportation System (NextGen) operations. The flight tests were conducted by a team of Honeywell, Gulfstream Aerospace Corporation and NASA personnel with the goal of obtaining pilot-in-the-loop test data for flight validation, verification, and demonstration of selected SVS/EFVS operational and system-level performance capabilities. Nine test flights were flown in Gulfstream's G450 flight test aircraft outfitted with the SVS/EFVS technologies under low visibility instrument meteorological conditions. Evaluation pilots flew 108 approaches in low visibility weather conditions (600 feet to 3600 feet reported visibility) under different obscurants (mist, fog, drizzle fog, frozen fog) and sky cover (broken, overcast). Flight test videos were evaluated at three different altitudes (decision altitude, 100 feet radar altitude, and touchdown) to determine the visual advantage afforded to the pilot using the EFVS/Forward-Looking InfraRed (FLIR) imagery compared to natural vision. Results indicate the EFVS provided a visual advantage of two to three times over that of the out-the-window (OTW) view. The EFVS allowed pilots to view the runway environment, specifically runway lights, before they would be able to OTW with natural vision.

Spatial and temporal variation in suspended sediment, organic matter, and turbidity in a Minnesota prairie river: implications for TMDLs.

PubMed

Lenhart, Christian F; Brooks, Kenneth N; Heneley, Daniel; Magner, Joseph A

2010-06-01

The Minnesota River Basin (MRB), situated in the prairie pothole region of the Upper Midwest, contributes excessive sediment and nutrient loads to the Upper Mississippi River. Over 330 stream channels in the MRB are listed as impaired by the Minnesota Pollution Control Agency, with turbidity levels exceeding water quality standards in much of the basin. Addressing turbidity impairment requires an understanding of pollutant sources that drive turbidity, which was the focus of this study. Suspended volatile solids (SVS), total suspended solids (TSS), and turbidity were measured over two sampling seasons at ten monitoring stations in Elm Creek, a turbidity impaired tributary in the MRB. Turbidity levels exceeded the Minnesota standard of 25 nephelometric units in 73% of Elm Creek samples. Turbidity and TSS were correlated (r (2) = 0.76), yet they varied with discharge and season. High levels of turbidity occurred during periods of high stream flow (May-June) because of excessive suspended inorganic sediment from watershed runoff, stream bank, and channel contributions. Both turbidity and TSS increased exponentially downstream with increasing stream power, bank height, and bluff erosion. However, organic matter discharged from wetlands and eutrophic lakes elevated SVS levels and stream turbidity in late summer when flows were low. SVS concentrations reached maxima at lake outlets (50 mg/l) in August. Relying on turbidity measurements alone fails to identify the cause of water quality impairment whether from suspended inorganic sediment or organic matter. Therefore, developing mitigation measures requires monitoring of both TSS and SVS from upstream to downstream reaches.

Non-Pharmacological Countermeasure to Decrease Landing Sickness and Improve Functional Performance

NASA Technical Reports Server (NTRS)

Rosenberg, M. J. F.; Kreutzberg, G. A.; Galvan-Garza, R. C.; Mulavara, A. P.; Reschke, M. F.

2017-01-01

Upon return from long-duration spaceflight, 100% of crewmembers experience motion sickness (MS) symptoms. The interactions between crewmembers' adaptation to a gravitational transition, the performance decrements resulting from MS and/or use of promethazine (PMZ), and the constraints imposed by mission task demands could significantly challenge and limit an astronaut's ability to perform functional tasks during gravitational transitions. Stochastic resonance (SR) is "noise benefit": adding noise to a system might increase the information (examples to the left and above). Stochastic vestibular stimulation (SVS), or low levels of noise applied to the vestibular system, improves balance and locomotor performance (Goel et al. 2015, Mulavara et al. 2011, 2015). In hemi-lesioned rat models, Samoudi et al. 2012 found that SVS increased GABA release on the lesioned, but not the intact side. Activation of the GABA pathway is important in modulating MS and promoting adaptability (Cohen 2008) and was seen to reverse MS symptoms in rats after unilateral labyrinthectomy (Magnusson et al. 2000). Thus, SVS could be used to promote GABA pathways to reduce MS and promote adaptability, eliminate the need for PMZ or other performance-inhibiting drugs.

Subdiffractional tracking of internalized molecules reveals heterogeneous motion states of synaptic vesicles

PubMed Central

Morrow, Isabel C.; Harper, Callista B.

2016-01-01

Our understanding of endocytic pathway dynamics is severely restricted by the diffraction limit of light microscopy. To address this, we implemented a novel technique based on the subdiffractional tracking of internalized molecules (sdTIM). This allowed us to image anti–green fluorescent protein Atto647N-tagged nanobodies trapped in synaptic vesicles (SVs) from live hippocampal nerve terminals expressing vesicle-associated membrane protein 2 (VAMP2)–pHluorin with 36-nm localization precision. Our results showed that, once internalized, VAMP2–pHluorin/Atto647N–tagged nanobodies exhibited a markedly lower mobility than on the plasma membrane, an effect that was reversed upon restimulation in presynapses but not in neighboring axons. Using Bayesian model selection applied to hidden Markov modeling, we found that SVs oscillated between diffusive states or a combination of diffusive and transport states with opposite directionality. Importantly, SVs exhibiting diffusive motion were relatively less likely to switch to the transport motion. These results highlight the potential of the sdTIM technique to provide new insights into the dynamics of endocytic pathways in a wide variety of cellular settings. PMID:27810917

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals

PubMed Central

Cousin, Michael A.

2017-01-01

Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion. The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain. Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals. These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity. This review article will assess the evidence for the role of classical adaptor protein complexes in SV retrieval, discuss the role of monomeric adaptors and how interactions between specific SV cargoes can facilitate retrieval. In addition it will consider the evidence for preassembled plasma membrane cargo complexes and their role in facilitating these endocytosis modes. Finally it will present a unifying model for cargo retrieval at the presynapse, which integrates endocytosis modes in time and space. PMID:28824381

Primary Synovial Sarcoma of the Thyroid Gland: Case Report and Review of the Literature

PubMed Central

Boudin, Laurys; Fakhry, Nicolas; Chetaille, Bruno; Perrot, Delphine; Nguyen, Anh Tuan; Daidj, Nassima; Guiramand, Jérôme; Sarran, Anthony; Moureau-Zabotto, Laurence; Bertucci, François

2014-01-01

Synovial sarcoma (SVS) of the thyroid gland is exceedingly rare. We report the case of a 55-year-old man with a rapidly growing 7-cm neck mass. Because of suspicion of anaplastic thyroid carcinoma, a total thyroidectomy was planned, without preoperative cytology. During surgery, the tumor ruptured, leading to fragmented and incomplete resection. The morphological and immunohistochemical aspects suggested thyroid SVS, which was confirmed by fluorescent in situ hybridization (SYT gene rearrangement). The patient experienced immediate local relapse in close contact with large vessels and the thyroid cartilage and was referred to our institution. Doxorubicin-ifosfamide chemotherapy led to a minor response that authorized secondary conservative surgery. Because of microscopically incomplete resection, adjuvant radiotherapy was chosen and is ongoing 10 months after initial surgery. The prognosis of thyroid SVS is associated with a high risk for local and metastatic relapses. Pretreatment diagnosis is fundamental and may benefit from molecular analysis. Margin-free monobloc surgical excision is the best chance for cure, but adjuvant chemotherapy and radiotherapy deserve to be discussed. PMID:24575008

Primary synovial sarcoma of the thyroid gland: case report and review of the literature.

PubMed

Boudin, Laurys; Fakhry, Nicolas; Chetaille, Bruno; Perrot, Delphine; Nguyen, Anh Tuan; Daidj, Nassima; Guiramand, Jérôme; Sarran, Anthony; Moureau-Zabotto, Laurence; Bertucci, François

2014-01-01

Synovial sarcoma (SVS) of the thyroid gland is exceedingly rare. We report the case of a 55-year-old man with a rapidly growing 7-cm neck mass. Because of suspicion of anaplastic thyroid carcinoma, a total thyroidectomy was planned, without preoperative cytology. During surgery, the tumor ruptured, leading to fragmented and incomplete resection. The morphological and immunohistochemical aspects suggested thyroid SVS, which was confirmed by fluorescent in situ hybridization (SYT gene rearrangement). The patient experienced immediate local relapse in close contact with large vessels and the thyroid cartilage and was referred to our institution. Doxorubicin-ifosfamide chemotherapy led to a minor response that authorized secondary conservative surgery. Because of microscopically incomplete resection, adjuvant radiotherapy was chosen and is ongoing 10 months after initial surgery. The prognosis of thyroid SVS is associated with a high risk for local and metastatic relapses. Pretreatment diagnosis is fundamental and may benefit from molecular analysis. Margin-free monobloc surgical excision is the best chance for cure, but adjuvant chemotherapy and radiotherapy deserve to be discussed.

A dynamin 1-, dynamin 3- and clathrin-independent pathway of synaptic vesicle recycling mediated by bulk endocytosis

PubMed Central

Wu, Yumei; O'Toole, Eileen T; Girard, Martine; Ritter, Brigitte; Messa, Mirko; Liu, Xinran; McPherson, Peter S; Ferguson, Shawn M; De Camilli, Pietro

2014-01-01

The exocytosis of synaptic vesicles (SVs) elicited by potent stimulation is rapidly compensated by bulk endocytosis of SV membranes leading to large endocytic vacuoles (‘bulk’ endosomes). Subsequently, these vacuoles disappear in parallel with the reappearance of new SVs. We have used synapses of dynamin 1 and 3 double knock-out neurons, where clathrin-mediated endocytosis (CME) is dramatically impaired, to gain insight into the poorly understood mechanisms underlying this process. Massive formation of bulk endosomes was not defective, but rather enhanced, in the absence of dynamin 1 and 3. The subsequent conversion of bulk endosomes into SVs was not accompanied by the accumulation of clathrin coated buds on their surface and this process proceeded even after further clathrin knock-down, suggesting its independence of clathrin. These findings support the existence of a pathway for SV reformation that bypasses the requirement for clathrin and dynamin 1/3 and that operates during intense synaptic activity. DOI: http://dx.doi.org/10.7554/eLife.01621.001 PMID:24963135

Performance Characterization of Obstacle Detection Algorithms for Aircraft Navigation

NASA Technical Reports Server (NTRS)

Kasturi, Rangachar; Camps, Octavia; Coraor, Lee; Gandhi, Tarak; Hartman, Kerry; Yang, Mau-Tsuen

2000-01-01

The research reported here is a part of NASA's Synthetic Vision System (SVS) project for the development of a High Speed Civil Transport Aircraft (HSCT). One of the components of the SVS is a module for detection of potential obstacles in the aircraft's flight path by analyzing the images captured by an on-board camera in real-time. Design of such a module includes the selection and characterization of robust, reliable, and fast techniques and their implementation for execution in real-time. This report describes the results of our research in realizing such a design.

Direct spectroscopic evidence for ionized polycyclic aromatic hydrocarbons in the interstellar medium.

PubMed

Sloan, G C; Hayward, T L; Allamandola, L J; Bregman, J D; DeVito, B; Hudgins, D M

1999-03-01

Long-slit 8-13 micrometers spectroscopy of the nebula around NGC 1333 SVS 3 reveals spatial variations in the strength and shape of emission features that are probably produced by polycyclic aromatic hydrocarbons (PAHs). Close to SVS 3, the 11.2 micrometers feature develops an excess at approximately 10.8-11.0 micrometers and a feature appears at approximately 10 micrometers. These features disappear with increasing distance from the central source, and they show striking similarities to recent laboratory data of PAH cations, providing the first identification of emission features arising specifically from ionized PAHs in the interstellar medium.

Genome-Wide Sequence Variation Identification and Floral-Associated Trait Comparisons Based on the Re-sequencing of the ‘Nagafu No. 2’ and ‘Qinguan’ Varieties of Apple (Malus domestica Borkh.)

PubMed Central

Xing, Libo; Zhang, Dong; Song, Xiaomin; Weng, Kai; Shen, Yawen; Li, Youmei; Zhao, Caiping; Ma, Juanjuan; An, Na; Han, Mingyu

2016-01-01

Apple (Malus domestica Borkh.) is a commercially important fruit worldwide. Detailed information on genomic DNA polymorphisms, which are important for understanding phenotypic traits, is lacking for the apple. We re-sequenced two elite apple varieties, ‘Nagafu No. 2’ and ‘Qinguan,’ which have different characteristics. We identified many genomic variations, including 2,771,129 single nucleotide polymorphisms (SNPs), 82,663 structural variations (SVs), and 1,572,803 insertion/deletions (INDELs) in ‘Nagafu No. 2’ and 2,262,888 SNPs, 63,764 SVs, and 1,294,060 INDELs in ‘Qinguan.’ The ‘SNP,’ ‘INDEL,’ and ‘SV’ distributions were non-random, with variation-rich or -poor regions throughout the genomes. In ‘Nagafu No. 2’ and ‘Qinguan’ there were 171,520 and 147,090 non-synonymous SNPs spanning 23,111 and 21,400 genes, respectively; 3,963 and 3,196 SVs in 3,431 and 2,815 genes, respectively; and 1,834 and 1,451 INDELs in 1,681 and 1,345 genes, respectively. Genetic linkage maps of 190 flowering genes associated with multiple flowering pathways in ‘Nagafu No. 2,’ ‘Qinguan,’ and ‘Golden Delicious,’ identified complex regulatory mechanisms involved in floral induction, flower bud formation, and flowering characteristics, which might reflect the genetic variation of the flowering genes. Expression profiling of key flowering genes in buds and leaves suggested that the photoperiod and autonomous flowering pathways are major contributors to the different floral-associated traits between ‘Nagafu No. 2’ and ‘Qinguan.’ The genome variation data provided a foundation for the further exploration of apple diversity and gene–phenotype relationships, and for future research on molecular breeding to improve apple and related species. PMID:27446138

A proposed definition of symptomatic vasospasm based on treatment of cerebral vasospasm after subarachnoid hemorrhage in Japan: Consensus 2009, a project of the 25th Spasm Symposium

PubMed Central

Shirao, Satoshi; Yoneda, Hiroshi; Ishihara, Hideyuki; Kajiwara, Koji; Suzuki, Michiyasu

2011-01-01

Background: There is a lack of unified information on diagnosis and treatment of cerebral vasospasm (CV) after subarachnoid hemorrhage (SAH) among the hospitals in Japan. Thus, the aim of the study was to define the current practice in this area based on a survey by Japanese neurosurgeons. Methods: A survey on diagnosis and treatment of CV was sent to 414 hospitals each of which performs >100 neurosurgeries annually. Results: Responses were received from 240 hospitals (58.0%). Because accurate criteria for diagnosis of symptomatic vasospasm (SVS) were used in only 33.8% of the hospitals, we proposed a clinical definition of SVS that was approved at the 25th Spasm Symposium (Consensus 2009). This definition is simplified as follows: (1) the presence of neurological worsening; (2) no other identifiable cause of neurological worsening; and (3) confirmation of vasospasm by medical examinations. The results also showed that the Fisher CT scale is used differently for patients with ICH or IVH, with 41.3% of cases with ICH/IVH based on SAH that met Fisher criteria classified into Fisher group 1, 2 or 3, and 46.3% classified into Fisher group 4. There were no major differences in prophylactic therapies of CV and therapy for cerebral ischemia among the hospitals. Endovascular treatment for vasospasm was performed in most hospitals (78.7%); however, the criteria differed among the hospitals: (1) angiographic vasospasm and SVS appeared (37.9%), (2) only when aggressive therapy was ineffective (41.4%). Conclusion: We established a clinical definition of SVS based on the results of this survey (Consensus 2009). PMID:21748027

Quantitative mapping of total choline in healthy human breast using proton echo planar spectroscopic imaging (PEPSI) at 3 Tesla.

PubMed

Zhao, Chenguang; Bolan, Patrick J; Royce, Melanie; Lakkadi, Navneeth; Eberhardt, Steven; Sillerud, Laurel; Lee, Sang-Joon; Posse, Stefan

2012-11-01

To quantitatively measure tCho levels in healthy breasts using Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI). The two-dimensional mapping of tCho at 3 Tesla across an entire breast slice using PEPSI and a hybrid spectral quantification method based on LCModel fitting and integration of tCho using the fitted spectrum were developed. This method was validated in 19 healthy females and compared with single voxel spectroscopy (SVS) and with PRESS prelocalized conventional Magnetic Resonance Spectroscopic Imaging (MRSI) using identical voxel size (8 cc) and similar scan times (∼7 min). A tCho peak with a signal to noise ratio larger than 2 was detected in 10 subjects using both PEPSI and SVS. The average tCho concentration in these subjects was 0.45 ± 0.2 mmol/kg using PEPSI and 0.48 ± 0.3 mmol/kg using SVS. Comparable results were obtained in two subjects using conventional MRSI. High lipid content in the spectra of nine tCho negative subjects was associated with spectral line broadening of more than 26 Hz, which made tCho detection impossible. Conventional MRSI with PRESS prelocalization in glandular tissue in two of these subjects yielded tCho concentrations comparable to PEPSI. The detection sensitivity of PEPSI is comparable to SVS and conventional PRESS-MRSI. PEPSI can be potentially used in the evaluation of tCho in breast cancer. A tCho threshold concentration value of ∼0.7 mmol/kg might be used to differentiate between cancerous and healthy (or benign) breast tissues based on this work and previous studies. Copyright © 2012 Wiley Periodicals, Inc.

Quantitative Mapping of Total Choline in Healthy Human Breast Using Proton Echo Planar Spectroscopic Imaging (PEPSI) at 3 Tesla

PubMed Central

Zhao, Chenguang; Bolan, Patrick J.; Royce, Melanie; Lakkadi, Navneeth; Eberhardt, Steven; Sillerud, Laurel; Lee, Sang-Joon; Posse, Stefan

2012-01-01

Purpose To quantitatively measure tCho levels in healthy breasts using Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI). Material and Methods The 2-dimensional mapping of tCho at 3 Tesla across an entire breast slice using PEPSI and a hybrid spectral quantification method based on LCModel fitting and integration of tCho using the fitted spectrum were developed. This method was validated in 19 healthy females and compared with single voxel spectroscopy (SVS) and with PRESS prelocalized conventional Magnetic Resonance Spectroscopic Imaging (MRSI) using identical voxel size (8 cc) and similar scan times (~7 min). Results A tCho peak with a signal to noise ratio larger than 2 was detected in 10 subjects using both PEPSI and SVS. The average tCho concentration in these subjects was 0.45 ± 0.2 mmol/kg using PEPSI and 0.48±0.3 mmol/kg using SVS. Comparable results were obtained in 2 subjects using conventional MRSI. High lipid content in the spectra of 9 tCho negative subjects was associated with spectral line broadening of more than 26 Hz, which made tCho detection impossible. Conventional MRSI with PRESS prelocalization in glandular tissue in two of these subjects yielded tCho concentrations comparable to PEPSI. Conclusion The detection sensitivity of PEPSI is comparable to SVS and conventional PRESS-MRSI. PEPSI can be potentially used in the evaluation of tCho in breast cancer. A tCho threshold concentration value of ~0.7mmol/kg might be used to differentiate between cancerous and healthy (or benign) breast tissues based on this work and previous studies. PMID:22782667

Human values in the team leader selection process.

PubMed

Rovira, Núria; Ozgen, Sibel; Medir, Magda; Tous, Jordi; Alabart, Joan Ramon

2012-03-01

The selection process of team leaders is fundamental if the effectiveness of teams is to be guaranteed. Human values have proven to be an important factor in the behaviour of individuals and leaders. The aim of this study is twofold. The first is to validate Schwartz's survey of human values. The second is to determine whether there are any relationships between the values held by individuals and their preferred roles in a team. Human values were measured by the items of the Schwartz Value Survey (SVS) and the preferred roles in a team were identified by the Belbin Self Perception Inventory (BSPI). The two questionnaires were answered by two samples of undergraduate students (183 and 177 students, respectively). As far as the first objective is concerned, Smallest Space Analysis (SSA) was performed at the outset to examine how well the two-dimensional circular structure, as postulated by Schwartz, was represented in the study population. Then, the results of this analysis were compared and contrasted with those of two other published studies; one by Schwartz (2006) and one by Ros and Grad (1991). As for the second objective, Pearson correlation coefficients were computed to assess the associations between the ratings on the SVS survey items and the ratings on the eight team roles as measured by the BSPI.

Evaluation of Alternate Concepts for Synthetic Vision Flight Displays With Weather-Penetrating Sensor Image Inserts During Simulated Landing Approaches

NASA Technical Reports Server (NTRS)

Parrish, Russell V.; Busquets, Anthony M.; Williams, Steven P.; Nold, Dean E.

2003-01-01

A simulation study was conducted in 1994 at Langley Research Center that used 12 commercial airline pilots repeatedly flying complex Microwave Landing System (MLS)-type approaches to parallel runways under Category IIIc weather conditions. Two sensor insert concepts of 'Synthetic Vision Systems' (SVS) were used in the simulated flights, with a more conventional electro-optical display (similar to a Head-Up Display with raster capability for sensor imagery), flown under less restrictive visibility conditions, used as a control condition. The SVS concepts combined the sensor imagery with a computer-generated image (CGI) of an out-the-window scene based on an onboard airport database. Various scenarios involving runway traffic incursions (taxiing aircraft and parked fuel trucks) and navigational system position errors (both static and dynamic) were used to assess the pilots' ability to manage the approach task with the display concepts. The two SVS sensor insert concepts contrasted the simple overlay of sensor imagery on the CGI scene without additional image processing (the SV display) to the complex integration (the AV display) of the CGI scene with pilot-decision aiding using both object and edge detection techniques for detection of obstacle conflicts and runway alignment errors.

The Efficacy of Using Synthetic Vision Terrain-Textured Images to Improve Pilot Situation Awareness

NASA Technical Reports Server (NTRS)

Uenking, Michael D.; Hughes, Monica F.

2002-01-01

The General Aviation Element of the Aviation Safety Program's Synthetic Vision Systems (SVS) Project is developing technology to eliminate low visibility induced General Aviation (GA) accidents. SVS displays present computer generated 3-dimensional imagery of the surrounding terrain on the Primary Flight Display (PFD) to greatly enhance pilot's situation awareness (SA), reducing or eliminating Controlled Flight into Terrain, as well as Low-Visibility Loss of Control accidents. SVS-conducted research is facilitating development of display concepts that provide the pilot with an unobstructed view of the outside terrain, regardless of weather conditions and time of day. A critical component of SVS displays is the appropriate presentation of terrain to the pilot. An experimental study is being conducted at NASA Langley Research Center (LaRC) to explore and quantify the relationship between the realism of the terrain presentation and resulting enhancements of pilot SA and performance. Composed of complementary simulation and flight test efforts, Terrain Portrayal for Head-Down Displays (TP-HDD) experiments will help researchers evaluate critical terrain portrayal concepts. The experimental effort is to provide data to enable design trades that optimize SVS applications, as well as develop requirements and recommendations to facilitate the certification process. In this part of the experiment a fixed based flight simulator was equipped with various types of Head Down flight displays, ranging from conventional round dials (typical of most GA aircraft) to glass cockpit style PFD's. The variations of the PFD included an assortment of texturing and Digital Elevation Model (DEM) resolution combinations. A test matrix of 10 terrain display configurations (in addition to the baseline displays) were evaluated by 27 pilots of various backgrounds and experience levels. Qualitative (questionnaires) and quantitative (pilot performance and physiological) data were collected during the experimental runs. This paper focuses on the experimental set-up and final physiological results of the TP-HDD simulation experiment. The physiological measures of skin temperature, heart rate, and muscle response, show a decreased engagement (while using the synthetic vision displays as compared to the baseline conventional display) of the sympathetic and somatic nervous system responses which, in turn, indicates a reduced level of mental workload. This decreased level of workload is expected to enable improvement in the pilot's situation and terrain awareness.

Effects of organ motion on proton prostate treatments, as determined from analysis of daily CT imaging for patient positioning.

PubMed

Maeda, Yoshikazu; Sato, Yoshitaka; Shibata, Satoshi; Bou, Sayuri; Yamamoto, Kazutaka; Tamamura, Hiroyasu; Fuwa, Nobukazu; Takamatsu, Shigeyuki; Sasaki, Makoto; Tameshige, Yuji; Kume, Kyo; Minami, Hiroki; Saga, Yusuke; Saito, Makoto

2018-05-01

We quantified interfractional movements of the prostate, seminal vesicles (SVs), and rectum during computed tomography (CT) image-guided proton therapy for prostate cancer and studied the range variation in opposed lateral proton beams. We analyzed 375 sets of daily CT images acquired throughout the proton therapy treatment of ten patients. We analyzed daily movements of the prostate, SVs, and rectum by simulating three image-matching strategies: bone matching, prostate center (PC) matching, and prostate-rectum boundary (PRB) matching. In the PC matching, translational movements of the prostate center were corrected after bone matching. In the PRB matching, we performed PC matching and correction along the anterior-posterior direction to match the boundary between the prostate and the rectum's anterior region. In each strategy, we evaluated systematic errors (Σ) and random errors (σ) by measuring the daily movements of certain points on each anatomic structure. The average positional deviations in millimeter of each point were determined by the Van Herk formula of 2.5Σ + 0.7σ. Using these positional deviations, we created planning target volumes of the prostate and SVs and analyzed the daily variation in the water equivalent length (WEL) from the skin surface to the target along the lateral beam directions using the density converted from the daily CT number. Based on this analysis, we designed prostate cancer treatment planning and evaluated the dose volume histograms (DVHs) for these strategies. The SVs' daily movements showed large variations over the superior-inferior direction, as did the rectum's anterior region. The average positional deviations of the prostate in the anterior, posterior, superior, inferior, and lateral sides (mm) in bone matching, PC matching, and PRB matching were (8.9, 9.8, 7.5, 3.6, 1.6), (5.6, 6.1, 3.5, 4.5, 1.9), and (8.6, 3.2, 3.5, 4.5, 1.9) (mm), respectively. Moreover, the ones of the SV tip were similarly (22.5, 15.5, 11.0, 7.6, 6.0), (11.8, 8.4, 7.8, 5.2, 6.3), and (9.9, 7.5, 7.8, 5.2, 6.3). PRB matching showed the smallest positional deviations at all portions except for the anterior portion of the prostate and was able to markedly reduce the positional deviations at the posterior portion. The averaged WEL variations at the distal and proximal sides of planning target volumes were estimated 7-9 mm and 4-6 mm, respectively, and showed the increasing of a few millimeters in PC and PRB matching compared to bone matching. In the treatment planning simulation, the DVH values of the rectum in PRB matching were reduced compared to those obtained with other matching strategies. The positional deviations for the prostate on the posterior side and the SVs were smaller by PRB matching than the other strategies and effectively reduced the rectal dose. 3D dose calculations indicate that PRB matching with CT image guidance may do a better job relative to other positioning methods to effectively reduce the rectal complications. The WEL variation was quite large, and the appropriate margin (approx. 10 mm) must be adapted to the proton range in an initial planning to maintain the coverage of target volumes throughout entire treatment. © 2018 American Association of Physicists in Medicine.

A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome

PubMed Central

Konkel, Miriam K.; Batzer, Mark A.

2010-01-01

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families – long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements – mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development. PMID:20307669

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

PubMed

Collins, Ryan L; Brand, Harrison; Redin, Claire E; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R; Glessner, Joseph T; Mason, Tamara; Pregno, Giulia; Dorrani, Naghmeh; Mandrile, Giorgia; Giachino, Daniela; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; An, Joon-Yong; Currall, Benjamin B; Seabra, Catarina M; Ragavendran, Ashok; Margolin, Lauren; Martinez-Agosto, Julian A; Lucente, Diane; Levy, Brynn; Sanders, Stephan J; Wapner, Ronald J; Quintero-Rivera, Fabiola; Kloosterman, Wigard; Talkowski, Michael E

2017-03-06

Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.

Efficacy of Stochastic Vestibular Stimulation to Improve Locomotor Performance in a Discordant Sensory Environment

NASA Technical Reports Server (NTRS)

Temple, D. R.; De Dios, Y. E.; Layne, C. S.; Bloomberg, J. J.; Mulavara, A. P.

2016-01-01

Astronauts exposed to microgravity face sensorimotor challenges incurred when readapting to a gravitational environment. Sensorimotor Adaptability (SA) training has been proposed as a countermeasure to improve locomotor performance during re-adaptation, and it is suggested that the benefits of SA training may be further enhanced by improving detection of weak sensory signals via mechanisms such as stochastic resonance when a non-zero level of stochastic white noise based electrical stimulation is applied to the vestibular system (stochastic vestibular stimulation, SVS). The purpose of this study was to test the efficacy of using SVS to improve short-term adaptation in a sensory discordant environment during performance of a locomotor task.

Is seminal vesiculectomy necessary in all patients with biopsy Gleason score 6?

PubMed

Gofrit, Ofer N; Zorn, Kevin C; Shikanov, Sergey A; Zagaja, Gregory P; Shalhav, Arieh L

2009-04-01

Radiotherapists are excluding the seminal vesicles (SVs) from their target volume in cases of low-risk prostate cancer. However, these glands are routinely removed in every radical prostatectomy. Dissection of the SVs can damage the pelvic plexus, compromise trigonal, bladder neck, and cavernosal innervation, and contribute to delayed gain of continence and erectile function. In this study we evaluated the oncological benefit of routine removal of the SVs in currently operated patients. A total of 1003 patients (mean age, 59.7 years) with prostate cancer underwent robot-assisted radical prostatectomy between February 2003 and July 2007. Seminal vesicle invasion (SVI) was found in 46 of the operated patients (4.6%). Biopsy Gleason score (BGS), preoperative serum PSA, clinical tumor stage, percent of positive cores, and maximal percentage of cancer in a core had all a significant impact on the risk of SVI. Only 4/634 patients (0.6%) with BGS < or =6 suffered from SVI, as opposed to 42/369 (11.4%) with higher Gleason scores. Seminal vesiculectomy does not benefit more than 99% of the patients with BGS < or =6. Considering the potential neural and vascular damage associated with seminal vesiculectomy, we suggest that routine removal of these glands during radical prostatectomy in these cases is not necessary.

Advanced Pathway Guidance Evaluations on a Synthetic Vision Head-Up Display

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Prinzel, Lawrence J., III; Arthur, Jarvis J., III; Bailey, Randall E.

2005-01-01

NASA's Synthetic Vision Systems (SVS) project is developing technologies with practical applications to potentially eliminate low visibility conditions as a causal factor to civil aircraft accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. A major thrust of the SVS project involves the development/demonstration of affordable, certifiable display configurations that provide intuitive out-the-window terrain and obstacle information with advanced guidance for commercial and business aircraft. This experiment evaluated the influence of different pathway and guidance display concepts upon pilot situation awareness (SA), mental workload, and flight path tracking performance for Synthetic Vision display concepts using a Head-Up Display (HUD). Two pathway formats (dynamic and minimal tunnel presentations) were evaluated against a baseline condition (no tunnel) during simulated instrument meteorological conditions approaches to Reno-Tahoe International airport. Two guidance cues (tadpole, follow-me aircraft) were also evaluated to assess their influence. Results indicated that the presence of a tunnel on an SVS HUD had no effect on flight path performance but that it did have significant effects on pilot SA and mental workload. The dynamic tunnel concept with the follow-me aircraft guidance symbol produced the lowest workload and provided the highest SA among the tunnel concepts evaluated.

Pathway Design Effects on Synthetic Vision Head-Up Displays

NASA Technical Reports Server (NTRS)

Kramer, Lynda J.; Prinzel, Lawrence J., III; Arthur, Jarvis J., III; Bailey, Randall E.

2004-01-01

NASA s Synthetic Vision Systems (SVS) project is developing technologies with practical applications that will eliminate low visibility conditions as a causal factor to civil aircraft accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. A major thrust of the SVS project involves the development/demonstration of affordable, certifiable display configurations that provide intuitive out-the-window terrain and obstacle information with advanced pathway guidance for transport aircraft. This experiment evaluated the influence of different tunnel and guidance concepts upon pilot situation awareness (SA), mental workload, and flight path tracking performance for Synthetic Vision display concepts using a Head-Up Display (HUD). Two tunnel formats (dynamic, minimal) were evaluated against a baseline condition (no tunnel) during simulated IMC approaches to Reno-Tahoe International airport. Two guidance cues (tadpole, follow-me aircraft) were also evaluated to assess their influence on the tunnel formats. Results indicated that the presence of a tunnel on an SVS HUD had no effect on flight path performance but that it did have significant effects on pilot SA and mental workload. The dynamic tunnel concept with the follow-me aircraft guidance symbol produced the lowest workload and provided the highest SA among the tunnel concepts evaluated.

Growth of Tungsten Bronze Family Crystals

DTIC Science & Technology

1989-03-01

BaTiO, exhibits several plane.’ s A wide range of solid solutions can be obtained structural transitions, and it has a room-temperature tetrag- by...hiro117Ccrystals are as tbilbis Tu ngst en Hri nze (’’mpi s itiotis 71ungst en Hirwnze Ci injw site ’i ( It The\\~ are molticompi nent and siilid -siilut in svs...cttntrol temperature instabilitY because of poor .0OD-10.1i :NG t-St. G-0 IoCA, LSA.( .. Is...asSO* Ihermal (otnduc(ti\\ it ,. -"o~ s . .. O"oA’’ Ci(o~ ’ing

SU-E-T-434: Fixed Margin Or Online Adaptation for Intermediate-Risk Prostate Stereotactic Body Radiation Therapy? A Dosimetric Study

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

Sheng, Y; Li, T; Yin, F

2015-06-15

Purpose: To investigate the choice of fixed margin or online adaptation when treating intermediate-risk prostate cancer including seminal vesicles (SV) using stereotactic body radiation therapy (SBRT). Methods: 9 prostate SBRT patients were retrospectively studied. All patients were implanted with fiducial markers in the prostate for daily localization and verification. Each patient had 5 pairs of pre-treatment and post-treatment cone-beam CT (CBCT) per protocol. SVs were contoured on planning CT and all CBCTs by one attending physician. Simultaneous integral boost (SIB) IMRT plans were developed to deliver 25Gy/5fx to the SV while delivering 37Gy/5fx to the prostate. A 3mm isotropic marginmore » was added to the prostate while a 5 mm isotropic margin was used for the SV. The planning CT was registered to daily pre-treatment and post-treatment CBCT based on fiducial markers in the prostate to mimic online prostate localization; and the SV on daily CBCT was transferred to the CT structure set after the prostates were aligned. Daily pre-treatment and post-treatment SV dose coverage and the organ-at-risk (OAR) sparing were evaluated for the SIB regimen. At least 95% of the SV need to receive the prescription dose (5Gy per fraction). Results: For the total of 90 daily SVs analyzed (ten CBCTs for each of nine patients), only 45 daily SVs (50%) were able to meet the coverage that 95% of the SV received 25Gy. The OAR sparing performance was acceptable for most of the dosimetric constraints in low-risk prostate SBRT protocol with only two exceptions in bladder V100 (cc). Conclusion: A fixed 5mm margin for SV is not sufficient to provide consistent daily dose coverage due to SV’s substantial inter- and intra-fractional motion relative to the prostate. This finding calls for innovative strategies in margin design as well as online treatment adaptation. This work is partially supported a master research grant from Varian Medical Systems.« less

Using Videos Derived from Simulations to Support the Analysis of Spatial Awareness in Synthetic Vision Displays

NASA Technical Reports Server (NTRS)

Boton, Matthew L.; Bass, Ellen J.; Comstock, James R., Jr.

2006-01-01

The evaluation of human-centered systems can be performed using a variety of different methodologies. This paper describes a human-centered systems evaluation methodology where participants watch 5-second non-interactive videos of a system in operation before supplying judgments and subjective measures based on the information conveyed in the videos. This methodology was used to evaluate the ability of different textures and fields of view to convey spatial awareness in synthetic vision systems (SVS) displays. It produced significant results for both judgment based and subjective measures. This method is compared to other methods commonly used to evaluate SVS displays based on cost, the amount of experimental time required, experimental flexibility, and the type of data provided.

Study of Synthetic Vision Systems (SVS) and Velocity-vector Based Command Augmentation System (V-CAS) on Pilot Performance

NASA Technical Reports Server (NTRS)

Liu, Dahai; Goodrich, Ken; Peak, Bob

2006-01-01

This study investigated the effects of synthetic vision system (SVS) concepts and advanced flight controls on single pilot performance (SPP). Specifically, we evaluated the benefits and interactions of two levels of terrain portrayal, guidance symbology, and control-system response type on SPP in the context of lower-landing minima (LLM) approaches. Performance measures consisted of flight technical error (FTE) and pilot perceived workload. In this study, pilot rating, control type, and guidance symbology were not found to significantly affect FTE or workload. It is likely that transfer from prior experience, limited scope of the evaluation task, specific implementation limitations, and limited sample size were major factors in obtaining these results.

A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome.

PubMed

Konkel, Miriam K; Batzer, Mark A

2010-08-01

It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families - long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements - mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development. Copyright © 2010 Elsevier Ltd. All rights reserved.

Endoscopy in the treatment of slit ventricle syndrome

PubMed Central

Zheng, Jiaping; Chen, Guoqiang; Xiao, Qing; Huang, Yiyang; Guo, Yupeng

2017-01-01

The present study aimed to investigate the efficacy of endoscopy in the treatment of post-shunt placement for slit ventricle syndrome (SVS). Endoscopic surgery was performed on 18 patients with SVS between October 2004 and December 2012. Sex, age, causes of the hydrocephalus, ventricular size and imaging data were collected and analyzed. All patients were divided into two groups according to ventricular size and underwent endoscopic surgeries, including endoscopic third ventriculostomy (ETV), endoscopic aqueductoplasty and cystocisternostomy. All treated patients were observed postoperatively for a period of 2 to 3 weeks, and outpatient follow-up was subsequently scheduled for >12 months. Clinical results, including catheter adherence, shunt removal and complications, were analyzed during the follow-up period. The success rate of endoscopic surgery was indicated to be 82.7%. Syndromes caused by aqueductal stenosis in 15 patients who underwent ETV were relieved; however, syndromes in the 3 patients with cerebral cysticercosis, suprasellar arachnoid cysts, pinea larea glioma and communicating hydrocephalus, respectively, were not relieved and underwent shunt placement again. Brain parenchyma, choroid plexus and ependymal tissue were the predominant causes for catheter obstruction and the obstruction rate was indicated to be 77.8% (14/18). Complications, such as pseudobulbar paralysis, infection and intraventricular hemorrhage arose in 3 patients. The present study indicates that endoscopic treatments are effective and ETV may be considered as a recommended option in the treatment of post-shunt placement SVS in hydrocephalus patients. PMID:29042922

A multi-scale assessment of forest primary production across the eastern USA using Forest Inventory and Analysis (FIA) and MODIS data

NASA Astrophysics Data System (ADS)

Kwon, Youngsang

As evidence of global warming continues to increase, being able to predict the relationship between forest growth rate and climate factors will be vital to maintain the sustainability and productivity of forests. Comprehensive analyses of forest primary production across the eastern US were conducted using remotely sensed MODIS and field-based FIA datasets. This dissertation primarily explored spatial patterns of gross and net carbon uptake in the eastern USA, and addressed three objectives. 1) Examine the use of pixel- and plot-scale screening variables to validate MODIS GPP predictions with Forest Inventory and Analysis (FIA) NPP measures. 2) Assess the net primary production (NPP) from MODIS and FIA at increasing levels of spatial aggregation using a hexagonal tiling system. 3) Assess the carbon use efficiency (CUE) calculated using a direct ratio of MODIS NPP to MODIS GPP and a standardized ratio of FIA NPP to MODIS GPP. The first objective was analyzed using total of 54,969 MODIS pixels and co-located FIA plots to validate MODIS GPP estimates. Eight SVs were used to test six hypotheses about the conditions under which MODIS GPP would be most strongly validated. SVs were assessed in terms of the tradeoff between improved relations and reduced number of samples. MODIS seasonal variation and FIA tree density were the two most efficient SVs followed by basic quality checks for each data set. The sequential application of SVs provided an efficient dataset of 17,090 co-located MODIS pixels and FIA plots, that raised the Pearson's correlation coefficient from 0.01 for the complete dataset of 54,969 plots to 0.48 for this screened subset of 17,090 plots. The second objective was addressed by aggregating data over increasing spatial extents so as to not lose plot- and pixel-level information. These data were then analyzed to determine the optimal scale with which to represent the spatial pattern of NPP. The results suggested an optimal scale of 390 km2. At that scale MODIS and FIA were most strongly correlated while maximizing the number of observation. The maps conveyed both local-scale spatial structure from FIA and broad-scale climatic trends from MODIS. The third objective examined whether carbon use efficiency (CUE) was constant or variable in relation to forest types, and to geographic and climatic variables. The results indicated that while CUEs exhibited unclear patterns by forest types, CUEs are variable to other environmental variables. CUEs are most strongly related to the climatic factors of precipitation followed by temperature. More complex and weaker relationships were found for the geographic factors of latitude and altitude, as they reflected a combination of phenomenological driving forces. The results of the three objectives will help us to identify factors that control carbon cycles and to quantify forest productivity. This will help improve our knowledge about how forest primary productivity may change in relation to ongoing climate change.

Terrain Portrayal for Synthetic Vision Systems Head-Down Displays Evaluation Results

NASA Technical Reports Server (NTRS)

Hughes, Monica F.; Glaab, Louis J.

2007-01-01

A critical component of SVS displays is the appropriate presentation of terrain to the pilot. At the time of this study, the relationship between the complexity of the terrain presentation and resulting enhancements of pilot SA and pilot performance had been largely undefined. The terrain portrayal for SVS head-down displays (TP-HDD) simulation examined the effects of two primary elements of terrain portrayal on the primary flight display (PFD): variations of digital elevation model (DEM) resolution and terrain texturing. Variations in DEM resolution ranged from sparsely spaced (30 arc-sec) to very closely spaced data (1 arc-sec). Variations in texture involved three primary methods: constant color, elevation-based generic, and photo-realistic, along with a secondary depth cue enhancer in the form of a fishnet grid overlay.

Analysis of Wallops Flight Test Data Through an Automated COTS System

NASA Technical Reports Server (NTRS)

Blackstock, Dexter Lee; Theobalds, Andre B.

2005-01-01

During the summer of 2004 NASA Langley Research Center flight tested a Synthetic Vision System (SVS) at the Reno/Tahoe International Airport (RNO) and the Wallops Flight Facility (WAL). The SVS included a Runway Incursion Prevention System (RIPS) to improve pilot situational awareness while operating near and on the airport surface. The flight tests consisted of air and ground operations to evaluate and validate the performance of the system. This paper describes the flight test and emphasizes how positioning data was collected, post processed and analyzed through the use of a COTS-derived software system. The system that was developed to analyze the data was constructed within the MATLAB(TM) environment. The software was modified to read the data, perform several if-then scenarios and produce the relevant graphs, figures and tables.

A Mesoscale Analysis of Column-Integrated Aerosol Properties in Northern India During the TIGERZ 2008 Pre-Monsoon Period and a Comparison to MODIS Retrievals

NASA Technical Reports Server (NTRS)

Giles, D. M.; Holben, B. N.; Tripathi, S. N.; Eck, T. F.; Newcomb, W. W.; Slutsker, I.; Dickerson, R. R.; Thompson, A. M.; Wang, S.-H.; Singh, R. P.;

Human structural variation: mechanisms of chromosome rearrangements

PubMed Central

Weckselblatt, Brooke; Rudd, M. Katharine

2015-01-01

Chromosome structural variation (SV) is a normal part of variation in the human genome, but some classes of SV can cause neurodevelopmental disorders. Analysis of the DNA sequence at SV breakpoints can reveal mutational mechanisms and risk factors for chromosome rearrangement. Large-scale SV breakpoint studies have become possible recently owing to advances in next-generation sequencing (NGS) including whole-genome sequencing (WGS). These findings have shed light on complex forms of SV such as triplications, inverted duplications, insertional translocations, and chromothripsis. Sequence-level breakpoint data resolve SV structure and determine how genes are disrupted, fused, and/or misregulated by breakpoints. Recent improvements in breakpoint sequencing have also revealed non-allelic homologous recombination (NAHR) between paralogous long interspersed nuclear element (LINE) or human endogenous retrovirus (HERV) repeats as a cause of deletions, duplications, and translocations. This review covers the genomic organization of simple and complex constitutional SVs, as well as the molecular mechanisms of their formation. PMID:26209074

The bioartificial thyroid: a biotechnological perspective in endocrine organ engineering for transplantation replacement.

PubMed

Toni, Roberto; Casa, Claudia Della; Spaletta, Giulia; Marchetti, Giacomo; Mazzoni, Perseo; Bodria, Monica; Ravera, Simone; Dallatana, Davide; Castorina, Sergio; Riccioli, Vincenzo; Castorina, Emilio Giovanni; Antoci, Salvatore; Campanile, Enrico; Raise, Gabriella; Scalise, Gabriella; Rossi, Raffaella; Rossio, Raffaella; Ugolotti, Giorgio; Ugolottio, Giorgio; Martorella, Andrew; Roti, Elio; Rot, Elio; Sgallari, Fiorella; Pinchera, Aldo

2007-01-01

A new concept for ex situ endocrine organ bioengineering is presented, focused on the realization of a human bioartificial thyroid gland. It is based on the theoretical assumption and experimental evidence that symmetries in geometrical coordinates of the thyroid tissue remain invariant with respect to developmental, physiological or pathophysiological transformations occuring in the gland architecture. This topological arrangement is dependent upon physical connections established between cells, cell adhesion molecules and extracellular matrix, leading to the view that the thyroid parenchyma behaves like a deformable "putty", moulded onto an elastic stromal/vascular scaffold (SVS) dictating the final morphology of the gland. In particular, we have raised the idea that the geometry of the SVS per se provides pivotal epigenetic information to address the genetically-programmed, thyrocyte and endothelial/vascular proliferation and differentiation towards a functionally mature gland, making organ form a pre-requirementfor organ function. A number of experimental approaches are explored to obtain a reliable replica of a human thyroid SVS, and an informatic simulation is designed based on fractal growth of the thyroid intraparenchymal arterial tree. Various tissue-compatible and degradable synthetic or biomimetic polymers are discussed to act as a template of the thyroid SVS, onto which to co-seed autologous human thyrocyte (TPC) and endothelial/vascular (EVPC) progenitor cells. Harvest and expansion of both TPC and EVPC in primary culture are considered, with specific attention to the selection of normal thyrocytes growing at a satisfactory rate to colonize the synthetic matrix. In addition, both in vitro and in vivo techniques to authenticate TPC and EVPC lineage differentiation are reviewed, including immunocytochemistry, reverse trascriptase-polymerase chain reaction, flow cytomery and proteomics. Finally, analysis of viability of the thyroid construct following implantation in animal hosts is proposed, with the intent to obtain a bioartificial thyroid gland morphologically and functionally adequate for transplantation. We believe that the biotechnological scenario proposed herein may provide a template to construct other, more complex and clinically-relevant bioartificial endocrine organs ex situ, such as human pancreatic islets and the liver, and perhaps a new approach to brain bioengineering.

Molecular polygamy: The promiscuity of l-phenylalanyl-tRNA-synthetase triggers misincorporation of meta- and ortho-tyrosine in monoclonal antibodies expressed by Chinese hamster ovary cells.

PubMed

Popp, Oliver; Larraillet, Vincent; Kettenberger, Hubert; Gorr, Ingo H; Hilger, Maximiliane; Lipsmeier, Florian; Zeck, Anne; Beaucamp, Nicola

2015-06-01

In-depth analytical characterization of biotherapeutics originating from different production batches is mandatory to ensure product safety and consistent molecule efficacy. Previously, we have shown unintended incorporation of tyrosine (Tyr) and leucine/isoleucine (Leu/Ile) at phenylalanine (Phe) positions in a recombinant produced monoclonal antibody (mAb) using an orthogonal MASCOT/SIEVE based approach for mass spectrometry data analysis. The misincorporation could be avoided by sufficient supply of phenylalanine throughout the process. Several non-annotated signals in the primarily chromatographic peptide separation step for apparently single Phe→Tyr sequence variants (SVs) suggest a role for isobar tyrosine isoforms. Meta- and ortho-Tyr are spontaneously generated during aerobic fed-batch production processes using Chinese hamster ovary (CHO) cell lines. Process induced meta- and ortho-Tyr but not proteinogenic para-Tyr are incorporated at Phe locations in Phe-starved CHO cultures expressing a recombinant mAb. Furthermore, meta- and ortho-Tyr are preferably misincorporated over Leu. Structural modeling of the l-phenylalanyl-tRNA-synthetase (PheRS) substrate activation site indicates a possible fit of non-cognate ortho-Tyr and meta-Tyr substrates. Dose-dependent misincorporations of Tyr isoforms support the hypothesis that meta- and ortho-Tyr are competing, alternative substrates for PheRS in CHO processes. Finally, easily accessible at-line surrogate markers for Phe→Tyr SV formation in biotherapeutic production were defined by the calculation of critical ratios for meta-Tyr/Phe and ortho-Tyr/Phe to support early prediction of SV probability, and finally, to allow for immediate process controlled Phe→Tyr SV prevention. © 2014 Wiley Periodicals, Inc.

An integrated map of structural variation in 2,504 human genomes.

PubMed

Sudmant, Peter H; Rausch, Tobias; Gardner, Eugene J; Handsaker, Robert E; Abyzov, Alexej; Huddleston, John; Zhang, Yan; Ye, Kai; Jun, Goo; Fritz, Markus Hsi-Yang; Konkel, Miriam K; Malhotra, Ankit; Stütz, Adrian M; Shi, Xinghua; Casale, Francesco Paolo; Chen, Jieming; Hormozdiari, Fereydoun; Dayama, Gargi; Chen, Ken; Malig, Maika; Chaisson, Mark J P; Walter, Klaudia; Meiers, Sascha; Kashin, Seva; Garrison, Erik; Auton, Adam; Lam, Hugo Y K; Mu, Xinmeng Jasmine; Alkan, Can; Antaki, Danny; Bae, Taejeong; Cerveira, Eliza; Chines, Peter; Chong, Zechen; Clarke, Laura; Dal, Elif; Ding, Li; Emery, Sarah; Fan, Xian; Gujral, Madhusudan; Kahveci, Fatma; Kidd, Jeffrey M; Kong, Yu; Lameijer, Eric-Wubbo; McCarthy, Shane; Flicek, Paul; Gibbs, Richard A; Marth, Gabor; Mason, Christopher E; Menelaou, Androniki; Muzny, Donna M; Nelson, Bradley J; Noor, Amina; Parrish, Nicholas F; Pendleton, Matthew; Quitadamo, Andrew; Raeder, Benjamin; Schadt, Eric E; Romanovitch, Mallory; Schlattl, Andreas; Sebra, Robert; Shabalin, Andrey A; Untergasser, Andreas; Walker, Jerilyn A; Wang, Min; Yu, Fuli; Zhang, Chengsheng; Zhang, Jing; Zheng-Bradley, Xiangqun; Zhou, Wanding; Zichner, Thomas; Sebat, Jonathan; Batzer, Mark A; McCarroll, Steven A; Mills, Ryan E; Gerstein, Mark B; Bashir, Ali; Stegle, Oliver; Devine, Scott E; Lee, Charles; Eichler, Evan E; Korbel, Jan O

2015-10-01

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

Crew and Display Concepts Evaluation for Synthetic / Enhanced Vision Systems

NASA Technical Reports Server (NTRS)

Bailey, Randall E.; Kramer, Lynda J.; Prinzel, Lawrence J., III

2006-01-01

NASA s Synthetic Vision Systems (SVS) project is developing technologies with practical applications that strive to eliminate low-visibility conditions as a causal factor to civil aircraft accidents and replicate the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. Enhanced Vision System (EVS) technologies are analogous and complementary in many respects to SVS, with the principle difference being that EVS is an imaging sensor presentation, as opposed to a database-derived image. The use of EVS in civil aircraft is projected to increase rapidly as the Federal Aviation Administration recently changed the aircraft operating rules under Part 91, revising the flight visibility requirements for conducting operations to civil airports. Operators conducting straight-in instrument approach procedures may now operate below the published approach minimums when using an approved EVS that shows the required visual references on the pilot s Head-Up Display. An experiment was conducted to evaluate the complementary use of SVS and EVS technologies, specifically focusing on new techniques for integration and/or fusion of synthetic and enhanced vision technologies and crew resource management while operating under the newly adopted FAA rules which provide operating credit for EVS. Overall, the experimental data showed that significant improvements in SA without concomitant increases in workload and display clutter could be provided by the integration and/or fusion of synthetic and enhanced vision technologies for the pilot-flying and the pilot-not-flying.

The Application of Lidar to Synthetic Vision System Integrity

NASA Technical Reports Server (NTRS)

Campbell, Jacob L.; UijtdeHaag, Maarten; Vadlamani, Ananth; Young, Steve

2003-01-01

One goal in the development of a Synthetic Vision System (SVS) is to create a system that can be certified by the Federal Aviation Administration (FAA) for use at various flight criticality levels. As part of NASA s Aviation Safety Program, Ohio University and NASA Langley have been involved in the research and development of real-time terrain database integrity monitors for SVS. Integrity monitors based on a consistency check with onboard sensors may be required if the inherent terrain database integrity is not sufficient for a particular operation. Sensors such as the radar altimeter and weather radar, which are available on most commercial aircraft, are currently being investigated for use in a real-time terrain database integrity monitor. This paper introduces the concept of using a Light Detection And Ranging (LiDAR) sensor as part of a real-time terrain database integrity monitor. A LiDAR system consists of a scanning laser ranger, an inertial measurement unit (IMU), and a Global Positioning System (GPS) receiver. Information from these three sensors can be combined to generate synthesized terrain models (profiles), which can then be compared to the stored SVS terrain model. This paper discusses an initial performance evaluation of the LiDAR-based terrain database integrity monitor using LiDAR data collected over Reno, Nevada. The paper will address the consistency checking mechanism and test statistic, sensitivity to position errors, and a comparison of the LiDAR-based integrity monitor to a radar altimeter-based integrity monitor.

Vaginismus and dyspareunia: relationship with general and sex-related moral standards.

PubMed

Borg, Charmaine; de Jong, Peter J; Weijmar Schultz, Willibrord

2011-01-01

Relatively strong adherence to conservative values and/or relatively strict sex-related moral standards logically restricts the sexual repertoire and will lower the threshold for experiencing negative emotions in a sexual context. In turn, this may generate withdrawal and avoidance behavior, which is at the nucleus of vaginismus. To examine whether indeed strong adherence to conservative morals and/or strict sexual standards may be involved in vaginismus. The Schwartz Value Survey (SVS) to investigate the individual's value pattern and the Sexual Disgust Questionnaire (SDQ) to index the willingness to perform certain sexual activities as an indirect measure of sex-related moral standards. The SVS and SDQ were completed by three groups: women diagnosed with vaginismus (N=24), a group of women diagnosed with dyspareunia (N=24), and a healthy control group of women without sexual complaints (N=32). Specifically, the vaginismus group showed relatively low scores on liberal values together with comparatively high scores on conservative values. Additionally, the vaginismus group was more restricted in their readiness to perform particular sex-related behaviors than the control group. The dyspareunia group, on both the SVS and the SDQ, placed between the vaginismus and the control group, but not significantly different than either of the groups. The findings are consistent with the view that low liberal and high conservative values, along with restricted sexual standards, are involved in the development/maintenance of vaginismus. © 2010 International Society for Sexual Medicine.

Preliminary Results Obtained in Integrated Safety Analysis of NASA Aviation Safety Program Technologies

NASA Technical Reports Server (NTRS)

Reveley, Mary S.

2003-01-01

The goal of the NASA Aviation Safety Program (AvSP) is to develop and demonstrate technologies that contribute to a reduction in the aviation fatal accident rate by a factor of 5 by the year 2007 and by a factor of 10 by the year 2022. Integrated safety analysis of day-to-day operations and risks within those operations will provide an understanding of the Aviation Safety Program portfolio. Safety benefits analyses are currently being conducted. Preliminary results for the Synthetic Vision Systems (SVS) and Weather Accident Prevention (WxAP) projects of the AvSP have been completed by the Logistics Management Institute under a contract with the NASA Glenn Research Center. These analyses include both a reliability analysis and a computer simulation model. The integrated safety analysis method comprises two principal components: a reliability model and a simulation model. In the reliability model, the results indicate how different technologies and systems will perform in normal, degraded, and failed modes of operation. In the simulation, an operational scenario is modeled. The primary purpose of the SVS project is to improve safety by providing visual-flightlike situation awareness during instrument conditions. The current analyses are an estimate of the benefits of SVS in avoiding controlled flight into terrain. The scenario modeled has an aircraft flying directly toward a terrain feature. When the flight crew determines that the aircraft is headed toward an obstruction, the aircraft executes a level turn at speed. The simulation is ended when the aircraft completes the turn.

Flight Test Comparison Between Enhanced Vision (FLIR) and Synthetic Vision Systems

NASA Technical Reports Server (NTRS)

Arthur, Jarvis J., III; Kramer, Lynda J.; Bailey, Randall E.

2005-01-01

Limited visibility and reduced situational awareness have been cited as predominant causal factors for both Controlled Flight Into Terrain (CFIT) and runway incursion accidents. NASA s Synthetic Vision Systems (SVS) project is developing practical application technologies with the goal of eliminating low visibility conditions as a causal factor to civil aircraft accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. A major thrust of the SVS project involves the development/demonstration of affordable, certifiable display configurations that provide intuitive out-the-window terrain and obstacle information with advanced pathway guidance. A flight test evaluation was conducted in the summer of 2004 by NASA Langley Research Center under NASA s Aviation Safety and Security, Synthetic Vision System - Commercial and Business program. A Gulfstream G-V aircraft, modified and operated under NASA contract by the Gulfstream Aerospace Corporation, was flown over a 3-week period at the Reno/Tahoe International Airport and an additional 3-week period at the NASA Wallops Flight Facility to evaluate integrated Synthetic Vision System concepts. Flight testing was conducted to evaluate the performance, usability, and acceptance of an integrated synthetic vision concept which included advanced Synthetic Vision display concepts for a transport aircraft flight deck, a Runway Incursion Prevention System, an Enhanced Vision Systems (EVS), and real-time Database Integrity Monitoring Equipment. This paper focuses on comparing qualitative and subjective results between EVS and SVS display concepts.

Genomic Rearrangements in Arabidopsis Considered as Quantitative Traits.

PubMed

Imprialou, Martha; Kahles, André; Steffen, Joshua G; Osborne, Edward J; Gan, Xiangchao; Lempe, Janne; Bhomra, Amarjit; Belfield, Eric; Visscher, Anne; Greenhalgh, Robert; Harberd, Nicholas P; Goram, Richard; Hein, Jotun; Robert-Seilaniantz, Alexandre; Jones, Jonathan; Stegle, Oliver; Kover, Paula; Tsiantis, Miltos; Nordborg, Magnus; Rätsch, Gunnar; Clark, Richard M; Mott, Richard

2017-04-01

To understand the population genetics of structural variants and their effects on phenotypes, we developed an approach to mapping structural variants that segregate in a population sequenced at low coverage. We avoid calling structural variants directly. Instead, the evidence for a potential structural variant at a locus is indicated by variation in the counts of short-reads that map anomalously to that locus. These structural variant traits are treated as quantitative traits and mapped genetically, analogously to a gene expression study. Association between a structural variant trait at one locus, and genotypes at a distant locus indicate the origin and target of a transposition. Using ultra-low-coverage (0.3×) population sequence data from 488 recombinant inbred Arabidopsis thaliana genomes, we identified 6502 segregating structural variants. Remarkably, 25% of these were transpositions. While many structural variants cannot be delineated precisely, we validated 83% of 44 predicted transposition breakpoints by polymerase chain reaction. We show that specific structural variants may be causative for quantitative trait loci for germination and resistance to infection by the fungus Albugo laibachii , isolate Nc14. Further we show that the phenotypic heritability attributable to read-mapping anomalies differs from, and, in the case of time to germination and bolting, exceeds that due to standard genetic variation. Genes within structural variants are also more likely to be silenced or dysregulated. This approach complements the prevalent strategy of structural variant discovery in fewer individuals sequenced at high coverage. It is generally applicable to large populations sequenced at low-coverage, and is particularly suited to mapping transpositions. Copyright © 2017 by the Genetics Society of America.

2011 Vascular Research Initiatives Conference: basic foundations of translational research in vascular disease.

PubMed

Ziegler, Kenneth R; Dardik, Alan

2011-07-01

The Vascular Research Initiatives Conference (VRIC) is an annual conference organized by the Society for Vascular Surgery (SVS). The 2011 VRIC was held in Chicago (IL, USA) to precede and coincide with the first day of the meeting of the Council on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) of the American Heart Association. The event is designed to present world class vascular research results, encourage collaboration between vascular surgeons and basic scientists in related disciplines, as well as to stimulate interest in research among aspiring academic vascular surgeons. The 2011 VRIC featured plenary sessions addressing peripheral arterial disease, vascular endothelium and thrombosis, aneurysms, and stem cells and tissue engineering. Recipients of the SVS partner grants with the National Institutes of Health K08 awardees presented their progress reports, and keynote addresses were given by Linda Graham and Frank LoGerfo.

Development of an adaptive optics test-bed for relay mirror applications

NASA Astrophysics Data System (ADS)

Mansell, Justin D.; Jacobs, Arturo A.; Maynard, Morris

2005-08-01

The relay mirror concept involves deploying a passive optical station at a high altitude for relaying a beam from a laser weapon to a target. Relay mirrors have been proposed as a method of increasing the range of laser weapons that is less costly than deploying a larger number of laser weapons. Relay mirrors will only be effective if the beam spreading and beam quality degradation induced by atmospheric aberrations and thermal blooming can be mitigated. In this paper we present the first phase of a multi-year effort to develop a theoretical and experimental capability at Boeing-SVS to study these problems. A team from MZA and Boeing-SVS has developed a laboratory test-bed consisting of a distributed atmospheric path simulated by three liquid crystal phase screens, a Shack-Hartmann wavefront sensor, and a MEMS membrane deformable mirror. We present results of AO component calibration and evaluation, the system construction, and the system performance.

The dependence of nano-contact magnetoresistance on the bulk scattering spin asymmetry in CoFe alloys with oxidation impurities

NASA Astrophysics Data System (ADS)

Shiokawa, Yohei; Jung, JinWon; Otsuka, Takahiko; Sahashi, Masashi

2015-08-01

Nano-contact magnetoresistance (NCMR) spin-valves (SVs) using an AlOx nano-oxide-layer (NOL) have numerous nanocontacts in the thin AlOx oxide layer. The NCMR theoretically depends on the bulk scattering spin asymmetry ( β) of the ferromagnetic material in the nanocontacts. To determine the relationship between NCMR and β, we investigated the dependence of NCMR on the composition of the ferromagnetic material Co1-xFex. The samples were annealed at 270 °C and 380 °C to enhance the MR ratio. For both annealing temperatures, the magnetorsistance ratio in the low-resistance area product region at less than 1 Ω μm2 was maximized for Co0.5Fe0.5. To evaluate β exactly, we fabricated current-perpendicular-to-plane giant magnetoresistance SVs with Co1-xFex/Cu/Co1-xFex layers and used Valet and Fert's theory to solve the diffusion equation of the spin accumulation for a ferromagnetic layer/non-ferromagnetic layer of five layers with a finite diffusion length. The evaluated β for Co1-xFex was also maximized for Co0.5Fe0.5. Additionally, to determine the difference between the experimental MR ratio of NCMR SVs and the theoretical MR ratio, we fabricated Co0.5Fe0.5 with oxygen impurities and estimated the decrease in β with increasing oxygen impurity concentration. Our Co0.5Fe0.5 nano-contacts fabricated using ion-assisted oxidation may contain oxygen impurities, and the oxygen impurities might cause a decrease in β and the MR ratio.

Comparing Apples and Oranges: Using Reward-Specific and Reward-General Subjective Value Representation in the Brain

PubMed Central

Glimcher, Paul W.

2011-01-01

The ability of human subjects to choose between disparate kinds of rewards suggests that the neural circuits for valuing different reward types must converge. Economic theory suggests that these convergence points represent the subjective values (SVs) of different reward types on a common scale for comparison. To examine these hypotheses and to map the neural circuits for reward valuation we had food and water-deprived subjects make risky choices for money, food, and water both in and out of a brain scanner. We found that risk preferences across reward types were highly correlated; the level of risk aversion an individual showed when choosing among monetary lotteries predicted their risk aversion toward food and water. We also found that partially distinct neural networks represent the SVs of monetary and food rewards and that these distinct networks showed specific convergence points. The hypothalamic region mainly represented the SV for food, and the posterior cingulate cortex mainly represented the SV for money. In both the ventromedial prefrontal cortex (vmPFC) and striatum there was a common area representing the SV of both reward types, but only the vmPFC significantly represented the SVs of money and food on a common scale appropriate for choice in our data set. A correlation analysis demonstrated interactions across money and food valuation areas and the common areas in the vmPFC and striatum. This may suggest that partially distinct valuation networks for different reward types converge on a unified valuation network, which enables a direct comparison between different reward types and hence guides valuation and choice. PMID:21994386

Can stevioside in combination with a soy-based dietary supplement be a new useful treatment of type 2 diabetes? An in vivo study in the diabetic goto-kakizaki rat.

PubMed

Jeppesen, Per B; Dyrskog, Stig E; Agger, Andreas; Gregersen, Soren; Colombo, Michele; Xiao, Jianzhong; Hermansen, Kjeld

2006-01-01

The diterpene glycoside stevioside (SVS) and soy bean protein isolate have both been shown to have beneficial effects in diabetes treatment. As they each show different benefits we investigated whether the combination of both substances shows an improvement in the treatment of diabetes in Goto-Kakizaki (GK) rats. Over the course of 4 wk, the rats were fed with the following four test diets (n = 12 per group): 1. Standard carbohydrate-rich laboratory diet (chow), 2. chow + SVS (0.03 g/kg BW/day), 3. 80% SPI + 20% chow and 4. 80% SPI + 20 % chow + SVS (0.03 g/kg BW/day). At the end of the course conscious rats underwent an intra-arterial glucose tolerance test (IAGTT) (2.0 g glucose/kg BW). Compared to normal chow diet, stevioside in combination with SPI shows the following beneficial effects in GK rats with mild type 2 diabetes: 1. a 56% reduction in plasma glucose (p < 0.001), 2. a 118% increase in first-phase insulin (p < 0.005), 3. a 20% reduction in glucagons (p < 0.05), 4. a 28% reduction in total cholesterol (p < 0.001), 5. a 13% reduction in FFA (p < 0.01), 6. a 49% reduction in TG (p < 0.001) and 7. a 11% reduction in the systolic blood pressure (p < 0.001). In conclusion, the combination of stevioside and SPI has synergistic positive effects on the characteristic features of the metabolic syndrome, i.e. hyperglycemia, hypertension and dyslipidemia.

Cognitive mapping based on synthetic vision?

NASA Astrophysics Data System (ADS)

Helmetag, Arnd; Halbig, Christian; Kubbat, Wolfgang; Schmidt, Rainer

1999-07-01

The analysis of accidents focused our work on the avoidance of 'Controlled Flight Into Terrain' caused by insufficient situation awareness. Analysis of safety concepts led us to the design of the proposed synthetic vision system that will be described. Since most information on these 3D-Displays is shown in a graphical way, it can intuitively be understood by the pilot. What are the new possibilities using SVS enhancing situation awareness? First, detection of ground collision hazard is possible by monitoring a perspective Primary Flight Display. Under the psychological point of view it is based on the perception of expanding objects in the visual flow field. Supported by a Navigation Display a local conflict resolution can be mentally worked out very fast. Secondly, it is possible to follow a 3D flight path visualized as a 'Tunnel in the sky.' This can further be improved by using a flight path prediction. These are the prerequisites for a safe and adequate movement in any kind of spatial environment. However situation awareness requires the ability of navigation and spatial problem solving. Both abilities are based on higher cognitive functions in real as well as in a synthetic environment. In this paper the current training concept will be analyzed. Advantages resulting from the integration of a SVS concerning pilot training will be discussed and necessary requirements in terrain depiction will be pinpointed. Finally a modified Computer Based Training for the familiarization with Salzburg Airport for a SVS equipped aircraft will be presented. It is developed by Darmstadt University of Technology in co-operation with Lufthansa Flight Training.

Metallic few-layered VS2 ultrathin nanosheets: high two-dimensional conductivity for in-plane supercapacitors.

PubMed

Feng, Jun; Sun, Xu; Wu, Changzheng; Peng, Lele; Lin, Chenwen; Hu, Shuanglin; Yang, Jinlong; Xie, Yi

2011-11-09

With the rapid development of portable electronics, such as e-paper and other flexible devices, practical power sources with ultrathin geometries become an important prerequisite, in which supercapacitors with in-plane configurations are recently emerging as a favorable and competitive candidate. As is known, electrode materials with two-dimensional (2D) permeable channels, high-conductivity structural scaffolds, and high specific surface areas are the indispensible requirements for the development of in-plane supercapacitors with superior performance, while it is difficult for the presently available inorganic materials to make the best in all aspects. In this sense, vanadium disulfide (VS(2)) presents an ideal material platform due to its synergic properties of metallic nature and exfoliative characteristic brought by the conducting S-V-S layers stacked up by weak van der Waals interlayer interactions, offering great potential as high-performance in-plane supercapacitor electrodes. Herein, we developed a unique ammonia-assisted strategy to exfoliate bulk VS(2) flakes into ultrathin VS(2) nanosheets stacked with less than five S-V-S single layers, representing a brand new two-dimensional material having metallic behavior aside from graphene. Moreover, highly conductive VS(2) thin films were successfully assembled for constructing the electrodes of in-plane supercapacitors. As is expected, a specific capacitance of 4760 μF/cm(2) was realized here in a 150 nm in-plane configuration, of which no obvious degradation was observed even after 1000 charge/discharge cycles, offering as a new in-plane supercapacitor with high performance based on quasi-two-dimensional materials.

A Role for an Hsp70 Nucleotide Exchange Factor in the Regulation of Synaptic Vesicle Endocytosis

PubMed Central

Morgan, Jennifer R.; Jiang, Jianwen; Oliphint, Paul A.; Jin, Suping; Gimenez, Luis E.; Busch, David J.; Foldes, Andrea E.; Zhuo, Yue; Sousa, Rui; Lafer, Eileen M.

2013-01-01

Neurotransmission requires a continuously available pool of synaptic vesicles (SVs) that can fuse with the plasma membrane and release their neurotransmitter contents upon stimulation. After fusion, SV membranes and membrane proteins are retrieved from the presynaptic plasma membrane by clathrin-mediated endocytosis. Following the internalization of a clathrin coated vesicle (CCV), the vesicle must uncoat to replenish the pool of SVs. CCV uncoating requires ATP and is mediated by the ubiquitous molecular chaperone Hsc70. In vitro, depolymerized clathrin forms a stable complex with Hsc70*ADP. This complex can be dissociated by nucleotide exchange factors (NEFs) that release ADP from Hsc70, allowing ATP to bind and induce disruption of the clathrin:Hsc70 association. Whether NEFs generally play similar roles in vesicle trafficking in vivo, and whether they play such roles in SV endocytosis in particular is unknown. To address this question we used information from recent structural and mechanistic studies of Hsp70:NEF and Hsp70:cochaperone interactions to design a NEF inhibitor. Using acute perturbations at giant reticulospinal synapses of the sea lamprey (Petromyzon marinus), we found that this NEF inhibitor inhibited SV endocytosis. When this inhibitor was mutated so it could no longer bind and inhibit Hsp110--a NEF that we find to be highly abundant in brain cytosol--its ability to inhibit SV endocytosis was eliminated. These observations indicate that the action of a NEF, most likely Hsp110, is normally required during SV trafficking to release clathrin from Hsc70 and make it available for additional rounds of endocytosis. PMID:23637191

SVS (Self-Propagating High-Temperature Synthesis)

NASA Image and Video Library

2009-08-21

ISS020-E-032798 (21 Aug. 2009) --- Cosmonaut Roman Romanenko, Expedition 20 flight engineer, works with video equipment and a Russian payload TkhN-7 Self-Propagating High-Temperature Synthesis in the Zvezda Service Module of the International Space Station.

Science Comes Alive at NASA Goddard

NASA Image and Video Library

2017-05-17

Science Comes Alive at NASA Goddard: Welcome to the NASA Goddard Space Flight Center. Where innovation and science never sleep and new discoveries never get old... At NASA Goddard. For Higher Resolutions and Other Versions: https://svs.gsfc.nasa.gov/12533

Predictive Ability of the SVS WIfI Classification System Following Infrapopliteal Endovascular Interventions for CLI

PubMed Central

Darling, Jeremy D.; McCallum, John C.; Soden, Peter A.; Meng, Yifan; Wyers, Mark C.; Hamdan, Allen D.; Verhagen, Hence H.J.; Schermerhorn, Marc L.

2016-01-01

OBJECTIVES The Society for Vascular Surgery (SVS) Lower Extremity Guidelines Committee has composed a new threatened lower extremity classification system that reflects the three major factors that impact amputation risk and clinical management: wound, ischemia, and foot infection (WIfI). Our goal was to evaluate the predictive ability of this scale following any infrapopliteal endovascular intervention for critical limb ischemia (CLI). METHODS From 2004 to 2014, a single institution, retrospective chart review was performed at the Beth Israel Deaconess Medical Center for all patients undergoing an infrapopliteal angioplasty for CLI. Throughout these years, 673 limbs underwent an infrapopliteal endovascular intervention for tissue loss (77%), rest pain (13%), stenosis of a previously treated vessel (5%), acute limb ischemia (3%), or claudication (2%). Limbs missing a grade in any WIfI component were excluded. Limbs were stratified into clinical stages 1 to 4 based on the SVS WIfI classification for 1-year amputation risk, as well as a novel WIfI composite score from 0 to 9. Outcomes included patient functional capacity, living status, wound healing, major amputation, major adverse limb events (MALE), RAS events (reintervention, major amputation, or stenosis [>3.5x step-up by duplex]), amputation-free survival (AFS), and mortality. Predictors were identified using Kaplan-Meier survival estimates and Cox regression models. RESULTS Of the 596 limbs with CLI, 551 were classified in all three WIfI domains on a scale of 0 (least severe) to 3 (most severe). Of these 551, 84% were treated for tissue loss and 16% for rest pain. A Cox regression model illustrated that an increase in clinical stage increases the rate of major amputation (Hazard Ratio (HR), 1.6; 95% Confidence Interval [CI], 1.1–2.3). Separate regression models showed that a one-unit increase in the WIfI composite score is associated with a decrease in wound healing (1.2 [1.1–1.4]) and an increase in the rate of RAS events (1.2 [1.1–1.4]) and major amputations (1.4 [1.2–1.8]). CONCLUSIONS This study supports the ability of the SVS WIfI classification system to predict 1-year amputation, RAS events, and wound healing in patients with CLI undergoing endovascular infrapopliteal revascularization procedures. PMID:27380993

Integration of a synthetic vision system with airborne laser range scanner-based terrain referenced navigation for precision approach guidance

NASA Astrophysics Data System (ADS)

Uijt de Haag, Maarten; Campbell, Jacob; van Graas, Frank

2005-05-01

Synthetic Vision Systems (SVS) provide pilots with a virtual visual depiction of the external environment. When using SVS for aircraft precision approach guidance systems accurate positioning relative to the runway with a high level of integrity is required. Precision approach guidance systems in use today require ground-based electronic navigation components with at least one installation at each airport, and in many cases multiple installations to service approaches to all qualifying runways. A terrain-referenced approach guidance system is envisioned to provide precision guidance to an aircraft without the use of ground-based electronic navigation components installed at the airport. This autonomy makes it a good candidate for integration with an SVS. At the Ohio University Avionics Engineering Center (AEC), work has been underway in the development of such a terrain referenced navigation system. When used in conjunction with an Inertial Measurement Unit (IMU) and a high accuracy/resolution terrain database, this terrain referenced navigation system can provide navigation and guidance information to the pilot on a SVS or conventional instruments. The terrain referenced navigation system, under development at AEC, operates on similar principles as other terrain navigation systems: a ground sensing sensor (in this case an airborne laser scanner) gathers range measurements to the terrain; this data is then matched in some fashion with an onboard terrain database to find the most likely position solution and used to update an inertial sensor-based navigator. AEC's system design differs from today's common terrain navigators in its use of a high resolution terrain database (~1 meter post spacing) in conjunction with an airborne laser scanner which is capable of providing tens of thousands independent terrain elevation measurements per second with centimeter-level accuracies. When combined with data from an inertial navigator the high resolution terrain database and laser scanner system is capable of providing near meter-level horizontal and vertical position estimates. Furthermore, the system under development capitalizes on 1) The position and integrity benefits provided by the Wide Area Augmentation System (WAAS) to reduce the initial search space size and; 2) The availability of high accuracy/resolution databases. This paper presents results from flight tests where the terrain reference navigator is used to provide guidance cues for a precision approach.

Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy

PubMed Central

Sun, Rong; Zhang, Bin; Qi, Lei; Shivakoti, Sakar; Tian, Chong-Li; Lau, Pak-Ming

2018-01-01

As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ∼12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25–60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABAA receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions. SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered “discus-shaped” ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions. PMID:29311144

G23D: Online tool for mapping and visualization of genomic variants on 3D protein structures.

PubMed

Solomon, Oz; Kunik, Vered; Simon, Amos; Kol, Nitzan; Barel, Ortal; Lev, Atar; Amariglio, Ninette; Somech, Raz; Rechavi, Gidi; Eyal, Eran

2016-08-26

Evaluation of the possible implications of genomic variants is an increasingly important task in the current high throughput sequencing era. Structural information however is still not routinely exploited during this evaluation process. The main reasons can be attributed to the partial structural coverage of the human proteome and the lack of tools which conveniently convert genomic positions, which are the frequent output of genomic pipelines, to proteins and structure coordinates. We present G23D, a tool for conversion of human genomic coordinates to protein coordinates and protein structures. G23D allows mapping of genomic positions/variants on evolutionary related (and not only identical) protein three dimensional (3D) structures as well as on theoretical models. By doing so it significantly extends the space of variants for which structural insight is feasible. To facilitate interpretation of the variant consequence, pathogenic variants, functional sites and polymorphism sites are displayed on protein sequence and structure diagrams alongside the input variants. G23D also provides modeling of the mutant structure, analysis of intra-protein contacts and instant access to functional predictions and predictions of thermo-stability changes. G23D is available at http://www.sheba-cancer.org.il/G23D . G23D extends the fraction of variants for which structural analysis is applicable and provides better and faster accessibility for structural data to biologists and geneticists who routinely work with genomic information.

GSFC_20171019_m12750_HSTMessier

NASA Image and Video Library

2017-10-19

This is a recording from Goddard Facebook Live Event on October 19, 2017, promoting the Hubble Messier Catalog for amateur astronomers. Hosting is Erin Kisliuk with Michelle Thaller and Kevin Hartnett as talents. Download this program in multiple formats at: http://svs.gsfc.nasa.gov/12750

Acute stroke with major intracranial vessel occlusion: Characteristics of cardioembolism and atherosclerosis-related in situ stenosis/occlusion.

PubMed

Horie, Nobutaka; Tateishi, Yohei; Morikawa, Minoru; Morofuji, Yoichi; Hayashi, Kentaro; Izumo, Tsuyoshi; Tsujino, Akira; Nagata, Izumi; Matsuo, Takayuki

2016-10-01

Acute ischemic stroke with major intracranial vessel occlusion is commonly due to cardioembolic or atherosclerosis-related in situ stenosis/occlusion, and immediate identification of these subtypes is important to establish the optimal treatment strategy. The aim of this study was to clarify the differences in clinical presentation, radiological findings, neurological temporal courses, and outcomes between these etiologies, which have not been fully evaluated. Consecutive emergency patients with acute ischemic stroke were retrospectively reviewed. Among them, patients with stroke with major intracranial vessel occlusion were analyzed with a focus on clinical and radiological findings, and a comparison was performed for those with cardioembolic or atherosclerosis-related in situ stenosis/occlusion. Of 1053 patients, 80 had stroke with acute major intracranial vessel occlusion (45 with cardioembolic and 35 with atherosclerosis-related in situ stenosis/occlusion). Interestingly, the susceptibility vessel sign (SVS) on T2-weighted MR angiography was more frequently detected in cardioembolic stroke (80.0%) than in atherosclerosis (in situ stenosis: 5.9%, chronic occlusion: 14.3%). Moreover, the proximal intra-arterial signal (IAS) on arterial spin labeling MRI and the distal IAS on fluid attenuated inversion recovery MRI was less frequently detected in chronic occlusion (27.3% and 50.0%, respectively) than in acute occlusion due to cardioembolic or in situ stenosis. Multivariate regression analysis showed that the SVS was significantly related to cardioembolism (adjusted odds ratio (OR): 21.68, P=0.004). Clinical characteristics of acute stroke with major intracranial vessel occlusion differ depending on the etiology. The SVS and proximal/distal IAS on MRI are useful to distinguish between cardioembolic and atherosclerotic-related in situ stenosis/occlusion. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design Considerations for Attitude State Awareness and Prevention of Entry into Unusual Attitudes

NASA Technical Reports Server (NTRS)

Ellis, Kyle K. E.; Prinzel, Lawrence J., III; Arthur, Jarvis J.; Nicholas, Stephanie N.; Kiggins, Daniel; Verstynen, Harry; Hubbs, Clay; Wilkerson, James

2017-01-01

Loss of control - inflight (LOC-I) has historically represented the largest category of commercial aviation fatal accidents. A review of the worldwide transport airplane accidents (2001-2010) evinced that loss of attitude or energy state awareness was responsible for a large majority of the LOC-I events. A Commercial Aviation Safety Team (CAST) study of 18 worldwide loss-of-control accidents and incidents determined that flight crew loss of attitude awareness or energy state awareness due to lack of external visual reference cues was a significant causal factor in 17 of the 18 reviewed flights. CAST recommended that "Virtual Day-Visual Meteorological Condition" (Virtual Day-VMC) displays be developed to provide the visual cues necessary to prevent loss-of-control resulting from flight crew spatial disorientation and loss of energy state awareness. Synthetic vision or equivalent systems (SVS) were identified for a design "safety enhancement" (SE-200). Part of this SE involves the conduct of research for developing minimum aviation system performance standards (MASPS) for these flight deck display technologies to aid flight crew attitude and energy state awareness similar to that of a virtual day-VMC-like environment. This paper will describe a novel experimental approach to evaluating a flight crew's ability to maintain attitude awareness and to prevent entry into unusual attitudes across several SVS optical flow design considerations. Flight crews were subjected to compound-event scenarios designed to elicit channelized attention and startle/surprise within the crew. These high-fidelity scenarios, designed from real-world events, enable evaluation of the efficacy of SVS at improving flight crew attitude awareness to reduce the occurrence of LOC-I incidents in commercial flight operations.

Obstacle Detection Algorithms for Aircraft Navigation: Performance Characterization of Obstacle Detection Algorithms for Aircraft Navigation

NASA Technical Reports Server (NTRS)

Kasturi, Rangachar; Camps, Octavia; Coraor, Lee

2000-01-01

The research reported here is a part of NASA's Synthetic Vision System (SVS) project for the development of a High Speed Civil Transport Aircraft (HSCT). One of the components of the SVS is a module for detection of potential obstacles in the aircraft's flight path by analyzing the images captured by an on-board camera in real-time. Design of such a module includes the selection and characterization of robust, reliable, and fast techniques and their implementation for execution in real-time. This report describes the results of our research in realizing such a design. It is organized into three parts. Part I. Data modeling and camera characterization; Part II. Algorithms for detecting airborne obstacles; and Part III. Real time implementation of obstacle detection algorithms on the Datacube MaxPCI architecture. A list of publications resulting from this grant as well as a list of relevant publications resulting from prior NASA grants on this topic are presented.

An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence

PubMed Central

Frahm, Silke; Antolin-Fontes, Beatriz; Görlich, Andreas; Zander, Johannes-Friedrich; Ahnert-Hilger, Gudrun; Ibañez-Tallon, Ines

2015-01-01

A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior. DOI: http://dx.doi.org/10.7554/eLife.11396.001 PMID:26623516

Terrain Portrayal for Synthetic Vision Systems Head-Down Displays Evaluation Results: Compilation of Pilot Transcripts

NASA Technical Reports Server (NTRS)

Hughes, Monica F.; Glaab, Louis J.

2007-01-01

The Terrain Portrayal for Head-Down Displays (TP-HDD) simulation experiment addressed multiple objectives involving twelve display concepts (two baseline concepts without terrain and ten synthetic vision system (SVS) variations), four evaluation maneuvers (two en route and one approach maneuver, plus a rare-event scenario), and three pilot group classifications. The TP-HDD SVS simulation was conducted in the NASA Langley Research Center's (LaRC's) General Aviation WorkStation (GAWS) facility. The results from this simulation establish the relationship between terrain portrayal fidelity and pilot situation awareness, workload, stress, and performance and are published in the NASA TP entitled Terrain Portrayal for Synthetic Vision Systems Head-Down Displays Evaluation Results. This is a collection of pilot comments during each run of the TP-HDD simulation experiment. These comments are not the full transcripts, but a condensed version where only the salient remarks that applied to the scenario, the maneuver, or the actual research itself were compiled.

Seasonal morphological variations and age-related changes of the seminal vesicle of viscacha (Lagostomus maximus maximus): an ultrastructural and immunohistochemical study.

PubMed

Chaves, Eduardo M; Aguilera-Merlo, Claudia; Cruceño, Albana; Fogal, Teresa; Piezzi, Ramón; Scardapane, Luis; Dominguez, Susana

2012-05-01

The viscacha is a seasonal rodent that exhibit an annual reproductive cycle with periods of maximum reproductive activity and gonadal regression. We studied seasonal variations in the morphology and cellular population of the seminal vesicles (SVs) during both periods and in impuber animals. Seminal vesicles were studied by light and electronic microscopy. Measurements of epithelial height, nuclear diameter, luminal diameter, and muscular layer were performed. Also, we studied the distribution of androgen receptors (AR) in this gland during the reproductive cycle and in impuber animal. During gonadal regression, principal and clear cells showed signs of reduced functional activity. These were characterized by an epithelium of smaller height, irregular nuclei, and cytoplasm with few organelles, dilated cisterns, and glycogen granules. In impuber animals, the principal cells showed large nuclei with chromatin lax and cytoplasm with small mitochondria, poorly developed Golgi apparatus, and granules of glycogen. On the other hand, the cells exhibited seasonal variations in the distribution and percentage of immunolabeled cells to AR throughout the annual reproductive cycle. During the gonadal regression period, glandular mucosa exhibited numerous epithelial cells with intense nuclear staining. However, fibromuscular stromal cells were weakly positive for AR in contrast to what was observed during the activity period. Considering that testosterone values are lower in adult animals during the period of gonadal regression and in impuber animals, our immunohistochemical results show a significant correlation with the percentage of AR-immunopositive cells. In conclusion, these results demonstrate that the structure of the SVs changes in the activity period of viscacha, probably because of elevated levels of testosterone leading to an increase in the secretory activity of epithelial cells. Copyright © 2012 Wiley Periodicals, Inc.

Improving Balance Function Using Low Levels of Electrical Stimulation of the Balance Organs

NASA Technical Reports Server (NTRS)

Bloomberg, Jacob; Reschke, Millard; Mulavara, Ajitkumar; Wood, Scott; Serrador, Jorge; Fiedler, Matthew; Kofman, Igor; Peters, Brian T.; Cohen, Helen

2012-01-01

Crewmembers returning from long-duration space flight face significant challenges due to the microgravity-induced inappropriate adaptations in balance/sensorimotor function. The Neuroscience Laboratory at JSC is developing a method based on stochastic resonance to enhance the brain's ability to detect signals from the balance organs of the inner ear and use them for rapid improvement in balance skill, especially when combined with balance training exercises. This method involves a stimulus delivery system that is wearable/portable and provides imperceptible electrical stimulation to the balance organs of the human body. Stochastic resonance (SR) is a phenomenon whereby the response of a nonlinear system to a weak periodic input signal is optimized by the presence of a particular non-zero level of noise. This phenomenon of SR is based on the concept of maximizing the flow of information through a system by a non-zero level of noise. Application of imperceptible SR noise coupled with sensory input in humans has been shown to improve motor, cardiovascular, visual, hearing, and balance functions. SR increases contrast sensitivity and luminance detection; lowers the absolute threshold for tone detection in normal hearing individuals; improves homeostatic function in the human blood pressure regulatory system; improves noise-enhanced muscle spindle function; and improves detection of weak tactile stimuli using mechanical or electrical stimulation. SR noise has been shown to improve postural control when applied as mechanical noise to the soles of the feet, or when applied as electrical noise at the knee and to the back muscles. SR using imperceptible stochastic electrical stimulation of the vestibular system (stochastic vestibular stimulation, SVS) applied to normal subjects has shown to improve the degree of association between the weak input periodic signals introduced via venous blood pressure receptors and the heart-rate responses. Also, application of SVS over 24 hours improves the long-term heart-rate dynamics and motor responsiveness as indicated by daytime trunk activity measurements in patients with multi-system atrophy, Parkinson s disease, or both, including patients who were unresponsive to standard therapy for Parkinson s disease. Recent studies conducted at the NASA JSC Neurosciences Laboratories showed that imperceptible SVS, when applied to normal young healthy subjects, leads to significantly improved balance performance during postural disturbances on unstable compliant surfaces. These studies have shown the benefit of SR noise characteristic optimization with imperceptible SVS in the frequency range of 0-30 Hz, and amplitudes of stimulation have ranged from 100 to 400 microamperes.

A survey of current practice of vascular surgeons in venous disease management.

PubMed

Bush, Ruth L; Gloviczki, Peter

2013-01-01

Acute venous thromboembolism and chronic venous diseases are common conditions that affect a large proportion of the United States population. The diagnosis of venous disease has improved, and the treatment options have rapidly evolved over the past decade. To date, it is unclear to what extent vascular surgeons have become involved in the modern management of venous disorders. This survey was undertaken to explore the current interest and practice of vascular surgeons in the contemporary care of venous disease. A survey was administered via a web-based platform to active and candidate members of the Society for Vascular Surgery (SVS). The survey included 30 questions investigating the characteristics of venous surgeons and scope of venous practice. Open-ended questions were also included for commentary. A total of 1879 surveys were sent to SVS members nationwide, and 385 members participated (response rate of 20.5%). The participants were mostly men (89.6%) with 37.7% practicing in an academic setting and 59.2% in private practice. The respondents treated superficial veins (92.9%) and deep veins (85.8%) in clinical practice, with 89.9% having their own vascular laboratory. A wide spectrum of interventions for superficial (91.9%), deep (85.8%), and perforator veins (52.7% endovenous, 19.4% subfascial endoscopic perforator surgery) are being performed by respondents. Only 26.2% had learned endovenous thermal ablation in their training program; however, over 96% of those performing venous interventions utilized this technique. Overall, the majority (85.5%) devoted 50% or less of practice to venous disorders. Respondents indicated that limitations to expansion of vein practices mainly involved challenges with third party payers, local competition, and existing large volumes of arterial interventions needing to be performed. Despite the widespread incorporation of venous disease into current vascular practices, 66.1% are not members of the American Venous Forum (AVF) or other venous society. Many believe there is still a lack of standardization of care and guidelines for venous disease. The care of patients with venous disease has become more widespread among SVS members, with most offering both deep and superficial venous interventions as well as incorporation of minimally invasive techniques into their treatment armamentarium. Dissemination and incorporation of protocols and guidelines into clinical practice as well as postgraduate courses in venous disease may be areas in which the SVS could facilitate members' involvement in the care of patients with venous disease. Published by Elsevier Inc.

G2S: a web-service for annotating genomic variants on 3D protein structures.

PubMed

Wang, Juexin; Sheridan, Robert; Sumer, S Onur; Schultz, Nikolaus; Xu, Dong; Gao, Jianjiong

2018-06-01

Accurately mapping and annotating genomic locations on 3D protein structures is a key step in structure-based analysis of genomic variants detected by recent large-scale sequencing efforts. There are several mapping resources currently available, but none of them provides a web API (Application Programming Interface) that supports programmatic access. We present G2S, a real-time web API that provides automated mapping of genomic variants on 3D protein structures. G2S can align genomic locations of variants, protein locations, or protein sequences to protein structures and retrieve the mapped residues from structures. G2S API uses REST-inspired design and it can be used by various clients such as web browsers, command terminals, programming languages and other bioinformatics tools for bringing 3D structures into genomic variant analysis. The webserver and source codes are freely available at https://g2s.genomenexus.org. g2s@genomenexus.org. Supplementary data are available at Bioinformatics online.

Validation and Genotyping of Multiple Human Polymorphic Inversions Mediated by Inverted Repeats Reveals a High Degree of Recurrence

PubMed Central

Aguado, Cristina; Gayà-Vidal, Magdalena; Villatoro, Sergi; Oliva, Meritxell; Izquierdo, David; Giner-Delgado, Carla; Montalvo, Víctor; García-González, Judit; Martínez-Fundichely, Alexander; Capilla, Laia; Ruiz-Herrera, Aurora; Estivill, Xavier; Puig, Marta; Cáceres, Mario

2014-01-01

In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6–24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ∼12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies. PMID:24651690

Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy.

PubMed

Tao, Chang-Lu; Liu, Yun-Tao; Sun, Rong; Zhang, Bin; Qi, Lei; Shivakoti, Sakar; Tian, Chong-Li; Zhang, Peijun; Lau, Pak-Ming; Zhou, Z Hong; Bi, Guo-Qiang

2018-02-07

As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ∼12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25-60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABA A receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions. SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered "discus-shaped" ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions. Copyright © 2018 Tao, Liu et al.

Molecular models of NS3 protease variants of the Hepatitis C virus.

PubMed

da Silveira, Nelson J F; Arcuri, Helen A; Bonalumi, Carlos E; de Souza, Fátima P; Mello, Isabel M V G C; Rahal, Paula; Pinho, João R R; de Azevedo, Walter F

2005-01-21

Hepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed. The atomic coordinates of crystallographic structure 1CU1 and 1DY9 were used as starting model for modeling of the NS3 protease variant structures. The NS3 protease variant structures are composed of six subdomains, which occur in sequence along the polypeptide chain. The protease domain exhibits the dual beta-barrel fold that is common among members of the chymotrypsin serine protease family. The helicase domain contains two structurally related beta-alpha-beta subdomains and a third subdomain of seven helices and three short beta strands. The latter domain is usually referred to as the helicase alpha-helical subdomain. The rmsd value of bond lengths and bond angles, the average G-factor and Verify 3D values are presented for NS3 protease variant structures. This project increases the certainty that homology modeling is an useful tool in structural biology and that it can be very valuable in annotating genome sequence information and contributing to structural and functional genomics from virus. The structural models will be used to guide future efforts in the structure-based drug design of a new generation of NS3 protease variants inhibitors. All models in the database are publicly accessible via our interactive website, providing us with large amount of structural models for use in protein-ligand docking analysis.

Structural variants of yeast prions show conformer-specific requirements for chaperone activity

PubMed Central

Stein, Kevin C.; True, Heather L.

2016-01-01

Summary Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1, and its human ortholog Hdj1, had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation. PMID:25060529

Atypical face shape and genomic structural variants in epilepsy

PubMed Central

Chinthapalli, Krishna; Bartolini, Emanuele; Novy, Jan; Suttie, Michael; Marini, Carla; Falchi, Melania; Fox, Zoe; Clayton, Lisa M. S.; Sander, Josemir W.; Guerrini, Renzo; Depondt, Chantal; Hennekam, Raoul; Hammond, Peter

2012-01-01

Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development. PMID:22975390

76 FR 33194 - Pure Magnesium From the People's Republic of China: Preliminary Results of the 2009-2010...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

... financial statements and comments on surrogate country selection, respectively. TMI submitted comments... TMI for our consideration as potential SVs and surrogate financial ratios are sourced from India. Finally, on the record of this review, we have usable SV data (including financial data) from India, but...

Subjective Vitality and Patterns of Acculturation: Four Cases

ERIC Educational Resources Information Center

Ehala, Martin; Vedernikova, Elena

2015-01-01

The article presents a comparative analysis of the subjective vitalities (SVs) of the minority groups of Latvia (Russian-speakers), Lithuania (Russian-speakers and Poles) and Mari El (Maris) in the Russian Federation, with a particular focus on the Mari case. The same extended version of the SV questionnaire was used in quantitative surveys in all…

Real-Time Integrity Monitoring of Stored Geo-Spatial Data Using Forward-Looking Remote Sensing Technology

NASA Technical Reports Server (NTRS)

Young, Steven D.; Harrah, Steven D.; deHaag, Maarten Uijt

2002-01-01

Terrain Awareness and Warning Systems (TAWS) and Synthetic Vision Systems (SVS) provide pilots with displays of stored geo-spatial data (e.g. terrain, obstacles, and/or features). As comprehensive validation is impractical, these databases typically have no quantifiable level of integrity. This lack of a quantifiable integrity level is one of the constraints that has limited certification and operational approval of TAWS/SVS to "advisory-only" systems for civil aviation. Previous work demonstrated the feasibility of using a real-time monitor to bound database integrity by using downward-looking remote sensing technology (i.e. radar altimeters). This paper describes an extension of the integrity monitor concept to include a forward-looking sensor to cover additional classes of terrain database faults and to reduce the exposure time associated with integrity threats. An operational concept is presented that combines established feature extraction techniques with a statistical assessment of similarity measures between the sensed and stored features using principles from classical detection theory. Finally, an implementation is presented that uses existing commercial-off-the-shelf weather radar sensor technology.

Analysis of programming properties and the row-column generation method for 1-norm support vector machines.

PubMed

Zhang, Li; Zhou, WeiDa

2013-12-01

This paper deals with fast methods for training a 1-norm support vector machine (SVM). First, we define a specific class of linear programming with many sparse constraints, i.e., row-column sparse constraint linear programming (RCSC-LP). In nature, the 1-norm SVM is a sort of RCSC-LP. In order to construct subproblems for RCSC-LP and solve them, a family of row-column generation (RCG) methods is introduced. RCG methods belong to a category of decomposition techniques, and perform row and column generations in a parallel fashion. Specially, for the 1-norm SVM, the maximum size of subproblems of RCG is identical with the number of Support Vectors (SVs). We also introduce a semi-deleting rule for RCG methods and prove the convergence of RCG methods when using the semi-deleting rule. Experimental results on toy data and real-world datasets illustrate that it is efficient to use RCG to train the 1-norm SVM, especially in the case of small SVs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Spectral (Finite) Volume Method for Conservation Laws on Unstructured Grids II: Extension to Two Dimensional Scalar Equation

NASA Technical Reports Server (NTRS)

Wang, Z. J.; Liu, Yen; Kwak, Dochan (Technical Monitor)

2002-01-01

The framework for constructing a high-order, conservative Spectral (Finite) Volume (SV) method is presented for two-dimensional scalar hyperbolic conservation laws on unstructured triangular grids. Each triangular grid cell forms a spectral volume (SV), and the SV is further subdivided into polygonal control volumes (CVs) to supported high-order data reconstructions. Cell-averaged solutions from these CVs are used to reconstruct a high order polynomial approximation in the SV. Each CV is then updated independently with a Godunov-type finite volume method and a high-order Runge-Kutta time integration scheme. A universal reconstruction is obtained by partitioning all SVs in a geometrically similar manner. The convergence of the SV method is shown to depend on how a SV is partitioned. A criterion based on the Lebesgue constant has been developed and used successfully to determine the quality of various partitions. Symmetric, stable, and convergent linear, quadratic, and cubic SVs have been obtained, and many different types of partitions have been evaluated. The SV method is tested for both linear and non-linear model problems with and without discontinuities.

Graphene-passivated cobalt as a spin-polarized electrode: growth and application to organic spintronics

NASA Astrophysics Data System (ADS)

Zhou, Guoqing; Tang, Guoqiang; Li, Tian; Pan, Guoxing; Deng, Zanhong; Zhang, Fapei

2017-03-01

The ferromagnetic electrode on which a clean high-quality electrode/interlayer interface is formed, is critical to achieve efficient injection of spin-dependent electrons in spintronic devices. In this work, we report on the preparation of graphene-passivated cobalt electrodes for application in vertical spin valves (SVs). In this strategy, high-quality monolayer and bi-layer graphene sheets have been grown directly on the crystal Co film substrates in a controllable process by chemical vapor deposition. The electrode is oxidation resistant and ensures a clean crystalline graphene/Co interface. The AlO x -based magnetic junction devices using such bottom electrodes, exhibit a negative tunnel magneto-resistance (TMR) of ca. 1.0% in the range of 5 K-300 K. Furthermore, we have also fabricated organic-based SVs employing a thin layer of fullerene C60 or an N-type polymeric semiconductor as the interlayer. The devices of both materials show a tunneling behavior of spin-polarized electron transport as well as appreciable TMR effect, demonstrating the high potential of such graphene-coated Co electrodes for organic-based spintronics.

Parallel Key Frame Extraction for Surveillance Video Service in a Smart City.

PubMed

Zheng, Ran; Yao, Chuanwei; Jin, Hai; Zhu, Lei; Zhang, Qin; Deng, Wei

2015-01-01

Surveillance video service (SVS) is one of the most important services provided in a smart city. It is very important for the utilization of SVS to provide design efficient surveillance video analysis techniques. Key frame extraction is a simple yet effective technique to achieve this goal. In surveillance video applications, key frames are typically used to summarize important video content. It is very important and essential to extract key frames accurately and efficiently. A novel approach is proposed to extract key frames from traffic surveillance videos based on GPU (graphics processing units) to ensure high efficiency and accuracy. For the determination of key frames, motion is a more salient feature in presenting actions or events, especially in surveillance videos. The motion feature is extracted in GPU to reduce running time. It is also smoothed to reduce noise, and the frames with local maxima of motion information are selected as the final key frames. The experimental results show that this approach can extract key frames more accurately and efficiently compared with several other methods.

Synthetic vision systems: the effects of guidance symbology, display size, and field of view.

PubMed

Alexander, Amy L; Wickens, Christopher D; Hardy, Thomas J

2005-01-01

Two experiments conducted in a high-fidelity flight simulator examined the effects of guidance symbology, display size, and geometric field of view (GFOV) within a synthetic vision system (SVS). In Experiment 1, 18 pilots flew highlighted and low-lighted tunnel-in-the-sky displays, as well as a less cluttered follow-me aircraft (FMA), through a series of curved approaches over rugged terrain. The results revealed that both tunnels supported better flight path tracking and lower workload levels than did the FMA because of the availability of more preview information. Increasing tunnel intensity had no benefit on tracking and, in fact, degraded traffic awareness because of clutter and attentional tunneling. In Experiment 2, 24 pilots flew a lowlighted tunnel configured according to different display sizes (small or large) and GFOVs (30 degrees or 60 degrees). Measures of flight path tracking and terrain awareness generally favored the 60 degrees GFOV; however, there were no effects of display size. Actual or potential applications of this research include understanding the impact of SVS properties on flight path tracking, traffic and terrain awareness, workload, and the allocation of attention.

Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

PubMed

Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

2018-01-23

Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.

Shunt-dependent hydrocephalus: management style among members of the American Society of Pediatric Neurosurgeons.

PubMed

Kraemer, Mark R; Sandoval-Garcia, Carolina; Bragg, Taryn; Iskandar, Bermans J

2017-09-01

OBJECTIVE The authors conducted a survey to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among members of the American Society of Pediatric Neurosurgeons (ASPN). METHODS Surveys were sent to all 204 active ASPN members in September 2014. One hundred thirty responses were received, representing a 64% response rate. Respondents were asked 13 multiple-choice and free-response questions regarding 4 fundamental problems encountered in shunted-hydrocephalus management: shunt malfunction, chronic cerebrospinal fluid (CSF) overdrainage, chronic headaches, and slit ventricle syndrome (SVS). RESULTS Respondents agreed that shunt malfunction occurs most often as the result of ventricular catheter obstruction. Despite contrary evidence in the literature, most respondents (66%) also believed that choroid plexus is the tissue most often found in obstructed proximal catheters. However, free-text responses revealed that the respondents' understanding of the underlying pathophysiology of shunt obstruction was highly variable and included growth, migration, or adherence of choroid plexus, CSF debris, catheter position, inflammatory processes, and CSF overdrainage. Most respondents considered chronic CSF overdrainage to be a rare complication of shunting in their practice and reported wide variation in treatment protocols. Moreover, despite a lack of evidence in the literature, most respondents attributed chronic headaches in shunt patients to medical reasons (for example, migraines, tension). Accordingly, most respondents managed headaches with reassurance and/or referral to pain clinics. Lastly, there were variable opinions on the etiology of slit ventricle syndrome (SVS), which included early shunting, chronic overdrainage, and/or loss of brain compliance. Beyond shunt revision, respondents reported divergent SVS treatment preferences. CONCLUSIONS The survey shows that there is wide variability in the understanding and management of shunt-dependent hydrocephalus and its complications. Such discrepancies appear to be derived partly from inconsistent familiarity with existing literature but especially from a paucity of high-quality publications.

An early validation of the Society for Vascular Surgery lower extremity threatened limb classification system.

PubMed

Cull, David L; Manos, Ginger; Hartley, Michael C; Taylor, Spence M; Langan, Eugene M; Eidt, John F; Johnson, Brent L

2014-12-01

The Society for Vascular Surgery (SVS) recently established the Lower Extremity Threatened Limb Classification System, a staging system using Wound characteristic, Ischemia, and foot Infection (WIfI) to stratify the risk for limb amputation at 1 year. Although intuitive in nature, this new system has not been validated. The purpose of the following study was to determine whether the WIfI system is predictive of limb amputation and wound healing. Between 2007 and 2010, we prospectively obtained data related to wound characteristics, extent of infection, and degree of postrevascularization ischemia in 139 patients with foot wounds who presented for lower extremity revascularization (158 revascularization procedures). After adapting those data to the WIfI classifications, we analyzed the influence of wound characteristics, extent of infection, and degree of ischemia on time to wound healing; empirical Kaplan-Meier survival curves were compared with theoretical outcomes predicted by WIfI expert consensus opinion. Of the 158 foot wounds, 125 (79%) healed. The median time to wound healing was 2.7 months (range, 1-18 months). Factors associated with wound healing included presence of diabetes mellitus (P = .013), wound location (P = .049), wound size (P = .007), wound depth (P = .004), and degree of ischemia (P < .001). The WIfI clinical stage was predictive of 1-year limb amputation (stage 1, 3%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and wound nonhealing (stage 1, 8%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and correlated with the theoretical outcome estimated by the SVS expert panel. The theoretical framework for risk stratification among patients with critical limb ischemia provided by the SVS expert panel appears valid. Further validation of the WIfI classification system with multicenter data is justified. Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Residual Seminal Vesicle Displacement in Marker-Based Image-Guided Radiotherapy for Prostate Cancer and the Impact on Margin Design

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

Smitsmans, Monique H.P.; Bois, Josien de; Sonke, Jan-Jakob

Purpose: The objectives of this study were to quantify residual interfraction displacement of seminal vesicles (SV) and investigate the efficacy of rotation correction on SV displacement in marker-based prostate image-guided radiotherapy (IGRT). We also determined the effect of marker registration on the measured SV displacement and its impact on margin design. Methods and Materials: SV displacement was determined relative to marker registration by using 296 cone beam computed tomography scans of 13 prostate cancer patients with implanted markers. SV were individually registered in the transverse plane, based on gray-value information. The target registration error (TRE) for the SV due tomore » marker registration inaccuracies was estimated. Correlations between prostate gland rotations and SV displacement and between individual SV displacements were determined. Results: The SV registration success rate was 99%. Displacement amounts of both SVs were comparable. Systematic and random residual SV displacements were 1.6 mm and 2.0 mm in the left-right direction, respectively, and 2.8 mm and 3.1 mm in the anteroposterior (AP) direction, respectively. Rotation correction did not reduce residual SV displacement. Prostate gland rotation around the left-right axis correlated with SV AP displacement (R{sup 2} = 42%); a correlation existed between both SVs for AP displacement (R{sup 2} = 62%); considerable correlation existed between random errors of SV displacement and TRE (R{sup 2} = 34%). Conclusions: Considerable residual SV displacement exists in marker-based IGRT. Rotation correction barely reduced SV displacement, rather, a larger SV displacement was shown relative to the prostate gland that was not captured by the marker position. Marker registration error partly explains SV displacement when correcting for rotations. Correcting for rotations, therefore, is not advisable when SV are part of the target volume. Margin design for SVs should take these uncertainties into account.« less

Information hiding techniques for infrared images: exploring the state-of-the art and challenges

NASA Astrophysics Data System (ADS)

Pomponiu, Victor; Cavagnino, Davide; Botta, Marco; Nejati, Hossein

2015-10-01

The proliferation of Infrared technology and imaging systems enables a different perspective to tackle many computer vision problems in defense and security applications. Infrared images are widely used by the law enforcement, Homeland Security and military organizations to achieve a significant advantage or situational awareness, and thus is vital to protect these data against malicious attacks. Concurrently, sophisticated malware are developed which are able to disrupt the security and integrity of these digital media. For instance, illegal distribution and manipulation are possible malicious attacks to the digital objects. In this paper we explore the use of a new layer of defense for the integrity of the infrared images through the aid of information hiding techniques such as watermarking. In this context, we analyze the efficiency of several optimal decoding schemes for the watermark inserted into the Singular Value Decomposition (SVD) domain of the IR images using an additive spread spectrum (SS) embedding framework. In order to use the singular values (SVs) of the IR images with the SS embedding we adopt several restrictions that ensure that the values of the SVs will maintain their statistics. For both the optimal maximum likelihood decoder and sub-optimal decoders we assume that the PDF of SVs can be modeled by the Weibull distribution. Furthermore, we investigate the challenges involved in protecting and assuring the integrity of IR images such as data complexity and the error probability behavior, i.e., the probability of detection and the probability of false detection, for the applied optimal decoders. By taking into account the efficiency and the necessary auxiliary information for decoding the watermark, we discuss the suitable decoder for various operating situations. Experimental results are carried out on a large dataset of IR images to show the imperceptibility and efficiency of the proposed scheme against various attack scenarios.

Field-based evaluations of horizontal flat-plate fish screens

USGS Publications Warehouse

Rose, B.P.; Mesa, M.G.; Barbin-Zydlewski, G.

2008-01-01

Diversions from streams are often screened to prevent the loss of or injury to fish. Hydraulic criteria meant to protect fish that encounter screens have been developed, but primarily for screens that are vertical to the water flow rather than horizontal. For this reason, we measured selected hydraulic variables and released wild rainbow trout Oncorhynchus mykiss over two types of horizontal flat-plate fish screens in the field. Our goal was to assess the efficacy of these screens under a variety of conditions in the field and provide information that could be used to develop criteria for safe fish passage. We evaluated three different invertedweir screens over a range of stream (0.24-1.77 m3/s) and diversion flows (0.10-0.31 m3/s). Approach velocities (AVs) ranged from 3 to 8 cm/s and sweeping velocities (SVs) from 69 to 143 cm/s. We also evaluated a simple backwatered screen over stream flows of 0.23-0.79 m3/s and diversion flows of 0.08-0.32 m3/s. The mean SVs for this screen ranged from 15 to 66 cm/s and the mean AVs from 1 to 5 cm/s. The survival rates of fish held for 24 h after passage over these screens exceeded 98%. Overall, the number of fish-screen contacts was low and the injuries related to passage were infrequent and consisted primarily of minor fin injuries. Our results indicate that screens of this type have great potential as safe and effective fish screens for small diversions. Care must be taken, however, to avoid operating conditions that produce shallow or no water over the screen surface, situations of high AVs and low SVs at backwatered screens, and situations producing a localized high AV with spiraling flow. ?? Copyright by the American Fisheries Society 2008.

Comparative evaluation of Populus variants total sugar release and structural features following pretreatment and digestion by two distinct biological systems

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

Thomas, Vanessa A.; Kothari, Ninad; Bhagia, Samarthya

Populus natural variants have been shown to realize a broad range of sugar yields during saccharification, however, the structural features responsible for higher sugar release from natural variants are not clear. In addition, the sugar release patterns resulting from digestion with two distinct biological systems, fungal enzymes and Clostridium thermocellum, have yet to be evaluated and compared. This study evaluates the effect of structural features of three natural variant Populus lines, which includes the line BESC standard, with respect to the overall process of sugar release for two different biological systems.

Comparative evaluation of Populus variants total sugar release and structural features following pretreatment and digestion by two distinct biological systems

DOE PAGES

Thomas, Vanessa A.; Kothari, Ninad; Bhagia, Samarthya; ...

2017-11-30

Populus natural variants have been shown to realize a broad range of sugar yields during saccharification, however, the structural features responsible for higher sugar release from natural variants are not clear. In addition, the sugar release patterns resulting from digestion with two distinct biological systems, fungal enzymes and Clostridium thermocellum, have yet to be evaluated and compared. This study evaluates the effect of structural features of three natural variant Populus lines, which includes the line BESC standard, with respect to the overall process of sugar release for two different biological systems.

Glycolaldehyde in Perseus young solar analogs

NASA Astrophysics Data System (ADS)

De Simone, M.; Codella, C.; Testi, L.; Belloche, A.; Maury, A. J.; Anderl, S.; André, Ph.; Maret, S.; Podio, L.

2017-03-01

Context. The earliest evolutionary stages of low-mass protostars are characterised by the so-called hot-corino stage, when the newly born star heats the surrounding material and enrich the gas chemically. Studying this evolutionary phase of solar protostars may help understand the evolution of prebiotic complex molecules in the development of planetary systems. Aims: In this paper we focus on the occurrence of glycolaldehyde (HCOCH2OH) in young solar analogs by performing the first homogeneous and unbiased study of this molecule in the Class 0 protostars of the nearby Perseus star forming region. Methods: We obtained sub-arcsec angular resolution maps at 1.3 mm and 1.4 mm of glycolaldehyde emission lines using the IRAM Plateau de Bure (PdB) interferometer in the framework of the CALYPSO IRAM large program. Results: Glycolaldehyde has been detected towards 3 Class 0 and 1 Class I protostars out of the 13 continuum sources targeted in Perseus: NGC 1333-IRAS2A1, NGC 1333-IRAS4A2, NGC 1333-IRAS4B1, and SVS13-A. The NGC 1333 star forming region looks particularly glycolaldehyde rich, with a rate of occurrence up to 60%. The glycolaldehyde spatial distribution overlaps with the continuum one, tracing the inner 100 au around the protostar. A large number of lines (up to 18), with upper-level energies Eu from 37 K up to 375 K has been detected. We derived column densities ≥1015 cm-2 and rotational temperatures Trot between 115 K and 236 K, imaging for the first time hot-corinos around NGC 1333-IRAS4B1 and SVS13-A. Conclusions: In multiple systems glycolaldehyde emission is detected only in one component. The case of the SVS13-A+B and IRAS4-A1+A2 systems support that the detection of glycolaldehyde (at least in the present Perseus sample) indicates older protostars (I.e. SVS13-A and IRAS4-A2), evolved enough to develop the hot-corino region (I.e. 100 K in the inner 100 au). However, only two systems do not allow us to firmly conclude whether the primary factor leading to the detection of glycolaldehyde emission is the environments hosting the protostars, evolution (e.g. low value of Lsubmm/Lint), or accretion luminosity (high Lint). Based on observations carried out with the IRAM Plateau de Bure interferometer. IRAM is supported by INSU/CNRS (France), MPG (Germany), and IGN (Spain).Reduced datacube (FITS file) is available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/599/A121

Airport databases for 3D synthetic-vision flight-guidance displays: database design, quality assessment, and data generation

NASA Astrophysics Data System (ADS)

Friedrich, Axel; Raabe, Helmut; Schiefele, Jens; Doerr, Kai Uwe

1999-07-01

In future aircraft cockpit designs SVS (Synthetic Vision System) databases will be used to display 3D physical and virtual information to pilots. In contrast to pure warning systems (TAWS, MSAW, EGPWS) SVS serve to enhance pilot spatial awareness by 3-dimensional perspective views of the objects in the environment. Therefore all kind of aeronautical relevant data has to be integrated into the SVS-database: Navigation- data, terrain-data, obstacles and airport-Data. For the integration of all these data the concept of a GIS (Geographical Information System) based HQDB (High-Quality- Database) has been created at the TUD (Technical University Darmstadt). To enable database certification, quality- assessment procedures according to ICAO Annex 4, 11, 14 and 15 and RTCA DO-200A/EUROCAE ED76 were established in the concept. They can be differentiated in object-related quality- assessment-methods following the keywords accuracy, resolution, timeliness, traceability, assurance-level, completeness, format and GIS-related quality assessment methods with the keywords system-tolerances, logical consistence and visual quality assessment. An airport database is integrated in the concept as part of the High-Quality- Database. The contents of the HQDB are chosen so that they support both Flight-Guidance-SVS and other aeronautical applications like SMGCS (Surface Movement and Guidance Systems) and flight simulation as well. Most airport data are not available. Even though data for runways, threshold, taxilines and parking positions were to be generated by the end of 1997 (ICAO Annex 11 and 15) only a few countries fulfilled these requirements. For that reason methods of creating and certifying airport data have to be found. Remote sensing and digital photogrammetry serve as means to acquire large amounts of airport objects with high spatial resolution and accuracy in much shorter time than with classical surveying methods. Remotely sensed images can be acquired from satellite-platforms or aircraft-platforms. To achieve the highest horizontal accuracy requirements stated in ICAO Annex 14 for runway centerlines (0.50 meters), at the present moment only images acquired from aircraft based sensors can be used as source data. Still, ground reference by GCP (Ground Control-points) is obligatory. A DEM (Digital Elevation Model) can be created automatically in the photogrammetric process. It can be used as highly accurate elevation model for the airport area. The final verification of airport data is accomplished by independent surveyed runway- and taxiway- control-points. The concept of generation airport-data by means of remote sensing and photogrammetry was tested with the Stuttgart/Germany airport. The results proved that the final accuracy was within the accuracy specification defined by ICAO Annex 14.

Intact Protein Analysis at 21 Tesla and X-Ray Crystallography Define Structural Differences in Single Amino Acid Variants of Human Mitochondrial Branched-Chain Amino Acid Aminotransferase 2 (BCAT2)

NASA Astrophysics Data System (ADS)

Anderson, Lissa C.; Håkansson, Maria; Walse, Björn; Nilsson, Carol L.

2017-09-01

Structural technologies are an essential component in the design of precision therapeutics. Precision medicine entails the development of therapeutics directed toward a designated target protein, with the goal to deliver the right drug to the right patient at the right time. In the field of oncology, protein structural variants are often associated with oncogenic potential. In a previous proteogenomic screen of patient-derived glioblastoma (GBM) tumor materials, we identified a sequence variant of human mitochondrial branched-chain amino acid aminotransferase 2 as a putative factor of resistance of GBM to standard-of-care-treatments. The enzyme generates glutamate, which is neurotoxic. To elucidate structural coordinates that may confer altered substrate binding or activity of the variant BCAT2 T186R, a 45 kDa protein, we applied combined ETD and CID top-down mass spectrometry in a LC-FT-ICR MS at 21 T, and X-Ray crystallography in the study of both the variant and non-variant intact proteins. The combined ETD/CID fragmentation pattern allowed for not only extensive sequence coverage but also confident localization of the amino acid variant to its position in the sequence. The crystallographic experiments confirmed the hypothesis generated by in silico structural homology modeling, that the Lys59 side-chain of BCAT2 may repulse the Arg186 in the variant protein (PDB code: 5MPR), leading to destabilization of the protein dimer and altered enzyme kinetics. Taken together, the MS and novel 3D structural data give us reason to further pursue BCAT2 T186R as a precision drug target in GBM. [Figure not available: see fulltext.

Sequencing Structural Variants in Cancer for Precision Therapeutics.

PubMed

Macintyre, Geoff; Ylstra, Bauke; Brenton, James D

2016-09-01

The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of 'actionable' structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Automating the Fireshed Assessment Process with ArcGIS

Treesearch

Alan Ager; Klaus Barber

2006-01-01

A library of macros was developed to automate the Fireshed process within ArcGIS. The macros link a number of vegetation simulation and wildfire behavior models (FVS, SVS, FARSITE, and FlamMap) with ESRI geodatabases, desktop software (Access, Excel), and ArcGIS. The macros provide for (1) an interactive linkage between digital imagery, vegetation data, FVS-FFE, and...

76 FR 26696 - Certain Steel Threaded Rod From the People's Republic of China: Preliminary Results of the First...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-09

... terms of economic development.'' Id. Thus, we find India, the Philippines, Indonesia, Thailand, Ukraine... during the POR, the material terms of sale were established on the invoice date. The Department... Indian import SVs a surrogate freight cost using the shorter of the reported distance from the domestic...

Common genetic variants influence human subcortical brain structures.

PubMed

Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

2015-04-09

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Growth of L1{sub 0}-ordered crystal in FePt and FePd thin films on MgO(001) substrate

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

Futamoto, Masaaki, E-mail: futamoto@elect.chuo-u.ac.jp; Nakamura, Masahiro; Ohtake, Mitsuru

2016-08-15

Formation of L1{sub 0}-oredered structure from disordered A1 phase has been investigated for FePt and FePd films on MgO(001) substrates employing a two-step method consisting of low temperature deposition at 200 °C followed by high-temperature annealing at 600 °C. L1{sub 0}-(001) variant crystal with the c-axis perpendicular to the substrate grows preferentially in FePd films whereas L1{sub 0}-(100), (010) variants tend to be mixed with the L1{sub 0}-(001) variant in FePt films. The structure analysis by X-ray diffraction indicates that a difference in A1 lattice strain is the influential factor that determines the resulting L1{sub 0}-variant structure in ordered thinmore » films. Misfit dislocations and anti-phase boundaries are observed in high-resolution transmission electron micrographs of 10 nm-thick Fe(Pt, Pd) film consisting of L1{sub 0}-(001) variants which are formed through atomic diffusion at 600 °C in a laterally strained FePt/PeFd epitaxial thin film. Based on the experimental results, a nucleation and growth model for explaining L1{sub 0}-variant formation is proposed, which suggests a possibility in tailoring the L1{sub 0} variant structure in ordered magnetic thin films by controlling the alloy composition, the layer structure, and the substrate material.« less

Wild yeast harbor a variety of distinct amyloid structures with strong prion-inducing capabilities

PubMed Central

Westergard, Laura; True, Heather L.

2014-01-01

Summary Variation in amyloid structures profoundly influences a wide array of pathological phenotypes in mammalian protein conformation disorders and dominantly inherited phenotypes in yeast. Here, we describe, for the first time, naturally occurring, self-propagating, structural variants of a prion protein isolated from wild strains of the yeast Saccharomyces cerevisiae. Variants of the [RNQ+] prion propagating in a variety of wild yeast differ biochemically, in their intracellular distributions, and in their ability to promote formation of the [PSI+] prion. [PSI+] is an epigenetic regulator of cellular phenotype and adaptability. Strikingly, we find that most natural [RNQ+] variants induced [PSI+] at high frequencies and the majority of [PSI+] variants elicited strong cellular phenotypes. We hypothesize that the presence of an efficient [RNQ+] template primes the cell for [PSI+] formation in order to induce [PSI+] in conditions where it would be advantageous. These studies utilize naturally occurring structural variants to expand our understanding of the consequences of diverse prion conformations on cellular phenotypes. PMID:24673812

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

PubMed

Carss, Keren J; Arno, Gavin; Erwood, Marie; Stephens, Jonathan; Sanchis-Juan, Alba; Hull, Sarah; Megy, Karyn; Grozeva, Detelina; Dewhurst, Eleanor; Malka, Samantha; Plagnol, Vincent; Penkett, Christopher; Stirrups, Kathleen; Rizzo, Roberta; Wright, Genevieve; Josifova, Dragana; Bitner-Glindzicz, Maria; Scott, Richard H; Clement, Emma; Allen, Louise; Armstrong, Ruth; Brady, Angela F; Carmichael, Jenny; Chitre, Manali; Henderson, Robert H H; Hurst, Jane; MacLaren, Robert E; Murphy, Elaine; Paterson, Joan; Rosser, Elisabeth; Thompson, Dorothy A; Wakeling, Emma; Ouwehand, Willem H; Michaelides, Michel; Moore, Anthony T; Webster, Andrew R; Raymond, F Lucy

2017-01-05

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease. Copyright © 2017. Published by Elsevier Inc.

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

PubMed

Smith, Douglas R; Stanley, Christine M; Foss, Theodore; Boles, Richard G; McKernan, Kevin

2017-01-01

Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

G-CNV: A GPU-Based Tool for Preparing Data to Detect CNVs with Read-Depth Methods.

PubMed

Manconi, Andrea; Manca, Emanuele; Moscatelli, Marco; Gnocchi, Matteo; Orro, Alessandro; Armano, Giuliano; Milanesi, Luciano

2015-01-01

Copy number variations (CNVs) are the most prevalent types of structural variations (SVs) in the human genome and are involved in a wide range of common human diseases. Different computational methods have been devised to detect this type of SVs and to study how they are implicated in human diseases. Recently, computational methods based on high-throughput sequencing (HTS) are increasingly used. The majority of these methods focus on mapping short-read sequences generated from a donor against a reference genome to detect signatures distinctive of CNVs. In particular, read-depth based methods detect CNVs by analyzing genomic regions with significantly different read-depth from the other ones. The pipeline analysis of these methods consists of four main stages: (i) data preparation, (ii) data normalization, (iii) CNV regions identification, and (iv) copy number estimation. However, available tools do not support most of the operations required at the first two stages of this pipeline. Typically, they start the analysis by building the read-depth signal from pre-processed alignments. Therefore, third-party tools must be used to perform most of the preliminary operations required to build the read-depth signal. These data-intensive operations can be efficiently parallelized on graphics processing units (GPUs). In this article, we present G-CNV, a GPU-based tool devised to perform the common operations required at the first two stages of the analysis pipeline. G-CNV is able to filter low-quality read sequences, to mask low-quality nucleotides, to remove adapter sequences, to remove duplicated read sequences, to map the short-reads, to resolve multiple mapping ambiguities, to build the read-depth signal, and to normalize it. G-CNV can be efficiently used as a third-party tool able to prepare data for the subsequent read-depth signal generation and analysis. Moreover, it can also be integrated in CNV detection tools to generate read-depth signals.

CFIT Prevention Using Synthetic Vision

NASA Technical Reports Server (NTRS)

Arthur, Jarvis J., III; Prinzel, Lawrence J., III; Kramer, Lynda J.; Bailey, Randall E.; Parrish, Russell V.

2003-01-01

In commercial aviation, over 30-percent of all fatal accidents worldwide are categorized as Controlled Flight Into Terrain (CFIT) accidents where a fully functioning airplane is inadvertently flown into the ground, water, or an obstacle. An experiment was conducted at NASA Langley Research Center investigating the presentation of a synthetic terrain database scene to the pilot on a Primary Flight Display (PFD). The major hypothesis for the experiment is that a synthetic vision system (SVS) will improve the pilot s ability to detect and avoid a potential CFIT compared to conventional flight instrumentation. All display conditions, including the baseline, contained a Terrain Awareness and Warning System (TAWS) and Vertical Situation Display (VSD) enhanced Navigation Display (ND). Sixteen pilots each flew 22 approach - departure maneuvers in Instrument Meteorological Conditions (IMC) to the terrain challenged Eagle County Regional Airport (EGE) in Colorado. For the final run, the flight guidance cues were altered such that the departure path went into the terrain. All pilots with a SVS enhanced PFD (12 of 16 pilots) noticed and avoided the potential CFIT situation. All of the pilots who flew the anomaly with the baseline display configuration (which included a TAWS and VSD enhanced ND) had a CFIT event.

Ecological risk assessment of agricultural soils for the definition of soil screening values: A comparison between substance-based and matrix-based approaches.

PubMed

Pivato, Alberto; Lavagnolo, Maria Cristina; Manachini, Barbara; Vanin, Stefano; Raga, Roberto; Beggio, Giovanni

2017-04-01

The Italian legislation on contaminated soils does not include the Ecological Risk Assessment (ERA) and this deficiency has important consequences for the sustainable management of agricultural soils. The present research compares the results of two ERA procedures applied to agriculture (i) one based on the "substance-based" approach and (ii) a second based on the "matrix-based" approach. In the former the soil screening values (SVs) for individual substances were derived according to institutional foreign guidelines. In the latter, the SVs characterizing the whole-matrix were derived originally by the authors by means of experimental activity. The results indicate that the "matrix-based" approach can be efficiently implemented in the Italian legislation for the ERA of agricultural soils. This method, if compared to the institutionalized "substance based" approach is (i) comparable in economic terms and in testing time, (ii) is site specific and assesses the real effect of the investigated soil on a battery of bioassays, (iii) accounts for phenomena that may radically modify the exposure of the organisms to the totality of contaminants and (iv) can be considered sufficiently conservative.

Using X-band Weather Radar Measurements to Monitor the Integrity of Digital Elevation Models for Synthetic Vision Systems

NASA Technical Reports Server (NTRS)

Young, Steve; UijtdeHaag, Maarten; Sayre, Jonathon

2003-01-01

Synthetic Vision Systems (SVS) provide pilots with displays of stored geo-spatial data representing terrain, obstacles, and cultural features. As comprehensive validation is impractical, these databases typically have no quantifiable level of integrity. Further, updates to the databases may not be provided as changes occur. These issues limit the certification level and constrain the operational context of SVS for civil aviation. Previous work demonstrated the feasibility of using a realtime monitor to bound the integrity of Digital Elevation Models (DEMs) by using radar altimeter measurements during flight. This paper describes an extension of this concept to include X-band Weather Radar (WxR) measurements. This enables the monitor to detect additional classes of DEM errors and to reduce the exposure time associated with integrity threats. Feature extraction techniques are used along with a statistical assessment of similarity measures between the sensed and stored features that are detected. Recent flight-testing in the area around the Juneau, Alaska Airport (JNU) has resulted in a comprehensive set of sensor data that is being used to assess the feasibility of the proposed monitor technology. Initial results of this assessment are presented.

Cargo crowding at actin-rich regions along axons causes local traffic jams.

PubMed

Sood, Parul; Murthy, Kausalya; Kumar, Vinod; Nonet, Michael L; Menon, Gautam I; Koushika, Sandhya P

2018-03-01

Steady axonal cargo flow is central to the functioning of healthy neurons. However, a substantial fraction of cargo in axons remains stationary up to several minutes. We examine the transport of precursors of synaptic vesicles (pre-SVs), endosomes and mitochondria in Caenorhabditis elegans touch receptor neurons, showing that stationary cargo are predominantly present at actin-rich regions along the neuronal process. Stationary vesicles at actin-rich regions increase the propensity of moving vesicles to stall at the same location, resulting in traffic jams arising from physical crowding. Such local traffic jams at actin-rich regions are likely to be a general feature of axonal transport since they also occur in Drosophila neurons. Repeated touch stimulation of C. elegans reduces the density of stationary pre-SVs, indicating that these traffic jams can act as both sources and sinks of vesicles. This suggests that vesicles trapped in actin-rich regions are functional reservoirs that may contribute to maintaining robust cargo flow in the neuron. A video abstract of this article can be found at: Video S1; Video S2. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Peptide mediated intracellular delivery of semiconductor quantum dots

NASA Astrophysics Data System (ADS)

Kapur, Anshika; Safi, Malak; Domitrovic, Tatiana; Medina, Scott; Palui, Goutam; Johnson, John E.; Schneider, Joel; Mattoussi, Hedi

2017-02-01

As control over the growth, stabilization and functionalization of inorganic nanoparticles continue to advance, interest in integrating these materials with biological systems has steadily grown in the past decade. Much attention has been directed towards identifying effective approaches to promote cytosolic internalization of the nanoparticles while avoiding endocytosis. We describe the use of NωV virus derived gamma peptide and a chemically synthesized anticancer peptide, SVS-1 peptide, as vehicles to promote the non-endocytic uptake of luminescent quantum dots (QDs) inside live cells. The gamma peptide is expressed in E. coli as a fusion protein with poly-his tagged MBP (His-MBP-γ) to allow self-assembly onto QDs via metal-histidine conjugation. Conversely, the N-terminal cysteine residue of the SVS-1 peptide is attached to the functionalized QDs via covalent coupling chemistry. Epi-fluorescence microscopy images show that the QD-conjugate staining is distributed throughout the cytoplasm of cell cultures. Additionally, the QD staining does not show co-localization with transferrin-dye-labelled endosomes or DAPI stained nuclei. The QD uptake observed in the presence of physical and pharmacological endocytosis inhibitors further suggest that a physical translocation of QDs through the cell membrane is the driving mechanism for the uptake.

Child sexual abuse: an Italian perspective.

PubMed

Cattaneo, Cristina; Ruspa, Marina; Motta, Tiziano; Gentilomo, Andrea; Scagnelli, Chiara

2007-06-01

The problem of child sexual abuse is a growing reality in Italy. The experience of over 200 children seen by the SVS (Soccorso Violenza Sessuale) Centre in Milan (the first Italian large-scale study) may give more information on the European situation. This study is a retrospective study based on information contained in the files of children beneath the age of 14 seen at the SVS Centre between May 1996 and May 2003, who arrived with a suspicion of child sexual abuse. Over 80% of all cases fell within the normal-aspecific category according to Adams' 2001 classification. This first Italian survey, though not based on substantiated cases but only on cases of suspected sexual abuse, supplies a perspective on a large northern European city such as Milan. Data seem similar to those published in other non-European studies, particularly as regards clinical signs observed. Thus, the results of this study, with all their limitations, start to give a perspective on the frequency and type of child population reaching this Italian center, what the scenarios are, what signs the children present and how infrequent it is to find clinical anogenital signs concerning for sexual abuse.

Augmented brain function by coordinated reset stimulation with slowly varying sequences.

PubMed

Zeitler, Magteld; Tass, Peter A

2015-01-01

Several brain disorders are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was developed to selectively counteract abnormal neuronal synchrony by desynchronization. For this, phase resetting stimuli are delivered to different subpopulations in a timely coordinated way. In neural networks with spike timing-dependent plasticity CR stimulation may eventually lead to an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and abnormal synchrony. The spatiotemporal sequence by which all stimulation sites are stimulated exactly once is called the stimulation site sequence, or briefly sequence. So far, in simulations, pre-clinical and clinical applications CR was applied either with fixed sequences or rapidly varying sequences (RVS). In this computational study we show that appropriate repetition of the sequence with occasional random switching to the next sequence may significantly improve the anti-kindling effect of CR. To this end, a sequence is applied many times before randomly switching to the next sequence. This new method is called SVS CR stimulation, i.e., CR with slowly varying sequences. In a neuronal network with strong short-range excitatory and weak long-range inhibitory dynamic couplings SVS CR stimulation turns out to be superior to CR stimulation with fixed sequences or RVS.

Augmented brain function by coordinated reset stimulation with slowly varying sequences

PubMed Central

Zeitler, Magteld; Tass, Peter A.

2015-01-01

Several brain disorders are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was developed to selectively counteract abnormal neuronal synchrony by desynchronization. For this, phase resetting stimuli are delivered to different subpopulations in a timely coordinated way. In neural networks with spike timing-dependent plasticity CR stimulation may eventually lead to an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and abnormal synchrony. The spatiotemporal sequence by which all stimulation sites are stimulated exactly once is called the stimulation site sequence, or briefly sequence. So far, in simulations, pre-clinical and clinical applications CR was applied either with fixed sequences or rapidly varying sequences (RVS). In this computational study we show that appropriate repetition of the sequence with occasional random switching to the next sequence may significantly improve the anti-kindling effect of CR. To this end, a sequence is applied many times before randomly switching to the next sequence. This new method is called SVS CR stimulation, i.e., CR with slowly varying sequences. In a neuronal network with strong short-range excitatory and weak long-range inhibitory dynamic couplings SVS CR stimulation turns out to be superior to CR stimulation with fixed sequences or RVS. PMID:25873867

Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting

PubMed Central

Di Giovanni, Jerome; Sheng, Zu-Hang

2015-01-01

Recycling synaptic vesicles (SVs) transit through early endosomal sorting stations, which raises a fundamental question: are SVs sorted toward endolysosomal pathways? Here, we used snapin mutants as tools to assess how endolysosomal sorting and trafficking impact presynaptic activity in wild-type and snapin−/− neurons. Snapin acts as a dynein adaptor that mediates the retrograde transport of late endosomes (LEs) and interacts with dysbindin, a subunit of the endosomal sorting complex BLOC-1. Expressing dynein-binding defective snapin mutants induced SV accumulation at presynaptic terminals, mimicking the snapin−/− phenotype. Conversely, over-expressing snapin reduced SV pool size by enhancing SV trafficking to the endolysosomal pathway. Using a SV-targeted Ca2+ sensor, we demonstrate that snapin–dysbindin interaction regulates SV positional priming through BLOC-1/AP-3-dependent sorting. Our study reveals a bipartite regulation of presynaptic activity by endolysosomal trafficking and sorting: LE transport regulates SV pool size, and BLOC-1/AP-3-dependent sorting fine-tunes the Ca2+ sensitivity of SV release. Therefore, our study provides new mechanistic insights into the maintenance and regulation of SV pool size and synchronized SV fusion through snapin-mediated LE trafficking and endosomal sorting. PMID:26108535

Novel polymorphisms of the APOA2 gene and its promoter region affect body traits in cattle.

PubMed

Zhou, Yang; Li, Caixia; Cai, Hanfang; Xu, Yao; Lan, Xianyong; Lei, Chuzhao; Chen, Hong

2013-12-01

Apolipoprotein A-II (APOA2) is one of the major constituents of high-density lipoprotein and plays a critical role in lipid metabolism and obesity. However, similar research for the bovine APOA2 gene is lacking. In this study, polymorphisms of the bovine APOA2 gene and its promoter region were detected in 1021 cows from four breeds by sequencing and PCR-RFLP methods. Totally, we detected six novel mutations which included one mutation in the promoter region, two mutations in the exons and three mutations in the introns. There were four polymorphisms within APOA2 gene were analyzed. The allele A, T, T and G frequencies of the four loci were predominant in the four breeds when in separate or combinations analysis which suggested cows with those alleles to be more adapted to the steppe environment. The association analysis indicated three SVs in Nangyang cows, two SVs in Qinchun cows and the 9 haplotypes in Nangyang cows were significantly associated with body traits (P<0.05 or P<0.01). The results of this study suggested the bovine APOA2 gene may be a strong candidate gene for body traits in the cattle breeding program. © 2013.

STS-52 deployment of LAGEOS / IRIS spacecraft from OV-102's payload bay (PLB)

NASA Technical Reports Server (NTRS)

1992-01-01

During STS-52 deployment activities, the Italian Research Interim Stage (IRIS), a spinning solid fuel rocket, lifts the Laser Geodynamic Satellite II (LAGEOS II) out of its support cradle and above the thermal shield aboard Columbia, Orbiter Vehicle (OV) 102. The remote manipulator system (RMS) arm, with Material Exposure in Low Earth Orbit (MELEO), is positioned above the port side sill longeron. On the mission-peculiar equipment support structure (MPESS) carriers in the center foreground is the United States (U.S.) Microgravity Payload 1 (USMP-1) with Space Acceleration Measurement System (SAMS), MEPHISTO (its French abbreviation), Lambda Point Experiment (LPE) cryostat assembly (identified by JPL insignia), and LPE vacuum maintenance assembly. Other payload bay (PLB) experiments visible in this image include: (on the starboard wall (left)) the Canadian Experiments 2 (CANEX-2) Space Vision System (SVS) Canadian Target Assembly (CTA) (foreground) and the Attitude Sensor Package (ASP);

CNNdel: Calling Structural Variations on Low Coverage Data Based on Convolutional Neural Networks

PubMed Central

2017-01-01

Many structural variations (SVs) detection methods have been proposed due to the popularization of next-generation sequencing (NGS). These SV calling methods use different SV-property-dependent features; however, they all suffer from poor accuracy when running on low coverage sequences. The union of results from these tools achieves fairly high sensitivity but still produces low accuracy on low coverage sequence data. That is, these methods contain many false positives. In this paper, we present CNNdel, an approach for calling deletions from paired-end reads. CNNdel gathers SV candidates reported by multiple tools and then extracts features from aligned BAM files at the positions of candidates. With labeled feature-expressed candidates as a training set, CNNdel trains convolutional neural networks (CNNs) to distinguish true unlabeled candidates from false ones. Results show that CNNdel works well with NGS reads from 26 low coverage genomes of the 1000 Genomes Project. The paper demonstrates that convolutional neural networks can automatically assign the priority of SV features and reduce the false positives efficaciously. PMID:28630866

Common genetic variants influence human subcortical brain structures

PubMed Central

Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

2015-01-01

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

Dynamic response analysis of structure under time-variant interval process model

NASA Astrophysics Data System (ADS)

Xia, Baizhan; Qin, Yuan; Yu, Dejie; Jiang, Chao

2016-10-01

Due to the aggressiveness of the environmental factor, the variation of the dynamic load, the degeneration of the material property and the wear of the machine surface, parameters related with the structure are distinctly time-variant. Typical model for time-variant uncertainties is the random process model which is constructed on the basis of a large number of samples. In this work, we propose a time-variant interval process model which can be effectively used to deal with time-variant uncertainties with limit information. And then two methods are presented for the dynamic response analysis of the structure under the time-variant interval process model. The first one is the direct Monte Carlo method (DMCM) whose computational burden is relative high. The second one is the Monte Carlo method based on the Chebyshev polynomial expansion (MCM-CPE) whose computational efficiency is high. In MCM-CPE, the dynamic response of the structure is approximated by the Chebyshev polynomials which can be efficiently calculated, and then the variational range of the dynamic response is estimated according to the samples yielded by the Monte Carlo method. To solve the dependency phenomenon of the interval operation, the affine arithmetic is integrated into the Chebyshev polynomial expansion. The computational effectiveness and efficiency of MCM-CPE is verified by two numerical examples, including a spring-mass-damper system and a shell structure.

Pre- and Post-Conditions Expressed in Variants of the Modal µ-Calculus

NASA Astrophysics Data System (ADS)

Tanabe, Yoshinori; Sekizawa, Toshifusa; Yuasa, Yoshifumi; Takahashi, Koichi

Properties of Kripke structures can be expressed by formulas of the modal µ-calculus. Despite its strong expressive power, the validity problem of the modal µ-calculus is decidable, and so are some of its variants enriched by inverse programs, graded modalities, and nominals. In this study, we show that the pre- and post-conditions of transformations of Kripke structures, such as addition/deletion of states and edges, can be expressed using variants of the modal µ-calculus. Combined with decision procedures we have developed for those variants, the properties of sequences of transformations on Kripke structures can be deduced. We show that these techniques can be used to verify the properties of pointer-manipulating programs.

Three New Alpha1-Antitrypsin Deficiency Variants Help to Define a C-Terminal Region Regulating Conformational Change and Polymerization

PubMed Central

Fra, Anna M.; Gooptu, Bibek; Ferrarotti, Ilaria; Miranda, Elena; Scabini, Roberta; Ronzoni, Riccardo; Benini, Federica; Corda, Luciano; Medicina, Daniela; Luisetti, Maurizio; Schiaffonati, Luisa

2012-01-01

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state. PMID:22723858

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

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

Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.

Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s riskmore » variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.« less

Molecular dynamics simulations revealed structural differences among WRKY domain-DNA interaction in barley (Hordeum vulgare).

PubMed

Pandey, Bharati; Grover, Abhinav; Sharma, Pradeep

2018-02-12

The WRKY transcription factors are a class of DNA-binding proteins involved in diverse plant processes play critical roles in response to abiotic and biotic stresses. Genome-wide divergence analysis of WRKY gene family in Hordeum vulgare provided a framework for molecular evolution and functional roles. So far, the crystal structure of WRKY from barley has not been resolved; moreover, knowledge of the three-dimensional structure of WRKY domain is pre-requisites for exploring the protein-DNA recognition mechanisms. Homology modelling based approach was used to generate structures for WRKY DNA binding domain (DBD) and its variants using AtWRKY1 as a template. Finally, the stability and conformational changes of the generated model in unbound and bound form was examined through atomistic molecular dynamics (MD) simulations for 100 ns time period. In this study, we investigated the comparative binding pattern of WRKY domain and its variants with W-box cis-regulatory element using molecular docking and dynamics (MD) simulations assays. The atomic insight into WRKY domain exhibited significant variation in the intermolecular hydrogen bonding pattern, leading to the structural anomalies in the variant type and differences in the DNA-binding specificities. Based on the MD analysis, residual contribution and interaction contour, wild-type WRKY (HvWRKY46) were found to interact with DNA through highly conserved heptapeptide in the pre- and post-MD simulated complexes, whereas heptapeptide interaction with DNA was missing in variants (I and II) in post-MD complexes. Consequently, through principal component analysis, wild-type WRKY was also found to be more stable by obscuring a reduced conformational space than the variant I (HvWRKY34). Lastly, high binding free energy for wild-type and variant II allowed us to conclude that wild-type WRKY-DNA complex was more stable relative to variants I. The results of our study revealed complete dynamic and structural information about WRKY domain-DNA interactions. However, no structure base information reported to date for WRKY variants and their mechanism of interaction with DNA. Our findings highlighted the importance of selecting a sequence to generate newer transgenic plants that would be increasingly tolerance to stress conditions.

Do Structural Missense Variants in the ATM Gene Found in Women With Breast Cancer Cause Breast Cancer in Knock-in Mouse Strains?

DTIC Science & Technology

2006-04-01

W81XWH-05-1-0282 TITLE: Do Structural Missense Variants in the ATM Gene Found in Women with Breast Cancer Cause Breast Cancer in "Knock-in...5a. CONTRACT NUMBER Do Structural Missense Variants in the ATM Gene Found in Women with Breast Cancer Cause Breast Cancer in "Knock-in" Mouse...human cohort-specific missense mutations will develop breast cancer with dominant inheritance in a subset of animals. It also is hypothesized that

Read count-based method for high-throughput allelic genotyping of transposable elements and structural variants.

PubMed

Kuhn, Alexandre; Ong, Yao Min; Quake, Stephen R; Burkholder, William F

2015-07-08

Like other structural variants, transposable element insertions can be highly polymorphic across individuals. Their functional impact, however, remains poorly understood. Current genome-wide approaches for genotyping insertion-site polymorphisms based on targeted or whole-genome sequencing remain very expensive and can lack accuracy, hence new large-scale genotyping methods are needed. We describe a high-throughput method for genotyping transposable element insertions and other types of structural variants that can be assayed by breakpoint PCR. The method relies on next-generation sequencing of multiplex, site-specific PCR amplification products and read count-based genotype calls. We show that this method is flexible, efficient (it does not require rounds of optimization), cost-effective and highly accurate. This method can benefit a wide range of applications from the routine genotyping of animal and plant populations to the functional study of structural variants in humans.

Sustainability and durability analysis of reinforced concrete structures

NASA Astrophysics Data System (ADS)

Horáková, A.; Broukalová, I.; Kohoutková, A.; Vašková, J.

2017-09-01

The article describes an assessment of reinforced concrete structures in terms of durability and sustainable development. There is a short summary of findings from the literature on evaluation methods for environmental impacts and also about corrosive influences acting on the reinforced concrete structure, about factors influencing the durability of these structures and mathematical models describing the corrosion impacts. Variant design of reinforced concrete structure and assessment of these variants in terms of durability and sustainability was performed. The analysed structure was a concrete ceiling structure of a parking house for cars. The variants differ in strength class of concrete and thickness of concrete slab. It was found that in terms of durability and sustainable development it is significantly preferable to use higher class of concrete. There are significant differences in results of concrete structures durability for different mathematical models of corrosive influences.

Methodological Choices in Muscle Synergy Analysis Impact Differentiation of Physiological Characteristics Following Stroke

PubMed Central

Banks, Caitlin L.; Pai, Mihir M.; McGuirk, Theresa E.; Fregly, Benjamin J.; Patten, Carolynn

2017-01-01

Muscle synergy analysis (MSA) is a mathematical technique that reduces the dimensionality of electromyographic (EMG) data. Used increasingly in biomechanics research, MSA requires methodological choices at each stage of the analysis. Differences in methodological steps affect the overall outcome, making it difficult to compare results across studies. We applied MSA to EMG data collected from individuals post-stroke identified as either responders (RES) or non-responders (nRES) on the basis of a critical post-treatment increase in walking speed. Importantly, no clinical or functional indicators identified differences between the cohort of RES and nRES at baseline. For this exploratory study, we selected the five highest RES and five lowest nRES available from a larger sample. Our goal was to assess how the methodological choices made before, during, and after MSA affect the ability to differentiate two groups with intrinsic physiologic differences based on MSA results. We investigated 30 variations in MSA methodology to determine which choices allowed differentiation of RES from nRES at baseline. Trial-to-trial variability in time-independent synergy vectors (SVs) and time-varying neural commands (NCs) were measured as a function of: (1) number of synergies computed; (2) EMG normalization method before MSA; (3) whether SVs were held constant across trials or allowed to vary during MSA; and (4) synergy analysis output normalization method after MSA. MSA methodology had a strong effect on our ability to differentiate RES from nRES at baseline. Across all 10 individuals and MSA variations, two synergies were needed to reach an average of 90% variance accounted for (VAF). Based on effect sizes, differences in SV and NC variability between groups were greatest using two synergies with SVs that varied from trial-to-trial. Differences in SV variability were clearest using unit magnitude per trial EMG normalization, while NC variability was less sensitive to EMG normalization method. No outcomes were greatly impacted by output normalization method. MSA variability for some, but not all, methods successfully differentiated intrinsic physiological differences inaccessible to traditional clinical or biomechanical assessments. Our results were sensitive to methodological choices, highlighting the need for disclosure of all aspects of MSA methodology in future studies. PMID:28912707

Methodological Choices in Muscle Synergy Analysis Impact Differentiation of Physiological Characteristics Following Stroke.

PubMed

Banks, Caitlin L; Pai, Mihir M; McGuirk, Theresa E; Fregly, Benjamin J; Patten, Carolynn

2017-01-01

Muscle synergy analysis (MSA) is a mathematical technique that reduces the dimensionality of electromyographic (EMG) data. Used increasingly in biomechanics research, MSA requires methodological choices at each stage of the analysis. Differences in methodological steps affect the overall outcome, making it difficult to compare results across studies. We applied MSA to EMG data collected from individuals post-stroke identified as either responders (RES) or non-responders (nRES) on the basis of a critical post-treatment increase in walking speed. Importantly, no clinical or functional indicators identified differences between the cohort of RES and nRES at baseline. For this exploratory study, we selected the five highest RES and five lowest nRES available from a larger sample. Our goal was to assess how the methodological choices made before, during, and after MSA affect the ability to differentiate two groups with intrinsic physiologic differences based on MSA results. We investigated 30 variations in MSA methodology to determine which choices allowed differentiation of RES from nRES at baseline. Trial-to-trial variability in time-independent synergy vectors (SVs) and time-varying neural commands (NCs) were measured as a function of: (1) number of synergies computed; (2) EMG normalization method before MSA; (3) whether SVs were held constant across trials or allowed to vary during MSA; and (4) synergy analysis output normalization method after MSA. MSA methodology had a strong effect on our ability to differentiate RES from nRES at baseline. Across all 10 individuals and MSA variations, two synergies were needed to reach an average of 90% variance accounted for (VAF). Based on effect sizes, differences in SV and NC variability between groups were greatest using two synergies with SVs that varied from trial-to-trial. Differences in SV variability were clearest using unit magnitude per trial EMG normalization, while NC variability was less sensitive to EMG normalization method. No outcomes were greatly impacted by output normalization method. MSA variability for some, but not all, methods successfully differentiated intrinsic physiological differences inaccessible to traditional clinical or biomechanical assessments. Our results were sensitive to methodological choices, highlighting the need for disclosure of all aspects of MSA methodology in future studies.

Spatial distributions of Pseudomonas fluorescens colony variants in mixed-culture biofilms.

PubMed

Workentine, Matthew L; Wang, Siyuan; Ceri, Howard; Turner, Raymond J

2013-07-28

The emergence of colony morphology variants in structured environments is being recognized as important to both niche specialization and stress tolerance. Pseudomonas fluorescens demonstrates diversity in both its natural environment, the rhizosphere, and in laboratory grown biofilms. Sub-populations of these variants within a biofilm have been suggested as important contributors to antimicrobial stress tolerance given their altered susceptibility to various agents. As such it is of interest to determine how these variants might be distributed in the biofilm environment. Here we present an analysis of the spatial distribution of Pseudomonas fluorescens colony morphology variants in mixed-culture biofilms with the wildtype phenotype. These findings reveal that two variant colony morphotypes demonstrate a significant growth advantage over the wildtype morphotype in the biofilm environment. The two variant morphotypes out-grew the wildtype across the entire biofilm and this occurred within 24 h and was maintained through to 96 h. This competitive advantage was not observed in homogeneous broth culture. The significant advantage that the variants demonstrate in biofilm colonization over the wildtype denotes the importance of this phenotype in structured environments.

Population Structure of Two Rabies Hosts Relative to the Known Distribution of Rabies Virus Variants in Alaska

PubMed Central

Goldsmith, Elizabeth W.; Renshaw, Benjamin; Clement, Christopher J.; Himschoot, Elizabeth A.; Hundertmark, Kris J.; Hueffer, Karsten

2015-01-01

For pathogens that infect multiple species the distinction between reservoir hosts and spillover hosts is often difficult. In Alaska, three variants of the arctic rabies virus exist with distinct spatial distributions. We test the hypothesis that rabies virus variant distribution corresponds to the population structure of the primary rabies hosts in Alaska, arctic foxes (Vulpes lagopus) and red foxes (V. vulpes) in order to possibly distinguish reservoir and spill over hosts. We used mitochondrial DNA (mtDNA) sequence and nine microsatellites to assess population structure in those two species. mtDNA structure did not correspond to rabies virus variant structure in either species. Microsatellite analyses gave varying results. Bayesian clustering found 2 groups of arctic foxes in the coastal tundra region, but for red foxes it identified tundra and boreal types. Spatial Bayesian clustering and spatial principal components analysis identified 3 and 4 groups of arctic foxes, respectively, closely matching the distribution of rabies virus variants in the state. Red foxes, conversely, showed eight clusters comprising 2 regions (boreal and tundra) with much admixture. These results run contrary to previous beliefs that arctic fox show no fine-scale spatial population structure. While we cannot rule out that the red fox is part of the maintenance host community for rabies in Alaska, the distribution of virus variants appears to be driven primarily by the artic fox Therefore we show that host population genetics can be utilized to distinguish between maintenance and spillover hosts when used in conjunction with other approaches. PMID:26661691

Structure-based design of combinatorial mutagenesis libraries

PubMed Central

Verma, Deeptak; Grigoryan, Gevorg; Bailey-Kellogg, Chris

2015-01-01

The development of protein variants with improved properties (thermostability, binding affinity, catalytic activity, etc.) has greatly benefited from the application of high-throughput screens evaluating large, diverse combinatorial libraries. At the same time, since only a very limited portion of sequence space can be experimentally constructed and tested, an attractive possibility is to use computational protein design to focus libraries on a productive portion of the space. We present a general-purpose method, called “Structure-based Optimization of Combinatorial Mutagenesis” (SOCoM), which can optimize arbitrarily large combinatorial mutagenesis libraries directly based on structural energies of their constituents. SOCoM chooses both positions and substitutions, employing a combinatorial optimization framework based on library-averaged energy potentials in order to avoid explicitly modeling every variant in every possible library. In case study applications to green fluorescent protein, β-lactamase, and lipase A, SOCoM optimizes relatively small, focused libraries whose variants achieve energies comparable to or better than previous library design efforts, as well as larger libraries (previously not designable by structure-based methods) whose variants cover greater diversity while still maintaining substantially better energies than would be achieved by representative random library approaches. By allowing the creation of large-scale combinatorial libraries based on structural calculations, SOCoM promises to increase the scope of applicability of computational protein design and improve the hit rate of discovering beneficial variants. While designs presented here focus on variant stability (predicted by total energy), SOCoM can readily incorporate other structure-based assessments, such as the energy gap between alternative conformational or bound states. PMID:25611189

Structure-based design of combinatorial mutagenesis libraries.

PubMed

Verma, Deeptak; Grigoryan, Gevorg; Bailey-Kellogg, Chris

2015-05-01

The development of protein variants with improved properties (thermostability, binding affinity, catalytic activity, etc.) has greatly benefited from the application of high-throughput screens evaluating large, diverse combinatorial libraries. At the same time, since only a very limited portion of sequence space can be experimentally constructed and tested, an attractive possibility is to use computational protein design to focus libraries on a productive portion of the space. We present a general-purpose method, called "Structure-based Optimization of Combinatorial Mutagenesis" (SOCoM), which can optimize arbitrarily large combinatorial mutagenesis libraries directly based on structural energies of their constituents. SOCoM chooses both positions and substitutions, employing a combinatorial optimization framework based on library-averaged energy potentials in order to avoid explicitly modeling every variant in every possible library. In case study applications to green fluorescent protein, β-lactamase, and lipase A, SOCoM optimizes relatively small, focused libraries whose variants achieve energies comparable to or better than previous library design efforts, as well as larger libraries (previously not designable by structure-based methods) whose variants cover greater diversity while still maintaining substantially better energies than would be achieved by representative random library approaches. By allowing the creation of large-scale combinatorial libraries based on structural calculations, SOCoM promises to increase the scope of applicability of computational protein design and improve the hit rate of discovering beneficial variants. While designs presented here focus on variant stability (predicted by total energy), SOCoM can readily incorporate other structure-based assessments, such as the energy gap between alternative conformational or bound states. © 2015 The Protein Society.

Population structure of two rabies hosts relative to the known distribution of rabies virus variants in Alaska.

PubMed

Goldsmith, Elizabeth W; Renshaw, Benjamin; Clement, Christopher J; Himschoot, Elizabeth A; Hundertmark, Kris J; Hueffer, Karsten

2016-02-01

For pathogens that infect multiple species, the distinction between reservoir hosts and spillover hosts is often difficult. In Alaska, three variants of the arctic rabies virus exist with distinct spatial distributions. We tested the hypothesis that rabies virus variant distribution corresponds to the population structure of the primary rabies hosts in Alaska, arctic foxes (Vulpes lagopus) and red foxes (Vulpes vulpes) to possibly distinguish reservoir and spillover hosts. We used mitochondrial DNA (mtDNA) sequence and nine microsatellites to assess population structure in those two species. mtDNA structure did not correspond to rabies virus variant structure in either species. Microsatellite analyses gave varying results. Bayesian clustering found two groups of arctic foxes in the coastal tundra region, but for red foxes it identified tundra and boreal types. Spatial Bayesian clustering and spatial principal components analysis identified 3 and 4 groups of arctic foxes, respectively, closely matching the distribution of rabies virus variants in the state. Red foxes, conversely, showed eight clusters comprising two regions (boreal and tundra) with much admixture. These results run contrary to previous beliefs that arctic fox show no fine-scale spatial population structure. While we cannot rule out that the red fox is part of the maintenance host community for rabies in Alaska, the distribution of virus variants appears to be driven primarily by the arctic fox. Therefore, we show that host population genetics can be utilized to distinguish between maintenance and spillover hosts when used in conjunction with other approaches. © 2015 John Wiley & Sons Ltd.

The Loss and Gain of Functional Amino Acid Residues Is a Common Mechanism Causing Human Inherited Disease

PubMed Central

Lugo-Martinez, Jose; Pejaver, Vikas; Pagel, Kymberleigh A.; Mort, Matthew; Cooper, David N.; Mooney, Sean D.; Radivojac, Predrag

2016-01-01

Elucidating the precise molecular events altered by disease-causing genetic variants represents a major challenge in translational bioinformatics. To this end, many studies have investigated the structural and functional impact of amino acid substitutions. Most of these studies were however limited in scope to either individual molecular functions or were concerned with functional effects (e.g. deleterious vs. neutral) without specifically considering possible molecular alterations. The recent growth of structural, molecular and genetic data presents an opportunity for more comprehensive studies to consider the structural environment of a residue of interest, to hypothesize specific molecular effects of sequence variants and to statistically associate these effects with genetic disease. In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional attribute potentially underlying pathogenic molecular alterations. We first propose a formal model to assess probabilistically function-impacting variants. We then develop an array of structure-based functional residue predictors, evaluate their performance, and use them to quantify the impact of disease-causing amino acid substitutions on catalytic activity, metal binding, macromolecular binding, ligand binding, allosteric regulation and post-translational modifications. We show that our methodology generates actionable biological hypotheses for up to 41% of disease-causing genetic variants mapped to protein structures suggesting that it can be reliably used to guide experimental validation. Our results suggest that a significant fraction of disease-causing human variants mapping to protein structures are function-altering both in the presence and absence of stability disruption. PMID:27564311

The Loss and Gain of Functional Amino Acid Residues Is a Common Mechanism Causing Human Inherited Disease.

PubMed

Lugo-Martinez, Jose; Pejaver, Vikas; Pagel, Kymberleigh A; Jain, Shantanu; Mort, Matthew; Cooper, David N; Mooney, Sean D; Radivojac, Predrag

2016-08-01

Elucidating the precise molecular events altered by disease-causing genetic variants represents a major challenge in translational bioinformatics. To this end, many studies have investigated the structural and functional impact of amino acid substitutions. Most of these studies were however limited in scope to either individual molecular functions or were concerned with functional effects (e.g. deleterious vs. neutral) without specifically considering possible molecular alterations. The recent growth of structural, molecular and genetic data presents an opportunity for more comprehensive studies to consider the structural environment of a residue of interest, to hypothesize specific molecular effects of sequence variants and to statistically associate these effects with genetic disease. In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional attribute potentially underlying pathogenic molecular alterations. We first propose a formal model to assess probabilistically function-impacting variants. We then develop an array of structure-based functional residue predictors, evaluate their performance, and use them to quantify the impact of disease-causing amino acid substitutions on catalytic activity, metal binding, macromolecular binding, ligand binding, allosteric regulation and post-translational modifications. We show that our methodology generates actionable biological hypotheses for up to 41% of disease-causing genetic variants mapped to protein structures suggesting that it can be reliably used to guide experimental validation. Our results suggest that a significant fraction of disease-causing human variants mapping to protein structures are function-altering both in the presence and absence of stability disruption.

Identification of causal genes for complex traits.

PubMed

Hormozdiari, Farhad; Kichaev, Gleb; Yang, Wen-Yun; Pasaniuc, Bogdan; Eskin, Eleazar

2015-06-15

Although genome-wide association studies (GWAS) have identified thousands of variants associated with common diseases and complex traits, only a handful of these variants are validated to be causal. We consider 'causal variants' as variants which are responsible for the association signal at a locus. As opposed to association studies that benefit from linkage disequilibrium (LD), the main challenge in identifying causal variants at associated loci lies in distinguishing among the many closely correlated variants due to LD. This is particularly important for model organisms such as inbred mice, where LD extends much further than in human populations, resulting in large stretches of the genome with significantly associated variants. Furthermore, these model organisms are highly structured and require correction for population structure to remove potential spurious associations. In this work, we propose CAVIAR-Gene (CAusal Variants Identification in Associated Regions), a novel method that is able to operate across large LD regions of the genome while also correcting for population structure. A key feature of our approach is that it provides as output a minimally sized set of genes that captures the genes which harbor causal variants with probability ρ. Through extensive simulations, we demonstrate that our method not only speeds up computation, but also have an average of 10% higher recall rate compared with the existing approaches. We validate our method using a real mouse high-density lipoprotein data (HDL) and show that CAVIAR-Gene is able to identify Apoa2 (a gene known to harbor causal variants for HDL), while reducing the number of genes that need to be tested for functionality by a factor of 2. Software is freely available for download at genetics.cs.ucla.edu/caviar. © The Author 2015. Published by Oxford University Press.

Whole exome sequencing in recurrent early pregnancy loss.

PubMed

Qiao, Ying; Wen, Jiadi; Tang, Flamingo; Martell, Sally; Shomer, Naomi; Leung, Peter C K; Stephenson, Mary D; Rajcan-Separovic, Evica

2016-05-01

Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in 'complement and coagulation cascades pathway', and 'ciliary motility disorders'. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL. The size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative. This is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL. The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Whole exome sequencing in recurrent early pregnancy loss

PubMed Central

Qiao, Ying; Wen, Jiadi; Tang, Flamingo; Martell, Sally; Shomer, Naomi; Leung, Peter C.K.; Stephenson, Mary D.; Rajcan-Separovic, Evica

2016-01-01

STUDY HYPOTHESIS Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). STUDY FINDING We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. WHAT IS KNOWN ALREADY Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. MAIN RESULTS AND THE ROLE OF CHANCE Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in ‘complement and coagulation cascades pathway’, and ‘ciliary motility disorders’. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL. LIMITATIONS, REASONS FOR CAUTION The size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL. STUDY FUNDING AND COMPETING INTEREST(S) The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS. PMID:26826164

Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors.

PubMed

Ie, Susan I; Thedja, Meta D; Roni, Martono; Muljono, David H

2010-11-18

Selection of hepatitis B virus (HBV) by host immunity has been suggested to give rise to variants with amino acid substitutions at or around the 'a' determinant of the surface antigen (HBsAg), the main target of antibody neutralization and diagnostic assays. However, there have never been successful attempts to provide evidence for this hypothesis, partly because the 3 D structure of HBsAg molecules has not been determined. Tertiary structure prediction of HBsAg solely from its primary amino acid sequence may reveal the molecular energetic of the mutated proteins. We carried out this preliminary study to analyze the predicted HBsAg conformation changes of HBV variants isolated from Indonesian blood donors undetectable by HBsAg assays and its significance, compared to other previously-reported variants that were associated with diagnostic failure. Three HBV variants (T123A, M133L and T143M) and a wild type sequence were analyzed together with frequently emerged variants T123N, M133I, M133T, M133V, and T143L. Based on the Jameson-Wolf algorithm for calculating antigenic index, the first two amino acid substitutions resulted in slight changes in the antigenicity of the 'a' determinant, while all four of the comparative variants showed relatively more significant changes. In the pattern T143M, changes in antigenic index were more significant, both in its coverage and magnitude, even when compared to variant T143L. These data were also partially supported by the tertiary structure prediction, in which the pattern T143M showed larger shift in the HBsAg second loop structure compared to the others. Single amino acid substitutions within or near the 'a' determinant of HBsAg may alter antigenicity properties of variant HBsAg, which can be shown by both its antigenic index and predicted 3 D conformation. Findings in this study emphasize the significance of variant T143M, the prevalent isolate with highest degree of antigenicity changes found in Indonesian blood donors. This highlights the importance of evaluating the effects of protein structure alterations on the sensitivity of screening methods being used in detection of ongoing HBV infection, as well as the use of vaccines and immunoglobulin therapy in contributing to the selection of HBV variants.

Accounting for Population Structure in Gene-by-Environment Interactions in Genome-Wide Association Studies Using Mixed Models.

PubMed

Sul, Jae Hoon; Bilow, Michael; Yang, Wen-Yun; Kostem, Emrah; Furlotte, Nick; He, Dan; Eskin, Eleazar

2016-03-01

Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by-environment interactions (GEIs). Recently, several studies have conducted genome-wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants.

The Structures of the C185S and C185A Mutants of Sulfite Oxidase Reveal Rearrangement of the Active Site

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

Qiu, James A.; Wilson, Heather L.; Pushie, M. Jake

Sulfite oxidase (SO) catalyzes the physiologically critical conversion of sulfite to sulfate. Enzymatic activity is dependent on the presence of the metal molybdenum complexed with a pyranopterin-dithiolene cofactor termed molybdopterin. Comparison of the amino acid sequences of SOs from a variety of sources has identified a single conserved Cys residue essential for catalytic activity. The crystal structure of chicken liver sulfite oxidase indicated that this residue, Cys185 in chicken SO, coordinates the Mo atom in the active site. To improve our understanding of the role of this residue in the catalytic mechanism of sulfite oxidase, serine and alanine variants atmore » position 185 of recombinant chicken SO were generated. Spectroscopic and kinetic studies indicate that neither variant is capable of sulfite oxidation. The crystal structure of the C185S variant was determined to 1.9 {angstrom} resolution and to 2.4 {angstrom} resolution in the presence of sulfite, and the C185A variant to 2.8 {angstrom} resolution. The structures of the C185S and C185A variants revealed that neither the Ser or Ala side chains appeared to closely interact with the Mo atom and that a third oxo group replaced the usual cysteine sulfur ligand at the Mo center, confirming earlier extended X-ray absorption fine structure spectroscopy (EXAFS) work on the human C207S mutant. An unexpected result was that in the C185S variant, in the absence of sulfite, the active site residue Tyr322 became disordered as did the loop region flanking it. In the C185S variant crystallized in the presence of sulfite, the Tyr322 residue relocalized to the active site. The C185A variant structure also indicated the presence of a third oxygen ligand; however, Tyr322 remained in the active site. EXAFS studies of the Mo coordination environment indicate the Mo atom is in the oxidized Mo{sup VI} state in both the C185S and C185A variants of chicken SO and show the expected trioxodithiolene active site. Density functional theory calculations of the trioxo form of the cofactor reasonably reproducd the Mo=O distances of the complex; however, the calculated Mo-S distances were slightly longer than either crystallographic or EXAFS measurements. Taken together, these results indicate that the active sites of the C185S and C185A variants are essentially catalytically inactive, the crystal structures of C185S and C185A variants contain a fully oxidized, trioxo form of the cofactor, and Tyr322 can undergo a conformational change that is relevant to the reaction mechanism. Additional DFT calculations demonstrated that such methods can reasonably reproduce the geometry and bond lengths of the active site.« less

Multifunctional millimeter-wave radar system for helicopter safety

NASA Astrophysics Data System (ADS)

Goshi, Darren S.; Case, Timothy J.; McKitterick, John B.; Bui, Long Q.

2012-06-01

A multi-featured sensor solution has been developed that enhances the operational safety and functionality of small airborne platforms, representing an invaluable stride toward enabling higher-risk, tactical missions. This paper demonstrates results from a recently developed multi-functional sensor system that integrates a high performance millimeter-wave radar front end, an evidence grid-based integration processing scheme, and the incorporation into a 3D Synthetic Vision System (SVS) display. The front end architecture consists of a w-band real-beam scanning radar that generates a high resolution real-time radar map and operates with an adaptable antenna architecture currently configured with an interferometric capability for target height estimation. The raw sensor data is further processed within an evidence grid-based integration functionality that results in high-resolution maps in the region surrounding the platform. Lastly, the accumulated radar results are displayed in a fully rendered 3D SVS environment integrated with local database information to provide the best representation of the surrounding environment. The integrated system concept will be discussed and initial results from an experimental flight test of this developmental system will be presented. Specifically, the forward-looking operation of the system demonstrates the system's ability to produce high precision terrain mapping with obstacle detection and avoidance capability, showcasing the system's versatility in a true operational environment.

Flight Simulator Evaluation of Synthetic Vision Display Concepts to Prevent Controlled Flight Into Terrain (CFIT)

NASA Technical Reports Server (NTRS)

Arthur, Jarvis J., III; Prinzel, Lawrence J., III; Kramer, Lynda J.; Parrish, Russell V.; Bailey, Randall E.

2004-01-01

In commercial aviation, over 30-percent of all fatal accidents worldwide are categorized as Controlled Flight Into Terrain (CFIT) accidents, where a fully functioning airplane is inadvertently flown into the ground. The major hypothesis for a simulation experiment conducted at NASA Langley Research Center was that a Primary Flight Display (PFD) with synthetic terrain will improve pilots ability to detect and avoid potential CFITs compared to conventional instrumentation. All display conditions, including the baseline, contained a Terrain Awareness and Warning System (TAWS) and Vertical Situation Display (VSD) enhanced Navigation Display (ND). Each pilot flew twenty-two approach departure maneuvers in Instrument Meteorological Conditions (IMC) to the terrain challenged Eagle County Regional Airport (EGE) in Colorado. For the final run, flight guidance cues were altered such that the departure path went into terrain. All pilots with a synthetic vision system (SVS) PFD (twelve of sixteen pilots) noticed and avoided the potential CFIT situation. The four pilots who flew the anomaly with the conventional baseline PFD configuration (which included a TAWS and VSD enhanced ND) had a CFIT event. Additionally, all the SVS display concepts enhanced the pilot s situational awareness, decreased workload and improved flight technical error (FTE) compared to the baseline configuration.

Intra-variant substructure in Ni–Mn–Ga martensite: Conjugation boundaries

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

Muntifering, B.; Pond, R. C.; Kovarik, L.

2014-06-01

The microstructure of a Ni–Mn–Ga alloy in the martensitic phase was investigated using transmission electron microscopy. Inter-variant twin boundaries were observed separating non-modulated tetragonal martensite variants. In addition, intra-variant boundary structures, referred to here as “conjugation boundaries”, were also observed. We propose that conjugation boundaries originate at the transformation interface between austenite and a nascent martensite variant. In the alloy studied, deformation twinning was observed, consistent with being the mode of lattice-invariant deformation, and this can occur on either of two crystallographically equivalent conjugate View the MathML source{101}(101⁻) twinning systems: conjugation boundaries separate regions within a single variant in whichmore » the active modes were distinct. The defect structure of conjugation boundaries and the low-angle of misorientation across them are revealed in detail using high-resolution microscopy. Finally, we anticipate that the mobility of such boundaries is lower than that of inter-variant boundaries, and is therefore likely to significantly affect the kinetics of deformation in the martensitic phase.« less

RAPTR-SV: a hybrid method for the detection of structural variants

USDA-ARS?s Scientific Manuscript database

Motivation: Identification of Structural Variants (SV) in sequence data results in a large number of false positive calls using existing software, which overburdens subsequent validation. Results: Simulations using RAPTR-SV and another software package that uses a similar algorithm for SV detection...

The effect of rare variants on inflation of the test statistics in case-control analyses.

PubMed

Pirie, Ailith; Wood, Angela; Lush, Michael; Tyrer, Jonathan; Pharoah, Paul D P

2015-02-20

The detection of bias due to cryptic population structure is an important step in the evaluation of findings of genetic association studies. The standard method of measuring this bias in a genetic association study is to compare the observed median association test statistic to the expected median test statistic. This ratio is inflated in the presence of cryptic population structure. However, inflation may also be caused by the properties of the association test itself particularly in the analysis of rare variants. We compared the properties of the three most commonly used association tests: the likelihood ratio test, the Wald test and the score test when testing rare variants for association using simulated data. We found evidence of inflation in the median test statistics of the likelihood ratio and score tests for tests of variants with less than 20 heterozygotes across the sample, regardless of the total sample size. The test statistics for the Wald test were under-inflated at the median for variants below the same minor allele frequency. In a genetic association study, if a substantial proportion of the genetic variants tested have rare minor allele frequencies, the properties of the association test may mask the presence or absence of bias due to population structure. The use of either the likelihood ratio test or the score test is likely to lead to inflation in the median test statistic in the absence of population structure. In contrast, the use of the Wald test is likely to result in under-inflation of the median test statistic which may mask the presence of population structure.

In vivo study of the surgical anatomy of the axilla.

PubMed

Khan, A; Chakravorty, A; Gui, G P H

2012-06-01

Classical anatomical descriptions fail to describe variants often observed in the axilla as they are based on studies that looked at individual structures in isolation or textbooks of cadaveric dissections. The presence of variant anatomy heightens the risk of iatrogenic injury. The aim of this study was to document the nature and frequency of these anatomical variations based on in vivo peroperative surgical observations. Detailed anatomical relationships were documented prospectively during consecutive axillary dissections. Relationships between the thoracodorsal pedicle, course of the lateral thoracic vein, presence of latissimus dorsi muscle slips, variations in axillary and angular vein anatomy, and origins and branching of the intercostobrachial nerve were recorded. Among a total of 73 axillary dissections, 43 (59 per cent) revealed at least one anatomical variant. Most notable variants included aberrant courses of the thoracodorsal nerve in ten patients (14 per cent)--three variants; lateral thoracic vein in 12 patients (16 per cent)--four variants; bifid axillary veins in ten patients (14 per cent); latissimus dorsi muscle slips in four patients (5 per cent); and variants in intercostobrachial nerve origins and branching in 26 patients (36 per cent). The angular vein, a subscapular vein tributary, was found to be a constant axillary structure. Variations in axillary anatomical structures are common. Poor understanding of these variants can affect the adequacy of oncological clearance, lead to vascular injury, compromise planned microvascular procedures and result in chronic pain or numbness from nerve injury. Surgeons should be aware of the common anatomical variants to facilitate efficient and safe axillary surgery. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation*

PubMed Central

Rea, Matthew; Jiang, Tingting; Eleazer, Rebekah; Eckstein, Meredith; Marshall, Alan G.; Fondufe-Mittendorf, Yvonne N.

2016-01-01

Exposure to inorganic arsenic, a ubiquitous environmental toxic metalloid, leads to carcinogenesis. However, the mechanism is unknown. Several studies have shown that inorganic arsenic exposure alters specific gene expression patterns, possibly through alterations in chromatin structure. While most studies on understanding the mechanism of chromatin-mediated gene regulation have focused on histone post-translational modifications, the role of histone variants remains largely unknown. Incorporation of histone variants alters the functional properties of chromatin. To understand the global dynamics of chromatin structure and function in arsenic-mediated carcinogenesis, analysis of the histone variants incorporated into the nucleosome and their covalent modifications is required. Here we report the first global mass spectrometric analysis of histone H2B variants as cells undergo arsenic-mediated epithelial to mesenchymal transition. We used electron capture dissociation-based top-down tandem mass spectrometry analysis validated with quantitative reverse transcription real-time polymerase chain reaction to identify changes in the expression levels of H2B variants in inorganic arsenic-mediated epithelial-mesenchymal transition. We identified changes in the expression levels of specific histone H2B variants in two cell types, which are dependent on dose and length of exposure of inorganic arsenic. In particular, we found increases in H2B variants H2B1H/1K/1C/1J/1O and H2B2E/2F, and significant decreases in H2B1N/1D/1B as cells undergo inorganic arsenic-mediated epithelial-mesenchymal transition. The analysis of these histone variants provides a first step toward an understanding of the functional significance of the diversity of histone structures, especially in inorganic arsenic-mediated gene expression and carcinogenesis. PMID:27169413

Identification of causal genes for complex traits

PubMed Central

Hormozdiari, Farhad; Kichaev, Gleb; Yang, Wen-Yun; Pasaniuc, Bogdan; Eskin, Eleazar

2015-01-01

Motivation: Although genome-wide association studies (GWAS) have identified thousands of variants associated with common diseases and complex traits, only a handful of these variants are validated to be causal. We consider ‘causal variants’ as variants which are responsible for the association signal at a locus. As opposed to association studies that benefit from linkage disequilibrium (LD), the main challenge in identifying causal variants at associated loci lies in distinguishing among the many closely correlated variants due to LD. This is particularly important for model organisms such as inbred mice, where LD extends much further than in human populations, resulting in large stretches of the genome with significantly associated variants. Furthermore, these model organisms are highly structured and require correction for population structure to remove potential spurious associations. Results: In this work, we propose CAVIAR-Gene (CAusal Variants Identification in Associated Regions), a novel method that is able to operate across large LD regions of the genome while also correcting for population structure. A key feature of our approach is that it provides as output a minimally sized set of genes that captures the genes which harbor causal variants with probability ρ. Through extensive simulations, we demonstrate that our method not only speeds up computation, but also have an average of 10% higher recall rate compared with the existing approaches. We validate our method using a real mouse high-density lipoprotein data (HDL) and show that CAVIAR-Gene is able to identify Apoa2 (a gene known to harbor causal variants for HDL), while reducing the number of genes that need to be tested for functionality by a factor of 2. Availability and implementation: Software is freely available for download at genetics.cs.ucla.edu/caviar. Contact: eeskin@cs.ucla.edu PMID:26072484

Crystal structure of p44, a constitutively active splice variant of visual arrestin.

PubMed

Granzin, Joachim; Cousin, Anneliese; Weirauch, Moritz; Schlesinger, Ramona; Büldt, Georg; Batra-Safferling, Renu

2012-03-09

Visual arrestin specifically binds to photoactivated and phosphorylated rhodopsin and inactivates phototransduction. In contrast, the p44 splice variant can terminate phototransduction by binding to nonphosphorylated light-activated rhodopsin. Here we report the crystal structure of bovine p44 at a resolution of 1.85 Å. Compared to native arrestin, the p44 structure reveals significant differences in regions crucial for receptor binding, namely flexible loop V-VI and polar core regions. Additionally, electrostatic potential is remarkably positive on the N-domain and the C-domain. The p44 structure represents an active conformation that serves as a model to explain the 'constitutive activity' found in arrestin variants. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mapping genetic variations to three-dimensional protein structures to enhance variant interpretation: a proposed framework.

PubMed

Glusman, Gustavo; Rose, Peter W; Prlić, Andreas; Dougherty, Jennifer; Duarte, José M; Hoffman, Andrew S; Barton, Geoffrey J; Bendixen, Emøke; Bergquist, Timothy; Bock, Christian; Brunk, Elizabeth; Buljan, Marija; Burley, Stephen K; Cai, Binghuang; Carter, Hannah; Gao, JianJiong; Godzik, Adam; Heuer, Michael; Hicks, Michael; Hrabe, Thomas; Karchin, Rachel; Leman, Julia Koehler; Lane, Lydie; Masica, David L; Mooney, Sean D; Moult, John; Omenn, Gilbert S; Pearl, Frances; Pejaver, Vikas; Reynolds, Sheila M; Rokem, Ariel; Schwede, Torsten; Song, Sicheng; Tilgner, Hagen; Valasatava, Yana; Zhang, Yang; Deutsch, Eric W

2017-12-18

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods.

Structural and Functional Characterization of a New Double Variant Haemoglobin (HbG-Philadelphia/Duarte α(2)β(2)).

PubMed

Fais, Antonella; Casu, Mariano; Ruggerone, Paolo; Ceccarelli, Matteo; Porcu, Simona; Era, Benedetta; Anedda, Roberto; Sollaino, Maria Carla; Galanello, Renzo; Corda, Marcella

2011-01-01

WE REPORT THE FIRST CASE OF COSEGREGATION OF TWO HAEMOGLOBINS (HBS): HbG-Philadelphia [α68(E17)Asn → Lys] and HbDuarte [β62(E6)Ala → Pro]. The proband is a young patient heterozygous also for β°-thalassaemia. We detected exclusively two haemoglobin variants: HbDuarte and HbG-Philadelphia/Duarte. Functional study of the new double variant HbG-Philadelphia/Duarte exhibited an increase in oxygen affinity, with a slight decrease of cooperativity and Bohr effect. This functional behaviour is attributed to β62Ala → Pro instead of α68Asn → Lys substitution. Indeed, HbG-Philadelphia isolated in our laboratory from blood cells donor carrier for this variant is not affected by any functional modification, whereas purified Hb Duarte showed functional properties very similar to the double variant. NMR and MD simulation studies confirmed that the presence of Pro instead of Ala at the β62 position produces displacement of the E helix and modifications of the tertiary structure. The substitution α68(E17)Asn → Lys does not cause significant structural and dynamical modifications of the protein. A possible structure-based rational of substitution effects is suggested.

Structural analysis of an HLA-B27 functional variant, B27d detected in American blacks

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

Rojo, S.; Aparicio, P.; Hansen, J.A.

1987-11-15

The structure of a new functional variant B27d has been established by comparative peptide mapping and radiochemical sequencing. This analysis complete the structural characterization of the six know histocompatibility leukocyte antigen (HLA)-B27 subtypes. The only detected amino acid change between the main HLA-B27.1 subtype and B27d is that of Try/sub 59/ to His/sub 59/. Position 59 has not been previously found to vary among class I HLA or H-2 antigens. Such substitution accounts for the reported isoelectric focusing pattern of this variant. HLA-B27d is the only B27 variant found to differ from other subtypes by a single amino acid replacement.more » The nature of the change is compatible with its origin by a point mutation from HLB-B27.1. Because B27d was found only American blacks and in no other ethnic groups, it is suggested that this variant originated as a result of a mutation of the B27.1 gene that occurred within the black population. Structural analysis of B27d was done by comparative mapping. Radiochemical sequencing was carried out with /sup 14/C-labeled and /sup 3/H-labeled amino acids.« less

Mutations of Glucose-6-Phosphate Dehydrogenase Durham, Santa-Maria and A+ Variants Are Associated with Loss Functional and Structural Stability of the Protein

PubMed Central

Gómez-Manzo, Saúl; Marcial-Quino, Jaime; Vanoye-Carlo, America; Enríquez-Flores, Sergio; De la Mora-De la Mora, Ignacio; González-Valdez, Abigail; García-Torres, Itzhel; Martínez-Rosas, Víctor; Sierra-Palacios, Edgar; Lazcano-Pérez, Fernando; Rodríguez-Bustamante, Eduardo; Arreguin-Espinosa, Roberto

2015-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in the world. More than 160 mutations causing the disease have been identified, but only 10% of these variants have been studied at biochemical and biophysical levels. In this study we report on the functional and structural characterization of three naturally occurring variants corresponding to different classes of disease severity: Class I G6PD Durham, Class II G6PD Santa Maria, and Class III G6PD A+. The results showed that the G6PD Durham (severe deficiency), and the G6PD Santa Maria and A+ (less severe deficiency) (Class I, II and III, respectively) affect the catalytic efficiency of these enzymes, are more sensitive to temperature denaturing, and affect the stability of the overall protein when compared to the wild type WT-G6PD. In the variants, the exposure of more and buried hydrophobic pockets was induced and monitored with 8-Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence, directly affecting the compaction of structure at different levels and probably reducing the stability of the protein. The degree of functional and structural perturbation by each variant correlates with the clinical severity reported in different patients. PMID:26633385

Ferroelasticity and domain physics in two-dimensional transition metal dichalcogenide monolayers.

PubMed

Li, Wenbin; Li, Ju

2016-02-24

Monolayers of transition metal dichalcogenides can exist in several structural polymorphs, including 2H, 1T and 1T'. The low-symmetry 1T' phase has three orientation variants, resulting from the three equivalent directions of Peierls distortion in the parental 1T phase. Using first-principles calculations, we predict that mechanical strain can switch the relative thermodynamic stability between the orientation variants of the 1T' phase. We find that such strain-induced variant switching only requires a few percent elastic strain, which is eminently achievable experimentally with transition metal dichalcogenide monolayers. Calculations indicate that the transformation barrier associated with such variant switching is small (<0.2 eV per chemical formula unit), suggesting that strain-induced variant switching can happen under laboratory conditions. Monolayers of transition metal dichalcogenides with 1T' structure therefore have the potential to be ferroelastic and shape memory materials with interesting domain physics.

Ferroelasticity and domain physics in two-dimensional transition metal dichalcogenide monolayers

DOE PAGES

Li, Wenbin; Li, Ju

2016-02-24

Monolayers of transition metal dichalcogenides can exist in several structural polymorphs, including 2H, 1T and 1T'. The low-symmetry 1T' phase has three orientation variants, resulting from the three equivalent directions of Peierls distortion in the parental 1T phase. Using first-principles calculations, we predict that mechanical strain can switch the relative thermodynamic stability between the orientation variants of the 1T' phase. We find that such strain-induced variant switching only requires a few percent elastic strain, which is eminently achievable experimentally with transition metal dichalcogenide monolayers. Calculations indicate that the transformation barrier associated with such variant switching is small (<0.2 eV permore » chemical formula unit), suggesting that strain-induced variant switching can happen under laboratory conditions. Furthermore, monolayers of transition metal dichalcogenides with 1T' structure therefore have the potential to be ferroelastic and shape memory materials with interesting domain physics.« less

Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

PubMed

Zhang, Qianqian; Guldbrandtsen, Bernt; Calus, Mario P L; Lund, Mogens Sandø; Sahana, Goutam

2016-08-17

There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their effects from family mean effects. We compared the power of methods that are commonly applied in human genetics to map rare variants in cattle using whole-genome sequence data and simulated phenotypes. We also studied the power of mapping rare variants using linear mixed models (LMM), which are the method of choice to account for both family relationships and population structure in cattle. We observed that the power of the LMM approach was low for mapping a rare variant (defined as those that have frequencies lower than 0.01) with a moderate effect (5 to 8 % of phenotypic variance explained by multiple rare variants that vary from 5 to 21 in number) contributing to a QTL with a sample size of 1000. In contrast, across the scenarios studied, statistical methods that are specialized for mapping rare variants increased power regardless of whether multiple rare variants or a single rare variant underlie a QTL. Different methods for combining rare variants in the test single nucleotide polymorphism set resulted in similar power irrespective of the proportion of total genetic variance explained by the QTL. However, when the QTL variance is very small (only 0.1 % of the total genetic variance), these specialized methods for mapping rare variants and LMM generally had no power to map the variants within a gene with sample sizes of 1000 or 5000. We observed that the methods that combine multiple rare variants within a gene into a meta-variant generally had greater power to map rare variants compared to LMM. Therefore, it is recommended to use rare variant association mapping methods to map rare genetic variants that affect quantitative traits in livestock, such as bovine populations.

High-throughput interpretation of gene structure changes in human and nonhuman resequencing data, using ACE

PubMed Central

Majoros, William H.; Campbell, Michael S.; Holt, Carson; DeNardo, Erin K.; Ware, Doreen; Allen, Andrew S.; Yandell, Mark; Reddy, Timothy E.

2017-01-01

Abstract Motivation: The accurate interpretation of genetic variants is critical for characterizing genotype–phenotype associations. Because the effects of genetic variants can depend strongly on their local genomic context, accurate genome annotations are essential. Furthermore, as some variants have the potential to disrupt or alter gene structure, variant interpretation efforts stand to gain from the use of individualized annotations that account for differences in gene structure between individuals or strains. Results: We describe a suite of software tools for identifying possible functional changes in gene structure that may result from sequence variants. ACE (‘Assessing Changes to Exons’) converts phased genotype calls to a collection of explicit haplotype sequences, maps transcript annotations onto them, detects gene-structure changes and their possible repercussions, and identifies several classes of possible loss of function. Novel transcripts predicted by ACE are commonly supported by spliced RNA-seq reads, and can be used to improve read alignment and transcript quantification when an individual-specific genome sequence is available. Using publicly available RNA-seq data, we show that ACE predictions confirm earlier results regarding the quantitative effects of nonsense-mediated decay, and we show that predicted loss-of-function events are highly concordant with patterns of intolerance to mutations across the human population. ACE can be readily applied to diverse species including animals and plants, making it a broadly useful tool for use in eukaryotic population-based resequencing projects, particularly for assessing the joint impact of all variants at a locus. Availability and Implementation: ACE is written in open-source C ++ and Perl and is available from geneprediction.org/ACE Contact: myandell@genetics.utah.edu or tim.reddy@duke.edu Supplementary information: Supplementary information is available at Bioinformatics online. PMID:28011790

High-throughput interpretation of gene structure changes in human and nonhuman resequencing data, using ACE.

PubMed

Majoros, William H; Campbell, Michael S; Holt, Carson; DeNardo, Erin K; Ware, Doreen; Allen, Andrew S; Yandell, Mark; Reddy, Timothy E

2017-05-15

The accurate interpretation of genetic variants is critical for characterizing genotype-phenotype associations. Because the effects of genetic variants can depend strongly on their local genomic context, accurate genome annotations are essential. Furthermore, as some variants have the potential to disrupt or alter gene structure, variant interpretation efforts stand to gain from the use of individualized annotations that account for differences in gene structure between individuals or strains. We describe a suite of software tools for identifying possible functional changes in gene structure that may result from sequence variants. ACE ('Assessing Changes to Exons') converts phased genotype calls to a collection of explicit haplotype sequences, maps transcript annotations onto them, detects gene-structure changes and their possible repercussions, and identifies several classes of possible loss of function. Novel transcripts predicted by ACE are commonly supported by spliced RNA-seq reads, and can be used to improve read alignment and transcript quantification when an individual-specific genome sequence is available. Using publicly available RNA-seq data, we show that ACE predictions confirm earlier results regarding the quantitative effects of nonsense-mediated decay, and we show that predicted loss-of-function events are highly concordant with patterns of intolerance to mutations across the human population. ACE can be readily applied to diverse species including animals and plants, making it a broadly useful tool for use in eukaryotic population-based resequencing projects, particularly for assessing the joint impact of all variants at a locus. ACE is written in open-source C ++ and Perl and is available from geneprediction.org/ACE. myandell@genetics.utah.edu or tim.reddy@duke.edu. Supplementary information is available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Crystal Structure of Serine Racemase that Produces Neurotransmitter d-Serine for Stimulation of the NMDA Receptor

NASA Astrophysics Data System (ADS)

Goto, Masaru

d-Serine is an endogenous coagonist for the N-methyl-d-aspartate receptor and is involved in excitatory neurotransmission in the brain. Mammalian pyridoxal 5’-phosphate-dependent serine racemase, which is localized in the mammalian brain, catalyzes the racemization of l-serine to yield d-serine and vice versa. We have determined the structures of three forms of the mammalian enzyme homolog from Schizosaccharomyces pombe. Lys57 and Ser82 located on the protein and solvent sides, respectively, with respect to the cofactor plane, are acid-base catalysts that shuttle protons to the substrate. The modified enzyme, which has a unique lysino-d-alanyl residue at the active site, also binds the substrate serine in the active site, suggesting that the lysino-d-alanyl residue acts as a catalytic base in the same manner as Lys57 of the wild type enzyme.

A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones.

PubMed

Siebert, Matthias; Böhme, Mathias A; Driller, Jan H; Babikir, Husam; Mampell, Malou M; Rey, Ulises; Ramesh, Niraja; Matkovic, Tanja; Holton, Nicole; Reddy-Alla, Suneel; Göttfert, Fabian; Kamin, Dirk; Quentin, Christine; Klinedinst, Susan; Andlauer, Till Fm; Hell, Stefan W; Collins, Catherine A; Wahl, Markus C; Loll, Bernhard; Sigrist, Stephan J

2015-08-14

Synaptic vesicles (SVs) fuse at active zones (AZs) covered by a protein scaffold, at Drosophila synapses comprised of ELKS family member Bruchpilot (BRP) and RIM-binding protein (RBP). We here demonstrate axonal co-transport of BRP and RBP using intravital live imaging, with both proteins co-accumulating in axonal aggregates of several transport mutants. RBP, via its C-terminal Src-homology 3 (SH3) domains, binds Aplip1/JIP1, a transport adaptor involved in kinesin-dependent SV transport. We show in atomic detail that RBP C-terminal SH3 domains bind a proline-rich (PxxP) motif of Aplip1/JIP1 with submicromolar affinity. Pointmutating this PxxP motif provoked formation of ectopic AZ-like structures at axonal membranes. Direct interactions between AZ proteins and transport adaptors seem to provide complex avidity and shield synaptic interaction surfaces of pre-assembled scaffold protein transport complexes, thus, favouring physiological synaptic AZ assembly over premature assembly at axonal membranes.

Vesicular trafficking of immune mediators in human eosinophils revealed by immunoelectron microscopy.

PubMed

Melo, Rossana C N; Weller, Peter F

2016-10-01

Electron microscopy (EM)-based techniques are mostly responsible for our current view of cell morphology at the subcellular level and continue to play an essential role in biological research. In cells from the immune system, such as eosinophils, EM has helped to understand how cells package and release mediators involved in immune responses. Ultrastructural investigations of human eosinophils enabled visualization of secretory processes in detail and identification of a robust, vesicular trafficking essential for the secretion of immune mediators via a non-classical secretory pathway associated with secretory (specific) granules. This vesicular system is mainly organized as large tubular-vesicular carriers (Eosinophil Sombrero Vesicles - EoSVs) actively formed in response to cell activation and provides a sophisticated structural mechanism for delivery of granule-stored mediators. In this review, we highlight the application of EM techniques to recognize pools of immune mediators at vesicular compartments and to understand the complex secretory pathway within human eosinophils involved in inflammatory and allergic responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

PubMed Central

Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

2013-01-01

Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

Characterization of SNPs in the dopamine-β-hydroxylase gene providing new insights into its structure-function relationship.

PubMed

Punchaichira, Toyanji Joseph; Dey, Sanjay Kumar; Mukhopadhyay, Anirban; Kundu, Suman; Thelma, B K

2017-07-01

Dopamine-β-hydroxylase (DBH, EC 1.14.17.1), an oxido-reductase that catalyses the conversion of dopamine to norepinephrine, is largely expressed in sympathetic neurons and adrenal medulla. Several regulatory and structural variants in DBH associated with various neuropsychiatric, cardiovascular diseases and a few that may determine enzyme activity have also been identified. Due to paucity of studies on functional characterization of DBH variants, its structure-function relationship is poorly understood. The purpose of the study was to characterize five non-synonymous (ns) variants that were prioritized either based on previous association studies or Sorting Tolerant From Intolerant (SIFT) algorithm. The DBH ORF with wild type (WT) and site-directed mutagenized variants were transfected into HEK293 cells to generate transient and stable lines expressing these variant enzymes. Activity was determined by UPLC-PDA and corresponding quantity by MRM HR on a TripleTOF 5600 MS respectively of spent media from stable cell lines. Homospecific activity computed for the WT and variant proteins showed a marginal decrease in A318S, W544S and R549C variants. In transient cell lines, differential secretion was observed in the case of L317P, W544S and R549C. Secretory defect in L317P was confirmed by localization in ER. R549C exhibited both decreased homospecific activity and differential secretion. Of note, all the variants were seen to be destabilizing based on in silico folding analysis and molecular dynamics (MD) simulation, lending support to our experimental observations. These novel genotype-phenotype correlations in this gene of considerable pharmacological relevance have implications for dopamine-related disorders.

TU-AB-303-06: Does Online Adaptive Radiation Therapy Mean Zero Margin for Intermediate-Risk Prostate Cancer? An Intra-Fractional Seminal Vesicles Motion Analysis

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

Sheng, Y; Li, T; Lee, W

Purpose: To provide benchmark for seminal vesicles (SVs) margin selection to account for intra-fractional motion; and to investigate the effectiveness of two motion surrogates in predicting intra-fractional SV underdosage. Methods: 9 prostate SBRT patients were studied; each has five pairs of pre-treatment and post-treatment cone-beam CTs (CBCTs). Each pair of CBCTs was registered based on fiducial markers in the prostate. To provide “ground truth” for coverage evaluation, all pre-treatment SVs were expanded with isotropic margin of 1,2,3,5 and 8mm, and their overlap with post-treatment SVs were used to quantify intra-fractional coverage. Two commonly used motion surrogates, the center-of-mass (COM) andmore » the border of contour (the most distal points in SI/AP/LR directions) were evaluated using Receiver-Operating Characteristic (ROC) analyses for predicting SV underdosage due to intra-fractional motion. Action threshold of determining underdosage for each surrogate was calculated by selecting the optimal balancing between sensitivity and specificity. For comparison, margin for each surrogate was also calculated based on traditional margin recipe. Results: 90% post-treatment SV coverage can be achieved in 47%, 82%, 91%, 98% and 98% fractions for 1,2,3,5 and 8mm margins. 3mm margin ensured the 90% intra-fractional SV coverage in 90% fractions when prostate was aligned. The ROC analysis indicated the AUC for COM and border were 0.88 and 0.72. The underdosage threshold was 2.9mm for COM and 4.1mm for border. The Van Herk’s margin recipe recommended 0.5, 0 and 1.8mm margin in LR, AP and SI direction based on COM and for border, the corresponding margin was 2.1, 4.5 and 3mm. Conclusion: 3mm isotropic margin is the minimum required to mitigate the intra-fractional SV motion when prostate is aligned. ROC analysis reveals that both COM and border are acceptable predictors for SV underdosage with 2.9mm and 4.1mm action threshold. Traditional margin calculation is less reliable for this application. This work is partially supported a master research grant from Varian Medical Systems.« less

Estimation of methane emission from California natural gas industry.

PubMed

Kuo, Jeff; Hicks, Travis C; Drake, Brian; Chan, Tat Fu

2015-07-01

Energy generation and consumption are the main contributors to greenhouse gases emissions in California. Natural gas is one of the primary sources of energy in California. A study was recently conducted to develop current, reliable, and California-specific source emission factors (EFs) that could be used to establish a more accurate methane emission inventory for the California natural gas industry. Twenty-five natural gas facilities were surveyed; the surveyed equipment included wellheads (172), separators (131), dehydrators (17), piping segments (145), compressors (66), pneumatic devices (374), metering and regulating (M&R) stations (19), hatches (34), pumps (2), and customer meters (12). In total, 92,157 components were screened, including flanges (10,101), manual valves (10,765), open-ended lines (384), pressure relief valves (358), regulators (930), seals (146), threaded connections (57,061), and welded connections (12,274). Screening values (SVs) were measured using portable monitoring instruments, and Hi-Flow samplers were then used to quantify fugitive emission rates. For a given SV range, the measured leak rates might span several orders of magnitude. The correlation equations between the leak rates and SVs were derived. All the component leakage rate histograms appeared to have the same trend, with the majority of leakage rates<0.02 cubic feet per minute (cfm). Using the cumulative distribution function, the geometric mean was found to be a better indicator than the arithmetic mean, as the mean for each group of leakage rates found. For most component types, the pegged EFs for SVs of ≥10,000 ppmV and of ≥50,000 ppmV are relatively similar. The component-level average EFs derived in this study are often smaller than the corresponding ones in the 1996 U.S. Environmental Protection Agency/Gas Research Institute (EPA/GRI) study. Twenty-five natural gas facilities in California were surveyed to develop current, reliable, and California-specific source emission factors (EFs) for the natural gas industry. Screening values were measured by using portable monitoring instruments, and Hi-Flow samplers were then used to quantify fugitive emission rates. The component-level average EFs derived in this study are often smaller than the corresponding ones in the 1996 EPA/GRI study. The smaller EF values from this study might be partially attributable to the employment of the leak detection and repair program by most, if not all, of the facilities surveyed.

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization.

PubMed

Manos, Thanos; Zeitler, Magteld; Tass, Peter A

2018-01-01

In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

PubMed Central

Manos, Thanos; Zeitler, Magteld; Tass, Peter A.

2018-01-01

In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies. PMID:29706900

Trends in a changing vascular practice environment for members of the Society for Vascular Surgery

PubMed Central

Matthews, Mika A. B.; Satiani, Bhagwan; Lohr, Joann M.

2013-01-01

Objective To survey the Society for Vascular Surgery (SVS) membership with regard to practice trends related to work effort, employment status, practice ownership, endovascular cases, and anticipated changes in practice in the near future. Methods A survey questionnaire was developed to gather information about member demographics and practice, hours worked, full-time (FT) or part-time status, employment status, practice ownership, competition for referrals, proportion of endovascular vs open procedures, and anticipated changes in practice in the next 3 years. We used SurveyMonkey and distributed the survey to all active vascular surgeon (VS) members of the SVS. Results The response rate was 207 of 2230 (10.7%). Two thirds were in private practice, and 21% were in solo practice. Twenty-four percent were employed by hospitals/health systems. Those VS under the age of 50 years were more likely to exclusively practice vascular surgery compared with VS over the age of 50 years (P = .0003). Sixty-eight of the physicians (32.7%) were between 50 and 59 years old, 186 (90.3%) were men, 192 (92.8%) worked FT (>36 hours of patient care per week), and almost two thirds worked >60 hours per week. Those in physician-owned practices worked >40 hours of patient care per week more often than did FT employed VS (P = .012). Younger VS (age <50 years) more frequently reported >50% of their workload being endovascular compared with older VS (age ≥50 years; P < .001). Eighty percent of FT VS planned to continue their current practice over the next 3 years. Of the 43.6% indicating loss of referrals, 82% pointed to cardiologists as the competition. Conclusions The current workforce is predominately male and works FT; one-third is between the ages of 50 and 59 years. Younger VS (age <50 years) are more likely to exclusively practice VS and have a higher caseload of endovascular procedures. Those in physician-owned practices are more likely to put in >40 hours of patient care per week than are FT employed VS. Longitudinal surveys of SVS members are imperative to help tailor educational, training, and practice management offerings, guide governmental activities, advocate for issues important to members, improve branding initiatives, and sponsor workforce analyses. PMID:23254185

Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

PubMed Central

Alamo, Lorenzo; Ware, James S; Pinto, Antonio; Gillilan, Richard E; Seidman, Jonathan G; Seidman, Christine E; Padrón, Raúl

2017-01-01

Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis. DOI: http://dx.doi.org/10.7554/eLife.24634.001 PMID:28606303

PB1-F2 Influenza A Virus Protein Adopts a β-Sheet Conformation and Forms Amyloid Fibers in Membrane Environments

PubMed Central

Chevalier, Christophe; Al Bazzal, Ali; Vidic, Jasmina; Février, Vincent; Bourdieu, Christiane; Bouguyon, Edwige; Le Goffic, Ronan; Vautherot, Jean-François; Bernard, Julie; Moudjou, Mohammed; Noinville, Sylvie; Chich, Jean-François; Da Costa, Bruno; Rezaei, Human; Delmas, Bernard

2010-01-01

The influenza A virus PB1-F2 protein, encoded by an alternative reading frame in the PB1 polymerase gene, displays a high sequence polymorphism and is reported to contribute to viral pathogenesis in a sequence-specific manner. To gain insights into the functions of PB1-F2, the molecular structure of several PB1-F2 variants produced in Escherichia coli was investigated in different environments. Circular dichroism spectroscopy shows that all variants have a random coil secondary structure in aqueous solution. When incubated in trifluoroethanol polar solvent, all PB1-F2 variants adopt an α-helix-rich structure, whereas incubated in acetonitrile, a solvent of medium polarity mimicking the membrane environment, they display β-sheet secondary structures. Incubated with asolectin liposomes and SDS micelles, PB1-F2 variants also acquire a β-sheet structure. Dynamic light scattering revealed that the presence of β-sheets is correlated with an oligomerization/aggregation of PB1-F2. Electron microscopy showed that PB1-F2 forms amorphous aggregates in acetonitrile. In contrast, at low concentrations of SDS, PB1-F2 variants exhibited various abilities to form fibers that were evidenced as amyloid fibers in a thioflavin T assay. Using a recombinant virus and its PB1-F2 knock-out mutant, we show that PB1-F2 also forms amyloid structures in infected cells. Functional membrane permeabilization assays revealed that the PB1-F2 variants can perforate membranes at nanomolar concentrations but with activities found to be sequence-dependent and not obviously correlated with their differential ability to form amyloid fibers. All of these observations suggest that PB1-F2 could be involved in physiological processes through different pathways, permeabilization of cellular membranes, and amyloid fiber formation. PMID:20172856

PB1-F2 influenza A virus protein adopts a beta-sheet conformation and forms amyloid fibers in membrane environments.

PubMed

Chevalier, Christophe; Al Bazzal, Ali; Vidic, Jasmina; Février, Vincent; Bourdieu, Christiane; Bouguyon, Edwige; Le Goffic, Ronan; Vautherot, Jean-François; Bernard, Julie; Moudjou, Mohammed; Noinville, Sylvie; Chich, Jean-François; Da Costa, Bruno; Rezaei, Human; Delmas, Bernard

2010-04-23

The influenza A virus PB1-F2 protein, encoded by an alternative reading frame in the PB1 polymerase gene, displays a high sequence polymorphism and is reported to contribute to viral pathogenesis in a sequence-specific manner. To gain insights into the functions of PB1-F2, the molecular structure of several PB1-F2 variants produced in Escherichia coli was investigated in different environments. Circular dichroism spectroscopy shows that all variants have a random coil secondary structure in aqueous solution. When incubated in trifluoroethanol polar solvent, all PB1-F2 variants adopt an alpha-helix-rich structure, whereas incubated in acetonitrile, a solvent of medium polarity mimicking the membrane environment, they display beta-sheet secondary structures. Incubated with asolectin liposomes and SDS micelles, PB1-F2 variants also acquire a beta-sheet structure. Dynamic light scattering revealed that the presence of beta-sheets is correlated with an oligomerization/aggregation of PB1-F2. Electron microscopy showed that PB1-F2 forms amorphous aggregates in acetonitrile. In contrast, at low concentrations of SDS, PB1-F2 variants exhibited various abilities to form fibers that were evidenced as amyloid fibers in a thioflavin T assay. Using a recombinant virus and its PB1-F2 knock-out mutant, we show that PB1-F2 also forms amyloid structures in infected cells. Functional membrane permeabilization assays revealed that the PB1-F2 variants can perforate membranes at nanomolar concentrations but with activities found to be sequence-dependent and not obviously correlated with their differential ability to form amyloid fibers. All of these observations suggest that PB1-F2 could be involved in physiological processes through different pathways, permeabilization of cellular membranes, and amyloid fiber formation.

Comparative analysis of the folding dynamics and kinetics of an engineered knotted protein and its variants derived from HP0242 of Helicobacter pylori

NASA Astrophysics Data System (ADS)

Wang, Liang-Wei; Liu, Yu-Nan; Lyu, Ping-Chiang; Jackson, Sophie E.; Hsu, Shang-Te Danny

2015-09-01

Understanding the mechanism by which a polypeptide chain thread itself spontaneously to attain a knotted conformation has been a major challenge in the field of protein folding. HP0242 is a homodimeric protein from Helicobacter pylori with intertwined helices to form a unique pseudo-knotted folding topology. A tandem HP0242 repeat has been constructed to become the first engineered trefoil-knotted protein. Its small size renders it a model system for computational analyses to examine its folding and knotting pathways. Here we report a multi-parametric study on the folding stability and kinetics of a library of HP0242 variants, including the trefoil-knotted tandem HP0242 repeat, using far-UV circular dichroism and fluorescence spectroscopy. Equilibrium chemical denaturation of HP0242 variants shows the presence of highly populated dimeric and structurally heterogeneous folding intermediates. Such equilibrium folding intermediates retain significant amount of helical structures except those at the N- and C-terminal regions in the native structure. Stopped-flow fluorescence measurements of HP0242 variants show that spontaneous refolding into knotted structures can be achieved within seconds, which is several orders of magnitude faster than previously observed for other knotted proteins. Nevertheless, the complex chevron plots indicate that HP0242 variants are prone to misfold into kinetic traps, leading to severely rolled-over refolding arms. The experimental observations are in general agreement with the previously reported molecular dynamics simulations. Based on our results, kinetic folding pathways are proposed to qualitatively describe the complex folding processes of HP0242 variants.

Genomic variants in an inbred mouse model predict mania-like behaviors.

PubMed

Saul, Michael C; Stevenson, Sharon A; Zhao, Changjiu; Driessen, Terri M; Eisinger, Brian E; Gammie, Stephen C

2018-01-01

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

Predicting primary progressive aphasias with support vector machine approaches in structural MRI data.

PubMed

Bisenius, Sandrine; Mueller, Karsten; Diehl-Schmid, Janine; Fassbender, Klaus; Grimmer, Timo; Jessen, Frank; Kassubek, Jan; Kornhuber, Johannes; Landwehrmeyer, Bernhard; Ludolph, Albert; Schneider, Anja; Anderl-Straub, Sarah; Stuke, Katharina; Danek, Adrian; Otto, Markus; Schroeter, Matthias L

2017-01-01

Primary progressive aphasia (PPA) encompasses the three subtypes nonfluent/agrammatic variant PPA, semantic variant PPA, and the logopenic variant PPA, which are characterized by distinct patterns of language difficulties and regional brain atrophy. To validate the potential of structural magnetic resonance imaging data for early individual diagnosis, we used support vector machine classification on grey matter density maps obtained by voxel-based morphometry analysis to discriminate PPA subtypes (44 patients: 16 nonfluent/agrammatic variant PPA, 17 semantic variant PPA, 11 logopenic variant PPA) from 20 healthy controls (matched for sample size, age, and gender) in the cohort of the multi-center study of the German consortium for frontotemporal lobar degeneration. Here, we compared a whole-brain with a meta-analysis-based disease-specific regions-of-interest approach for support vector machine classification. We also used support vector machine classification to discriminate the three PPA subtypes from each other. Whole brain support vector machine classification enabled a very high accuracy between 91 and 97% for identifying specific PPA subtypes vs. healthy controls, and 78/95% for the discrimination between semantic variant vs. nonfluent/agrammatic or logopenic PPA variants. Only for the discrimination between nonfluent/agrammatic and logopenic PPA variants accuracy was low with 55%. Interestingly, the regions that contributed the most to the support vector machine classification of patients corresponded largely to the regions that were atrophic in these patients as revealed by group comparisons. Although the whole brain approach took also into account regions that were not covered in the regions-of-interest approach, both approaches showed similar accuracies due to the disease-specificity of the selected networks. Conclusion, support vector machine classification of multi-center structural magnetic resonance imaging data enables prediction of PPA subtypes with a very high accuracy paving the road for its application in clinical settings.

Proteomic characterization of histone variants in the mouse testis by mass spectrometry-based top-down analysis.

PubMed

Kwak, Ho-Geun; Dohmae, Naoshi

2016-11-15

Various histones, including testis-specific histones, exist during spermatogenesis and some of them have been reported to play a key role in chromatin remodeling. Mass spectrometry (MS)-based characterization has become the important step to understand histone structures. Although individual histones or partial histone variant groups have been characterized, the comprehensive analysis of histone variants has not yet been conducted in the mouse testis. Here, we present the comprehensive separation and characterization of histone variants from mouse testes by a top-down approach using MS. Histone variants were successfully separated on a reversed phase column using high performance liquid chromatography (HPLC) with an ion-pairing reagent. Increasing concentrations of testis-specific histones were observed in the mouse testis and some somatic histones increased in the epididymis. Specifically, the increase of mass abundance in H3.2 in the epididymis was inversely proportional to the decrease in H3t in the testis, which was approximately 80%. The top-down characterization of intact histone variants in the mouse testis was performed using LC-MS/MS. The masses of separated histone variants and their expected post-translation modifications were calculated by performing deconvolution with information taken from the database. TH2A, TH2B and H3t were characterized by MS/MS fragmentation. Our approach provides comprehensive knowledge for identification of histone variants in the mouse testis that will contribute to the structural and functional research of histone variants during spermatogenesis.

Symptoms of anxiety and depression in medical students and in humanities students: relationship with big-five personality dimensions and vulnerability to stress.

PubMed

Bunevicius, Adomas; Katkute, Arune; Bunevicius, Robertas

2008-11-01

To evaluate the prevalence of anxiety and depression in medical students and in humanities students. To assess the relationship between symptoms of anxiety, symptoms of depression and Big-Five personality dimensions and vulnerability to stress in medical students. Randomly selected 338 medical students and 73 humanities students were evaluated for symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS), for Big-Five personality dimensions using the Ten-Item Personality Inventory (TIPI), and for vulnerability to stress using the Stress Vulnerability Scale (SVS). Symptoms of anxiety and symptoms of depression were prevalent in medical students (43% and 14%, respectively) and in humanities students (52% and 12%, respectively). In medical students the score on the HADS anxiety subscale and the score on the HADS depression subscale correlated negatively with the score on the TIPI Emotional Stability scale (r = -0.39, p < 0.01 and r = -0.2, p < 0.01, respectively) and correlated positively with the score on the SVS (r = 0.38, p < 0.01 and r = 0.44, p < 0.01, respectively). Symptoms of anxiety and depression are prevalent in medical students and in humanities students. Severity of symptoms of anxiety and symptoms of depression in medical students is negatively related to emotional stability and positively related to stress vulnerability.

RIBEYE(B)-domain binds to lipid components of synaptic vesicles in an NAD(H)-dependent, redox-sensitive manner.

PubMed

Schwarz, Karin; Schmitz, Frank

2017-03-20

Synaptic ribbons are needed for fast and continuous exocytosis in ribbon synapses. RIBEYE is a main protein component of synaptic ribbons and is necessary to build the synaptic ribbon. RIBEYE consists of a unique A-domain and a carboxyterminal B-domain, which binds NAD(H). Within the presynaptic terminal, the synaptic ribbons are in physical contact with large numbers of synaptic vesicle (SV)s. How this physical contact between ribbons and synaptic vesicles is established at a molecular level is not well understood. In the present study, we demonstrate that the RIBEYE(B)-domain can directly interact with lipid components of SVs using two different sedimentation assays with liposomes of defined chemical composition. Similar binding results were obtained with a SV-containing membrane fraction. The binding of liposomes to RIBEYE(B) depends upon the presence of a small amount of lysophospholipids present in the liposomes. Interestingly, binding of liposomes to RIBEYE(B) depends on NAD(H) in a redox-sensitive manner. The binding is enhanced by NADH, the reduced form, and is inhibited by NAD + , the oxidized form. Lipid-mediated attachment of vesicles is probably part of a multi-step process that also involves additional, protein-dependent processes. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Integration of Irma tactical scene generator into directed-energy weapon system simulation

NASA Astrophysics Data System (ADS)

Owens, Monte A.; Cole, Madison B., III; Laine, Mark R.

2003-08-01

Integrated high-fidelity physics-based simulations that include engagement models, image generation, electro-optical hardware models and control system algorithms have previously been developed by Boeing-SVS for various tracking and pointing systems. These simulations, however, had always used images with featureless or random backgrounds and simple target geometries. With the requirement to engage tactical ground targets in the presence of cluttered backgrounds, a new type of scene generation tool was required to fully evaluate system performance in this challenging environment. To answer this need, Irma was integrated into the existing suite of Boeing-SVS simulation tools, allowing scene generation capabilities with unprecedented realism. Irma is a US Air Force research tool used for high-resolution rendering and prediction of target and background signatures. The MATLAB/Simulink-based simulation achieves closed-loop tracking by running track algorithms on the Irma-generated images, processing the track errors through optical control algorithms, and moving simulated electro-optical elements. The geometry of these elements determines the sensor orientation with respect to the Irma database containing the three-dimensional background and target models. This orientation is dynamically passed to Irma through a Simulink S-function to generate the next image. This integrated simulation provides a test-bed for development and evaluation of tracking and control algorithms against representative images including complex background environments and realistic targets calibrated using field measurements.

Synthetic Vision Systems in GA Cockpit-Evaluation of Basic Maneuvers Performed by Low Time GA Pilots During Transition from VMC to IMC

NASA Technical Reports Server (NTRS)

Takallu, M. A.; Wong, D. T.; Uenking, M. D.

2002-01-01

An experimental investigation was conducted to study the effectiveness of modern flight displays in general aviation cockpits for mitigating Low Visibility Loss of Control and the Controlled Flight Into Terrain accidents. A total of 18 General Aviation (GA) pilots with private pilot, single engine land rating, with no additional instrument training beyond private pilot license requirements, were recruited to evaluate three different display concepts in a fixed-based flight simulator at the NASA Langley Research Center's General Aviation Work Station. Evaluation pilots were asked to continue flight from Visual Meteorological Conditions (VMC) into Instrument Meteorological Conditions (IMC) while performing a series of 4 basic precision maneuvers. During the experiment, relevant pilot/vehicle performance variables, pilot control inputs and physiological data were recorded. Human factors questionnaires and interviews were administered after each scenario. Qualitative and quantitative data have been analyzed and the results are presented here. Pilot performance deviations from the established target values (errors) were computed and compared with the FAA Practical Test Standards. Results of the quantitative data indicate that evaluation pilots committed substantially fewer errors when using the Synthetic Vision Systems (SVS) displays than when they were using conventional instruments. Results of the qualitative data indicate that evaluation pilots perceived themselves to have a much higher level of situation awareness while using the SVS display concept.

Structure and dynamics of mesophilic variants from the homing endonuclease I-DmoI

NASA Astrophysics Data System (ADS)

Alba, Josephine; Marcaida, Maria Jose; Prieto, Jesus; Montoya, Guillermo; Molina, Rafael; D'Abramo, Marco

2017-12-01

I-DmoI, from the hyperthermophilic archaeon Desulfurococcus mobilis, belongs to the LAGLIDADG homing endonuclease protein family. Its members are highly specific enzymes capable of recognizing long DNA target sequences, thus providing potential tools for genome manipulation. Working towards this particular application, many efforts have been made to generate mesophilic variants of I-DmoI that function at lower temperatures than the wild-type. Here, we report a structural and computational analysis of two I-DmoI mesophilic mutants. Despite very limited structural variations between the crystal structures of these variants and the wild-type, a different dynamical behaviour near the cleavage sites is observed. In particular, both the dynamics of the water molecules and the protein perturbation effect on the cleavage site correlate well with the changes observed in the experimental enzymatic activity.

Optional elements and variant structures in the productions of bei2 'to give' dative constructions in Cantonese-speaking adults and three-year-old children.

PubMed

Wong, Anita M-Y; Chow, Dorcas C-C; McBride-Cheng, Catherine; Stokes, Stephanie F

2010-01-01

To express object transfer, Cantonese-speakers use a 'ditransitive' ([V-R-T] or [V-T-R] where V=Verb, T=Theme, R=Recipient), or a more complex prepositional/serial-verb (P/SV) construction. Clausal elements in Cantonese datives can be optional (resulting in 'full' versus 'non-full' forms) or appear in variant orders (full non-canonical and full canonical). We report on usage of dative constructions with the word bei2 'to give' in 86 parents and 53 three-year-old children during conversations. The parents used more P/SV than ditransitive bei2-datives, and vice versa for the children. Both groups showed a similar usage pattern of optional elements and variant structures in their ditransitive and P/SV bei2-datives. The roles of multiple construction types, optional elements and variant structures in children's learning of bei2-dative constructions are described.

Proteolysis of truncated hemolysin A yields a stable dimerization interface

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

Novak, Walter R. P.; Bhattacharyya, Basudeb; Grilley, Daniel P.

2017-02-21

Wild-type and variant forms of HpmA265 (truncated hemolysin A) fromProteus mirabilisreveal a right-handed, parallel β-helix capped and flanked by segments of antiparallel β-strands. The low-salt crystal structures form a dimeric structureviathe implementation of on-edge main-chain hydrogen bonds donated by residues 243–263 of adjacent monomers. Surprisingly, in the high-salt structures of two variants, Y134A and Q125A-Y134A, a new dimeric interface is formedviamain-chain hydrogen bonds donated by residues 203–215 of adjacent monomers, and a previously unobserved tetramer is formed. In addition, an eight-stranded antiparallel β-sheet is formed from the flap regions of crystallographically related monomers in the high-salt structures. This new interfacemore » is possible owing to additional proteolysis of these variants after Tyr240. The interface formed in the high-salt crystal forms of hemolysin A variants may mimic the on-edge β-strand positioning used in template-assisted hemolytic activity.« less

"weil--das ist eben doch richtig so" Teaching Variant Types of "Weil"- and "Obwohl"-Structures in German

ERIC Educational Resources Information Center

Bendig, Ina; Betz, Emma; Huth, Thorsten

2016-01-01

Researchers have observed that in spoken German, the conjunctions "weil" and "obwohl" commonly occur with verb-second (V2) instead of verb-final (V[subscript f]) word order (Gaumann, 1983; Gänthner, 1993, 1996; Uhmann, 1998). Current findings document that this syntactic variant of "weil/obwohl-structures" has an…

Predictive Ability of the SVS WIfI Classification System following First-time Lower Extremity Revascularizations

PubMed Central

Darling, Jeremy D.; McCallum, John C.; Soden, Peter A.; Guzman, Raul J.; Wyers, Mark C.; Hamdan, Allen D.; Verhagen, Hence J.; Schermerhorn, Marc L.

2017-01-01

OBJECTIVES The SVS WIfI (wound, ischemia, foot infection) classification system was proposed to predict 1-year amputation risk and potential benefit from revascularization. Our goal was to evaluate the predictive ability of this scale in a “real world” selection of patients undergoing a first time lower extremity revascularization for chronic limb threatening ischemia (CLTI). METHODS From 2005 to 2014, 1,336 limbs underwent a first time lower extremity revascularization for CLTI, of which 992 had sufficient data to classify all three WIfI components (wound, ischemia, and foot infection). Limbs were stratified into the SVS WIfI clinical stages (from 1 to 4) for 1-year amputation risk estimation, as well as a novel WIfI composite score from 0 to 9 (that weighs all WIfI variables equally) and a novel WIfI mean score from 0 to 3 (that can incorporate limbs missing any of the three WIfI components). Outcomes included major amputation, RAS events (revascularization, major amputation, or stenosis [>3.5× step-up by duplex]), and mortality. Predictors were identified using Cox regression models and Kaplan-Meier survival estimates. RESULTS Of the 1,336 first-time procedures performed, 992 limbs were classified in all three WIfI components (524 endovascular, 468 bypass; 26% rest pain, 74% tissue loss). Cox regression demonstrated that a one-unit increase in the WIfI clinical stage increases the risk of major amputation and RAS events in all limbs (Hazard Ratio [HR] 2.4; 95% Confidence Interval [CI] 1.7–3.2 and 1.2 [1.1–1.3], respectively). Separate models of the entire cohort, a bypass only cohort, and an endovascular only cohort showed that a one-unit increase in the WIfI mean score is associated with an increase in the risk of major amputation (all three cohorts; 5.3 [3.6–6.8], 4.1 [2.4–6.9], and 6.6 [3.8–11.6], respectively) and RAS events (all three cohorts; 1.7 [1.4–2.0], 1.9 [1.4–2.6], and 1.4 [1.1–1.9], respectively). The novel WIfI composite and WIfI mean scores were the only consistent predictors of mortality among the three cohorts, with the WIfI mean score proving most strongly predictive in the entire cohort (1.4 [1.1–1.7]), the bypass only cohort (1.5 [1.1–1.9]) and the endovascular only cohort (1.4 [1.0–1.8]). Although the individual WIfI wound component was able to predict mortality among all patients (1.1 [1.0–1.2]) and bypass only patients (1.2 [1.1–1.3]), no other individual WIfI component, nor the WIfI clinical stage, were able to significantly predict mortality among any cohort. CONCLUSION This study supports the ability of the SVS WIfI classification system to predict major amputation; however, the novel WIfI mean and WIfI composite scores predict amputation, RAS events, and mortality more consistently than any other current WIfI scoring system. The WIfI mean score allows inclusion of all limbs, and both novel scoring systems are easier to conceptualize, give equal weight to each WIfI component, and may provide clinicians more effective comparisons in outcomes between patients. PMID:28073665

Whole genome comparison between table and wine grapes reveals a comprehensive catalog of structural variants

PubMed Central

2014-01-01

Background Grapevine (Vitis vinifera L.) is the most important Mediterranean fruit crop, used to produce both wine and spirits as well as table grape and raisins. Wine and table grape cultivars represent two divergent germplasm pools with different origins and domestication history, as well as differential characteristics for berry size, cluster architecture and berry chemical profile, among others. ‘Sultanina’ plays a pivotal role in modern table grape breeding providing the main source of seedlessness. This cultivar is also one of the most planted for fresh consumption and raisins production. Given its importance, we sequenced it and implemented a novel strategy for the de novo assembly of its highly heterozygous genome. Results Our approach produced a draft genome of 466 Mb, recovering 82% of the genes present in the grapevine reference genome; in addition, we identified 240 novel genes. A large number of structural variants and SNPs were identified. Among them, 45 (21 SNPs and 24 INDELs) were experimentally confirmed in ‘Sultanina’ and six SNPs in other 23 table grape varieties. Transposable elements corresponded to ca. 80% of the repetitive sequences involved in structural variants and more than 2,000 genes were affected in their structure by these variants. Some of these genes are likely involved in embryo development, suggesting that they may contribute to seedlessness, a key trait for table grapes. Conclusions This work produced the first structural variants and SNPs catalog for grapevine, constituting a novel and very powerful tool for genomic studies in this key fruit crop, particularly useful to support marker assisted breeding in table grapes. PMID:24397443

Polymerization-Defective Fibrinogen Variant gammaD364A Binds Knob “A” Peptide Mimic

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

Bowley,S.; Merenbloom, B.; Heroux, A.

2008-01-01

Fibrin polymerization is supported in part by interactions called 'A:a'. Crystallographic studies revealed ?364Asp is part of hole 'a' that interacts with knob 'A' peptide mimic, GPRP. Biochemical studies have shown ?364Asp is critical to polymerization, as polymerization of variants ?D364A, ?D364H, and ?D364V is exceptionally impaired. To understand the molecular basis for the aberrant function, we solved the crystal structure of fragment D from ?D364A. Surprisingly, the structure (rfD-?D364A+GP) showed near normal 'A:a' interactions with GPRP bound to hole 'a' and no change in the overall structure of ?D364A. Of note, inspection of the structure showed negative electrostatic potentialmore » inside hole 'a' was diminished by this substitution. We examined GPRP binding to the ?364Asp variants in solution by plasmin protection assay. We found no protection of either ?D364H or ?D364V but partial protection of ?D364A, indicating the peptide does not bind to either ?D364H or ?D364V and binds more weakly than normal to ?D364A. We also examined protection by calcium and found all variants were indistinguishable from normal, suggesting the global structures of the variants are not markedly different from normal. Our data imply that ?364Asp per se is not required for knob 'A' binding to hole 'a'; rather, this residue's negative charge has a critical role in the electrostatic interactions that facilitate the important first step in fibrin polymerization.« less

A hetero-micro-seeding strategy for readily crystallizing closely related protein variants.

PubMed

Islam, Mohammad M; Kuroda, Yutaka

2017-11-04

Protein crystallization remains difficult to rationalize and screening for optimal crystallization conditions is a tedious and time consuming procedure. Here, we report a hetero-micro-seeding strategy for producing high resolution crystals of closely related protein variants, where micro crystals from a readily crystallized variant are used as seeds to develop crystals of other variants less amenable to crystallization. We applied this strategy to Bovine Pancreatic Trypsin Inhibitor (BPTI) variants, which would not crystallize using standard crystallization practice. Out of six variants in our analysis, only one called BPTI-[5,55]A14G formed well behaving crystals; and the remaining five (A14GA38G, A14GA38V, A14GA38L, A14GA38I, and A14GA38K) could be crystallized only using micro-seeds from the BPTI-[5,55]A14G crystal. All hetero-seeded crystals diffracted at high resolution with minimum mosaicity, retaining the same space group and cell dimension. Moreover, hetero-micro-seeding did not introduce any biases into the mutant's structure toward the seed structure, as demonstrated by A14GA38I structures solved using micro-seeds from A14GA38G, A14GA38L and A14GA38I. Though hetero-micro-seeding is a simple and almost naïve strategy, this is the first direct demonstration of its workability. We believe that hetero-micro-seeding, which is contrasting with the popular idea that crystallization requires highly purified proteins, could contribute a new tool for rapidly solving protein structures in mutational analysis studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1.

PubMed

Nishimasu, Hiroshi; Yamano, Takashi; Gao, Linyi; Zhang, Feng; Ishitani, Ryuichiro; Nureki, Osamu

2017-07-06

The RNA-guided Cpf1 nuclease cleaves double-stranded DNA targets complementary to the CRISPR RNA (crRNA), and it has been harnessed for genome editing technologies. Recently, Acidaminococcus sp. BV3L6 (AsCpf1) was engineered to recognize altered DNA sequences as the protospacer adjacent motif (PAM), thereby expanding the target range of Cpf1-mediated genome editing. Whereas wild-type AsCpf1 recognizes the TTTV PAM, the RVR (S542R/K548V/N552R) and RR (S542R/K607R) variants can efficiently recognize the TATV and TYCV PAMs, respectively. However, their PAM recognition mechanisms remained unknown. Here we present the 2.0 Å resolution crystal structures of the RVR and RR variants bound to a crRNA and its target DNA. The structures revealed that the RVR and RR variants primarily recognize the PAM-complementary nucleotides via the substituted residues. Our high-resolution structures delineated the altered PAM recognition mechanisms of the AsCpf1 variants, providing a basis for the further engineering of CRISPR-Cpf1. Copyright © 2017 Elsevier Inc. All rights reserved.

Alteration of the α1β2/α2β1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice

PubMed Central

Inoguchi, Noriko; Mizuno, Nobuhiro; Baba, Seiki; Kumasaka, Takashi; Natarajan, Chandrasekhar; Storz, Jay F.

2017-01-01

Background Deer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant. Results Highland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 Å. Using the smaller unit cell crystal, the structure was solved at 2.2 Å resolution. The asymmetric unit contained two tetrameric hemoglobin molecules. Conclusions The analyses revealed that αPro50 in the highland hemoglobin variant promoted a stable interaction between αHis45 and heme that was not seen in the αHis50 lowland variant. The αPro50 mutation also altered the nature of atomic contacts at the α1β2/α2β1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites. PMID:28362841

Alteration of the α1β2/α2β1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice

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

Inoguchi, Noriko; Mizuno, Nobuhiro; Baba, Seiki

2017-03-31

Deer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant. Highland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 Å. Using the smaller unit cell crystal, the structure was solved at 2.2 Å resolution. The asymmetric unit contained two tetramericmore » hemoglobin molecules. The analyses revealed that αPro50 in the highland hemoglobin variant promoted a stable interaction between αHis45 and heme that was not seen in the αHis50 lowland variant. The αPro50 mutation also altered the nature of atomic contacts at the α1β2/α2β1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites.« less

GSFC_20171112_M12778_Antares

NASA Image and Video Library

2017-11-12

The International Space Station received about 7,400 pounds of cargo, including new science and technology investigations, following the successful launch of Orbital ATK's Cygnus spacecraft from NASA's Wallops Flight Facility in Virginia on Sunday, Nov. 12, 2017. Orbital ATK's eighth contracted cargo delivery flight to the station launched at 7:19 a.m. EST on an Antares rocket from Pad 0A at Wallops, and arrived at the International Space Station Tuesday, Nov. 14, 2017. For more footage in higher resolution go to: https://svs.gsfc.nasa.gov/12778

DangerTrack: A scoring system to detect difficult-to-assess regions.

PubMed

Dolgalev, Igor; Sedlazeck, Fritz; Busby, Ben

2017-01-01

Over recent years, multiple groups have shown that a large number of structural variants, repeats, or problems with the underlying genome assembly have dramatic effects on the mapping, calling, and overall reliability of single nucleotide polymorphism calls. This project endeavored to develop an easy-to-use track for looking at structural variant and repeat regions. This track, DangerTrack, can be displayed alongside the existing Genome Reference Consortium assembly tracks to warn clinicians and biologists when variants of interest may be incorrectly called, of dubious quality, or on an insertion or copy number expansion. While mapping and variant calling can be automated, it is our opinion that when these regions are of interest to a particular clinical or research group, they warrant a careful examination, potentially involving localized reassembly. DangerTrack is available at https://github.com/DCGenomics/DangerTrack.

Structure–activity correlations of variant forms of the B pentamer of Escherichia coli type II heat-labile enterotoxin LT-IIb with Toll-like receptor 2 binding

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

Cody, Vivian, E-mail: cody@hwi.buffalo.edu; University at Buffalo, 700 Ellicott Street, Buffalo, NY 14203; Pace, Jim

2012-12-01

Structural data for the S74D variant of the pentameric B subunit of type II heat-labile enterotoxin of Escherichia coli reveal a smaller pore opening that may explain its reduced Toll-like receptor binding affinity compared to that of the wild type enterotoxin. The explanation for the enhanced Toll-like receptor binding affinity of the S74A variant is more complex than simply being attributed to the pore opening. The pentameric B subunit of the type II heat-labile enterotoxin of Escherichia coli (LT-IIb-B{sub 5}) is a potent signaling molecule capable of modulating innate immune responses. It has previously been shown that LT-IIb-B{sub 5}, butmore » not the LT-IIb-B{sub 5} Ser74Asp variant [LT-IIb-B{sub 5}(S74D)], activates Toll-like receptor (TLR2) signaling in macrophages. Consistent with this, the LT-IIb-B{sub 5}(S74D) variant failed to bind TLR2, in contrast to LT-IIb-B{sub 5} and the LT-IIb-B{sub 5} Thr13Ile [LT-IIb-B{sub 5}(T13I)] and LT-IIb-B{sub 5} Ser74Ala [LT-IIb-B{sub 5}(S74A)] variants, which displayed the highest binding activity to TLR2. Crystal structures of the Ser74Asp, Ser74Ala and Thr13Ile variants of LT-IIb-B{sub 5} have been determined to 1.90, 1.40 and 1.90 Å resolution, respectively. The structural data for the Ser74Asp variant reveal that the carboxylate side chain points into the pore, thereby reducing the pore size compared with that of the wild-type or the Ser74Ala variant B pentamer. On the basis of these crystallographic data, the reduced TLR2-binding affinity of the LT-IIb-B{sub 5}(S74D) variant may be the result of the pore of the pentamer being closed. On the other hand, the explanation for the enhanced TLR2-binding activity of the LT-IIb-B{sub 5}(S74A) variant is more complex as its activity is greater than that of the wild-type B pentamer, which also has an open pore as the Ser74 side chain points away from the pore opening. Data for the LT-IIb-B{sub 5}(T13I) variant show that four of the five variant side chains point to the outside surface of the pentamer and one residue points inside. These data are consistent with the lack of binding of the LT-IIb-B{sub 5}(T13I) variant to GD1a ganglioside.« less

The glycan structure of albumin Redhill, a glycosylated variant of human serum albumin.

PubMed

Kragh-Hansen, U; Donaldson, D; Jensen, P H

2001-11-26

Although human serum albumin is synthesized without carbohydrate, glycosylated variants of the protein can be found. We have determined the structure of the glycan bound to the double-mutant albumin Redhill (-1 Arg, 320 Ala-->Thr). The oligosaccharide was released from the protein using anhydrous hydrazine, and its structure was investigated using neuraminidase and a reagent array analysis method, which is based on the use of specific exoglycosidases. The glycan was shown to be a disialylated biantennary complex type oligosaccharide N-linked to 318 Asn. However, a minor part (11 mol%) of the glycan was without sialic acid. The structure is principally the same as that of glycans bound to two other types of glycosylated albumin variants. Glycosylation can affect, for example, the fatty acid binding properties of albumin. Taking the present information into account, it is apparent that different effects on binding are caused not by different glycan structures but by different locations of attachment, with the possible addition of local conformational changes in the protein molecule.

Using ClinVar as a Resource to Support Variant Interpretations

PubMed Central

Harrison, Steven M.; Riggs, Erin R.; Maglott, Donna R.; Lee, Jennifer M.; Azzariti, Danielle R.; Niehaus, Annie; Ramos, Erin M.; Martin, Christa L.; Landrum, Melissa J.; Rehm, Heidi L.

2016-01-01

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar with by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation. PMID:27037489

Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia

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

Wang, Chunxue; Pallan, Pradeep S.; Zhang, Wei

Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12more » variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37–13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3-progesterone, indicating that C–H bond breaking is a rate-limiting step over a 104-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.« less

affy2sv: an R package to pre-process Affymetrix CytoScan HD and 750K arrays for SNP, CNV, inversion and mosaicism calling.

PubMed

Hernandez-Ferrer, Carles; Quintela Garcia, Ines; Danielski, Katharina; Carracedo, Ángel; Pérez-Jurado, Luis A; González, Juan R

2015-05-20

The well-known Genome-Wide Association Studies (GWAS) had led to many scientific discoveries using SNP data. Even so, they were not able to explain the full heritability of complex diseases. Now, other structural variants like copy number variants or DNA inversions, either germ-line or in mosaicism events, are being studies. We present the R package affy2sv to pre-process Affymetrix CytoScan HD/750k array (also for Genome-Wide SNP 5.0/6.0 and Axiom) in structural variant studies. We illustrate the capabilities of affy2sv using two different complete pipelines on real data. The first one performing a GWAS and a mosaic alterations detection study, and the other detecting CNVs and performing an inversion calling. Both examples presented in the article show up how affy2sv can be used as part of more complex pipelines aimed to analyze Affymetrix SNP arrays data in genetic association studies, where different types of structural variants are considered.

Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A

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

Galaleldeen, Ahmad; Strange, Richard W.; Whitson, Lisa J.

2010-07-19

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper-zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here wemore » report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins.« less

Human Apolipoprotein A-I Natural Variants: Molecular Mechanisms Underlying Amyloidogenic Propensity

PubMed Central

Ramella, Nahuel A.; Schinella, Guillermo R.; Ferreira, Sergio T.; Prieto, Eduardo D.; Vela, María E.; Ríos, José Luis

2012-01-01

Human apolipoprotein A-I (apoA-I)-derived amyloidosis can present with either wild-type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA-I variants deposit causing multiple organ failure. More than 15 single amino acid replacement amyloidogenic apoA-I variants have been described, but the molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here, we have investigated by fluorescence and biochemical approaches the stabilities and propensities to aggregate of two disease-associated apoA-I variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that both variants share common structural properties including decreased stability compared to Wt apoA-I and a more flexible structure that gives rise to formation of partially folded states. Interestingly, however, distinct features appear to determine their pathogenic mechanisms. ApoA-ILys107-0 has an increased propensity to aggregate at physiological pH and in a pro-inflammatory microenvironment than Wt apoA-I, whereas apoA-IGly26Arg elicited macrophage activation, thus stimulating local chronic inflammation. Our results strongly suggest that some natural mutations in apoA-I variants elicit protein tendency to aggregate, but in addition the specific interaction of different variants with macrophages may contribute to cellular stress and toxicity in hereditary amyloidosis. PMID:22952757

Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease.

PubMed

Nho, Kwangsik; Horgusluoglu, Emrin; Kim, Sungeun; Risacher, Shannon L; Kim, Dokyoon; Foroud, Tatiana; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2016-08-12

Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). A total of 839 rare variants (MAF < 1/√(2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ε4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ε4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.

Structural insights into methanol-stable variants of lipase T6 from Geobacillus stearothermophilus.

PubMed

Dror, Adi; Kanteev, Margarita; Kagan, Irit; Gihaz, Shalev; Shahar, Anat; Fishman, Ayelet

2015-11-01

Enzymatic production of biodiesel by transesterification of triglycerides and alcohol, catalyzed by lipases, offers an environmentally friendly and efficient alternative to the chemically catalyzed process while using low-grade feedstocks. Methanol is utilized frequently as the alcohol in the reaction due to its reactivity and low cost. However, one of the major drawbacks of the enzymatic system is the presence of high methanol concentrations which leads to methanol-induced unfolding and inactivation of the biocatalyst. Therefore, a methanol-stable lipase is of great interest for the biodiesel industry. In this study, protein engineering was applied to substitute charged surface residues with hydrophobic ones to enhance the stability in methanol of a lipase from Geobacillus stearothermophilus T6. We identified a methanol-stable variant, R374W, and combined it with a variant found previously, H86Y/A269T. The triple mutant, H86Y/A269T/R374W, had a half-life value at 70 % methanol of 324 min which reflects an 87-fold enhanced stability compared to the wild type together with elevated thermostability in buffer and in 50 % methanol. This variant also exhibited an improved biodiesel yield from waste chicken oil compared to commercial Lipolase 100L® and Novozyme® CALB. Crystal structures of the wild type and the methanol-stable variants provided insights regarding structure-stability correlations. The most prominent features were the extensive formation of new hydrogen bonds between surface residues directly or mediated by structural water molecules and the stabilization of Zn and Ca binding sites. Mutation sites were also characterized by lower B-factor values calculated from the X-ray structures indicating improved rigidity.

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

PubMed Central

Richards, Mark W.; Law, Edward W. P.; Rennalls, La’Verne P.; Busacca, Sara; O’Regan, Laura; Fry, Andrew M.; Fennell, Dean A.; Bayliss, Richard

2014-01-01

Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners. PMID:24706829

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain.

PubMed

Richards, Mark W; Law, Edward W P; Rennalls, La'Verne P; Busacca, Sara; O'Regan, Laura; Fry, Andrew M; Fennell, Dean A; Bayliss, Richard

2014-04-08

Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners.

Descriptive norms for 350 Chinese idioms with seven syntactic structures.

PubMed

Li, Degao; Zhang, Yu; Wang, Xiaolu

2016-12-01

The most important forms of idioms in Chinese, chengyus (CYs), have a fixed length of four Chinese characters. Most CYs are joined structures of two, two-character words-subject-verb units (SVs), verb-object units (VOs), structures of modification (SMs), or verb-verb units-or of four, one-character words. Both the first and second pairs of words in a four-word CY form an SV, a VO, or an SM. In the present study, normative measures were obtained for knowledge, familiarity, subjective frequency, age of acquisition, predictability, literality, and compositionality for 350 CYs, and the influences of the CYs' syntactic structures on the descriptive norms were analyzed. Consistent with previous studies, all of the norms yielded a high reliability, and there were strong correlations between knowledge, familiarity, subjective frequency, and age of acquisition, and between familiarity and predictability. Unlike in previous studies (e.g., Libben & Titone in Memory & Cognition, 36, 1103-1121, 2008), however, we observed a strong correlation between literality and compositionality. In general, the results seem to support a hybrid view of idiom representation and comprehension. According to the evaluation scores, we further concluded that CYs consisting of just one SM are less likely to be decomposable than those with a VOVO composition, and also less likely to be recognized through their constituent words, or to be familiar to, known by, or encountered by users. CYs with an SMSM composition are less likely than VOVO CYs to be decomposable or to be known or encountered by users. Experimental studies should investigate how a CY's syntactic structure influences its representation and comprehension.

The structure and mobility of the intervariant boundaries in 18R martensite in a Cu-Zn-Al alloy

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

Zhang, J.X.; Zheng, Y.F.; Zhao, L.C.

1999-05-28

Detailed crystallographic analysis was carried out on the martensitic transformation and the various variant combinations in 18R martensite in a Cu-Zn-Al alloy. The self-accommodation of martensitic shear strain is quite perfect within a variant group, but not effective or even does not exist for variant combinations which belong to different groups. Twenty-three unique variant combinations between 24 martensite variants can be divided into four groups, i.e. reflection twin, 180 rotation twin, 120 rotation twin and 90 rotation twin. TEM and HREM observations show that the A C boundary is straight, well-defined and perfectly coherent, the A B boundary is irrational,more » coherent and gradually curved, and the A D boundary is stepped. The A C and A B boundaries have obvious mobility, and the mobility is not effective for A D boundary. The interplate group boundaries are curved, blurred and immobile. The morphology, structure and mobility of interplate boundary are all related to the degree of self-accommodation and the misorientation of twin boundary.« less

Is the Susceptibility Vessel Sign on 3-Tesla Magnetic Resonance T2*-Weighted Imaging a Useful Tool to Predict Recanalization in Intravenous Tissue Plasminogen Activator?

PubMed

Yamamoto, N; Satomi, J; Harada, M; Izumi, Y; Nagahiro, S; Kaji, R

2016-09-01

The aim of this study was to investigate the independent factors associated with the absence of recanalization approximately 24 h after intravenous administration of tissue-type plasminogen activator (IV TPA). The previous studies have been conducted using 1.5-Tesla (T) magnetic resonance imaging (MRI). We studied whether the characteristics of 3-T MRI findings were useful to predict outcome and recanalization after IV tPA. Patients with internal carotid artery (ICA) or middle cerebral artery (MCA) (horizontal portion, M1; Sylvian portion, M2) occlusion and treated by IV tPA were enrolled. We studied whether the presence of susceptibility vessel sign (SVS) at M1 and low clot burden score on T2*-weighted imaging (T2*-CBS) on 3-T MRI were associated with the absence of recanalization. A total of 49 patients were enrolled (27 men; mean age, 73.9 years). MR angiography obtained approximately 24 h after IV tPA revealed recanalization in 21 (42.9 %) patients. Independent factors associated with the absence of recanalization included ICA or proximal M1 occlusion (odds ratio, 69.6; 95 % confidence interval, 5.05-958.8, p = 0.002). In this study, an independent factor associated with the absence of recanalization may be proximal occlusion of the cerebral arteries rather than SVS in the MCA or low T2*-CBS on 3-T MRI.

Separate neural substrates in the human cerebellum for sensory-motor adaptation of reactive and of scanning voluntary saccades.

PubMed

Alahyane, N; Fonteille, V; Urquizar, C; Salemme, R; Nighoghossian, N; Pelisson, D; Tilikete, C

2008-01-01

Sensory-motor adaptation processes are critically involved in maintaining accurate motor behavior throughout life. Yet their underlying neural substrates and task-dependency bases are still poorly understood. We address these issues here by studying adaptation of saccadic eye movements, a well-established model of sensory-motor plasticity. The cerebellum plays a major role in saccadic adaptation but it has not yet been investigated whether this role can account for the known specificity of adaptation to the saccade type (e.g., reactive versus voluntary). Two patients with focal lesions in different parts of the cerebellum were tested using the double-step target paradigm. Each patient was submitted to two separate sessions: one for reactive saccades (RS) triggered by the sudden appearance of a visual target and the second for scanning voluntary saccades (SVS) performed when exploring a more complex scene. We found that a medial cerebellar lesion impaired adaptation of reactive-but not of voluntary-saccades, whereas a lateral lesion affected adaptation of scanning voluntary saccades, but not of reactive saccades. These findings provide the first evidence of an involvement of the lateral cerebellum in saccadic adaptation, and extend the demonstrated role of the cerebellum in RS adaptation to adaptation of SVS. The double dissociation of adaptive abilities is also consistent with our previous hypothesis of the involvement in saccadic adaptation of partially separated cerebellar areas specific to the reactive or voluntary task (Alahyane et al. Brain Res 1135:107-121 (2007)).

Stochastic subset selection for learning with kernel machines.

PubMed

Rhinelander, Jason; Liu, Xiaoping P

2012-06-01

Kernel machines have gained much popularity in applications of machine learning. Support vector machines (SVMs) are a subset of kernel machines and generalize well for classification, regression, and anomaly detection tasks. The training procedure for traditional SVMs involves solving a quadratic programming (QP) problem. The QP problem scales super linearly in computational effort with the number of training samples and is often used for the offline batch processing of data. Kernel machines operate by retaining a subset of observed data during training. The data vectors contained within this subset are referred to as support vectors (SVs). The work presented in this paper introduces a subset selection method for the use of kernel machines in online, changing environments. Our algorithm works by using a stochastic indexing technique when selecting a subset of SVs when computing the kernel expansion. The work described here is novel because it separates the selection of kernel basis functions from the training algorithm used. The subset selection algorithm presented here can be used in conjunction with any online training technique. It is important for online kernel machines to be computationally efficient due to the real-time requirements of online environments. Our algorithm is an important contribution because it scales linearly with the number of training samples and is compatible with current training techniques. Our algorithm outperforms standard techniques in terms of computational efficiency and provides increased recognition accuracy in our experiments. We provide results from experiments using both simulated and real-world data sets to verify our algorithm.

Using Scientific Visualizations to Enhance Scientific Thinking In K-12 Geoscience Education

NASA Astrophysics Data System (ADS)

Robeck, E.

2016-12-01

The same scientific visualizations, animations, and images that are powerful tools for geoscientists can serve an important role in K-12 geoscience education by encouraging students to communicate in ways that help them develop habits of thought that are similar to those used by scientists. Resources such as those created by NASA's Scientific Visualization Studio (SVS), which are intended to inform researchers and the public about NASA missions, can be used in classrooms to promote thoughtful, engaged learning. Instructional materials that make use of those visualizations have been developed and are being used in K-12 classrooms in ways that demonstrate the vitality of the geosciences. For example, the Center for Geoscience and Society at the American Geosciences Institute (AGI) helped to develop a publication that outlines an inquiry-based approach to introducing students to the interpretation of scientific visualizations, even when they have had little to no prior experience with such media. To facilitate these uses, the SVS team worked with Center staff and others to adapt the visualizations, primarily by removing most of the labels and annotations. Engaging with these visually compelling resources serves as an invitation for students to ask questions, interpret data, draw conclusions, and make use of other processes that are key components of scientific thought. This presentation will share specific resources for K-12 teaching (all of which are available online, from NASA, and/or from AGI), as well as the instructional principles that they incorporate.

Anti-microbial peptide facilitated cytosolic delivery of metallic gold nanomaterials

NASA Astrophysics Data System (ADS)

Kapur, Anshika; Wang, Wentao; Diaz Hernandez, Juan; Medina, Scott; Schneider, Joel P.; Mattoussi, Hedi

2018-02-01

The unique photophysical properties of gold nanomaterials combined with progress in developing effective surfacefunctionalization strategies has motivated researchers to employ them as tools for use in biomedical imaging, biosensing, diagnostics, photothermal therapy, and as drug and gene delivery vehicles. However, a major challenge limiting these advancements has been the unavailability of effective strategies to deliver these and other nanocrystals into the cytoplasm of live cells. In this study, we demonstrate that the use of a chemically-synthesized anti-microbial peptide, SVS-1, can promote non-endocytic uptake of both small size gold nanoparticles (AuNPs) and larger size gold nanorods (AuNRs) into mammalian cells. For this, colloidally stable AuNP and AuNRs, surface ligated with an amine-functionalized polymer, His-PIMA-PEG-OCH3/NH2 were prepared. The amine groups allow dual, covalent attachment of cysteine terminated SVS-1 (via a thioether linkage) and NHS-ester-Texas-Red dye onto the nanocrystal surfaces. We use fluorescence microscopy to demonstrate nanocrystal staining throughout the cytoplasmic volume of the cells incubated with these conjugates. More importantly, we have conducted additional endocytosis inhibition experiments where cells were incubated with the conjugates at 4°C. Here too, the imaging data have shown significant levels of nanocrystal uptake, further verifying that physical translocation of these conjugates takes place through the cell membrane independent of endocytosis. These findings are promising and can provide critical support for the widespread applications of nanomaterials in the field of biology.

Effect of Human Milk Appetite Hormones, Macronutrients, and Infant Characteristics on Gastric Emptying and Breastfeeding Patterns of Term Fully Breastfed Infants.

PubMed

Gridneva, Zoya; Kugananthan, Sambavi; Hepworth, Anna R; Tie, Wan J; Lai, Ching T; Ward, Leigh C; Hartmann, Peter E; Geddes, Donna T

2016-12-28

Human milk (HM) components influence infant feeding patterns and nutrient intake, yet it is unclear how they influence gastric emptying (GE), a key component of appetite regulation. This study analyzed GE of a single breastfeed, HM appetite hormones/macronutrients and demographics/anthropometrics/body composition of term fully breastfed infants ( n = 41, 2 and/or 5 mo). Stomach volumes (SV) were calculated from pre-/post-feed ultrasound scans, then repeatedly until the next feed. Feed volume (FV) was measured by the test-weigh method. HM samples were analyzed for adiponectin, leptin, fat, lactose, total carbohydrate, lysozyme, and total/whey/casein protein. Linear regression/mixed effect models were used to determine associations between GE/feed variables and HM components/infant anthropometrics/adiposity. Higher FVs were associated with faster (-0.07 [-0.10, -0.03], p < 0.001) GE rate, higher post-feed SVs (0.82 [0.53, 1.12], p < 0.001), and longer GE times (0.24 [0.03, 0.46], p = 0.033). Higher whey protein concentration was associated with higher post-feed SVs (4.99 [0.84, 9.13], p = 0.023). Longer GE time was associated with higher adiponectin concentration (2.29 [0.92, 3.66], p = 0.002) and dose (0.02 [0.01, 0.03], p = 0.005), and lower casein:whey ratio (-65.89 [-107.13, -2.66], p = 0.003). FV and HM composition influence GE and breastfeeding patterns in term breastfed infants.

High speed research system study. Advanced flight deck configuration effects

NASA Technical Reports Server (NTRS)

Swink, Jay R.; Goins, Richard T.

1992-01-01

In mid-1991 NASA contracted with industry to study the high-speed civil transport (HSCT) flight deck challenges and assess the benefits, prior to initiating their High Speed Research Program (HSRP) Phase 2 efforts, then scheduled for FY-93. The results of this nine-month effort are presented, and a number of the most significant findings for the specified advanced concepts are highlighted: (1) a no nose-droop configuration; (2) a far forward cockpit location; and (3) advanced crew monitoring and control of complex systems. The results indicate that the no nose-droop configuration is critically dependent upon the design and development of a safe, reliable, and certifiable Synthetic Vision System (SVS). The droop-nose configuration would cause significant weight, performance, and cost penalties. The far forward cockpit location, with the conventional side-by-side seating provides little economic advantage; however, a configuration with a tandem seating arrangement provides a substantial increase in either additional payload (i.e., passengers) or potential downsizing of the vehicle with resulting increases in performance efficiencies and associated reductions in emissions. Without a droop nose, forward external visibility is negated and takeoff/landing guidance and control must rely on the use of the SVS. The technologies enabling such capabilities, which de facto provides for Category 3 all-weather operations on every flight independent of weather, represent a dramatic benefits multiplier in a 2005 global ATM network: both in terms of enhanced economic viability and environmental acceptability.

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.

PubMed

Romanelli Tavares, Vanessa L; Gordon, Christopher T; Zechi-Ceide, Roseli M; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Y; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J; Papsin, Blake C; Torres, Tatiana T; Buermans, Henk; Capelo, Luciane Portas; den Dunnen, Johan T; Guion-Almeida, Maria L; Lyonnet, Stanislas; Amiel, Jeanne; Passos-Bueno, Maria Rita

2015-04-01

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.

Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

PubMed

Bravo-Alonso, Irene; Navarrete, Rosa; Arribas-Carreira, Laura; Perona, Almudena; Abia, David; Couce, María Luz; García-Cazorla, Angels; Morais, Ana; Domingo, Rosario; Ramos, María Antonia; Swanson, Michael A; Van Hove, Johan L K; Ugarte, Magdalena; Pérez, Belén; Pérez-Cerdá, Celia; Rodríguez-Pombo, Pilar

2017-06-01

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches. © 2017 Wiley Periodicals, Inc.

Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics.

PubMed

Borbulevych, Oleg Y; Do, Priscilla; Baker, Brian M

2010-09-01

Presentation of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126-134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex. Copyright 2010 Elsevier Ltd. All rights reserved.

Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes.

PubMed

Edrees, Burhan M; Athar, Mohammad; Abduljaleel, Zainularifeen; Al-Allaf, Faisal A; Taher, Mohiuddin M; Khan, Wajahatullah; Bouazzaoui, Abdellatif; Al-Harbi, Naffaa; Safar, Ramzia; Al-Edressi, Howaida; Alansary, Khawala; Anazi, Abulkareem; Altayeb, Naji; Ahmed, Muawia A

2016-12-01

A targeted customized sequencing of genes implicated in autosomal recessive polycystic kidney disease (ARPKD) phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified four potential pathogenic variants in PKHD1 gene [c.4870C > T, p.(Arg1624Trp), c.5725C > T, p.(Arg1909Trp), c.1736C > T, p.(Thr579Met) and c.10628T > G, p.(Leu3543Trp)] among 12 out of 18 samples. However, one variant c.4870C > T, p.(Arg1624Trp) was common among eight patients. Some patient samples also showed few variants in autosomal dominant polycystic kidney disease (ADPKD) disease causing genes PKD1 and PKD2 such as c.12433G > A, p.(Val4145Ile) and c.1445T > G, p.(Phe482Cys), respectively. All causative variants were validated by capillary sequencing and confirmed the presence of a novel homozygous variant c.10628T > G, p.(Leu3543Trp) in a male proband. We have recently published the results of these studies (Edrees et al., 2016). Here we report for the first time the effect of the common mutation p.(Arg1624Trp) found in eight samples on the protein structure and function due to the specific amino acid changes of PKHD1 protein using molecular dynamics simulations. The computational approaches provide tool predict the phenotypic effect of variant on the structure and function of the altered protein. The structural analysis with the common mutation p.(Arg1624Trp) in the native and mutant modeled protein were also studied for solvent accessibility, secondary structure and stabilizing residues to find out the stability of the protein between wild type and mutant forms. Furthermore, comparative genomics and evolutionary analyses of variants observed in PKHD1 , PKD1 , and PKD2 genes were also performed in some mammalian species including human to understand the complexity of genomes among closely related mammalian species. Taken together, the results revealed that the evolutionary comparative analyses and characterization of PKHD1 , PKD1 , and PKD2 genes among various related and unrelated mammalian species will provide important insights into their evolutionary process and understanding for further disease characterization and management.

Adaptation of tick-borne encephalitis virus from human brain to different cell cultures induces multiple genomic substitutions.

PubMed

Ponomareva, Eugenia P; Ternovoi, Vladimir A; Mikryukova, Tamara P; Protopopova, Elena V; Gladysheva, Anastasia V; Shvalov, Alexander N; Konovalova, Svetlana N; Chausov, Eugene V; Loktev, Valery B

2017-10-01

The C11-13 strain from the Siberian subtype of tick-borne encephalitis virus (TBEV) was isolated from human brain using pig embryo kidney (PEK), 293, and Neuro-2a cells. Analysis of the complete viral genome of the C11-13 variants during six passages in these cells revealed that the cell-adapted C11-13 variants had multiple amino acid substitutions as compared to TBEV from human brain. Seven out of eight amino acids substitutions in the high-replicating C11-13(PEK) variant mapped to non-structural proteins; 13 out of 14 substitutions in the well-replicating C11-13(293) variant, and all four substitutions in the low-replicating C11-13(Neuro-2a) variant were also localized in non-structural proteins, predominantly in the NS2a (2), NS3 (6) and NS5 (3) proteins. The substitutions NS2a 1067 (Asn → Asp), NS2a 1168 (Leu → Val) in the N-terminus of NS2a and NS3 1745 (His → Gln) in the helicase domain of NS3 were found in all selected variants. We postulate that multiple substitutions in the NS2a, NS3 and NS5 genes play a key role in adaptation of TBEV to different cells.

Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency.

PubMed

Breitfeld, Jana; Martens, Susanne; Klammt, Jürgen; Schlicke, Marina; Pfäffle, Roland; Krause, Kerstin; Weidle, Kerstin; Schleinitz, Dorit; Stumvoll, Michael; Führer, Dagmar; Kovacs, Peter; Tönjes, Anke

2013-12-01

The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.

Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency

PubMed Central

2013-01-01

Background The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. Methods We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Results Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. Conclusions A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD. PMID:24289245

Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system following infrapopliteal endovascular interventions for critical limb ischemia.

PubMed

Darling, Jeremy D; McCallum, John C; Soden, Peter A; Meng, Yifan; Wyers, Mark C; Hamdan, Allen D; Verhagen, Hence J; Schermerhorn, Marc L

2016-09-01

The Society for Vascular Surgery (SVS) Lower Extremity Guidelines Committee has composed a new threatened lower extremity classification system that reflects the three major factors that impact amputation risk and clinical management: Wound, Ischemia, and foot Infection (WIfI). Our goal was to evaluate the predictive ability of this scale following any infrapopliteal endovascular intervention for critical limb ischemia (CLI). From 2004 to 2014, a single institution, retrospective chart review was performed at the Beth Israel Deaconess Medical Center for all patients undergoing an infrapopliteal angioplasty for CLI. Throughout these years, 673 limbs underwent an infrapopliteal endovascular intervention for tissue loss (77%), rest pain (13%), stenosis of a previously treated vessel (5%), acute limb ischemia (3%), or claudication (2%). Limbs missing a grade in any WIfI component were excluded. Limbs were stratified into clinical stages 1 to 4 based on the SVS WIfI classification for 1-year amputation risk, as well as a novel WIfI composite score from 0 to 9. Outcomes included patient functional capacity, living status, wound healing, major amputation, major adverse limb events, reintervention, major amputation, or stenosis (RAS) events (> ×3.5 step-up by duplex), amputation-free survival, and mortality. Predictors were identified using Kaplan-Meier survival estimates and Cox regression models. Of the 596 limbs with CLI, 551 were classified in all three WIfI domains on a scale of 0 (least severe) to 3 (most severe). Of these 551, 84% were treated for tissue loss and 16% for rest pain. A Cox regression model illustrated that an increase in clinical stage increases the rate of major amputation (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.3). Separate regression models showed that a one-unit increase in the WIfI composite score is associated with a decrease in wound healing (HR, 1.2; 95% CI, 1.1-1.4) and an increase in the rate of RAS events (HR, 1.2; 95% CI, 1.1-1.4) and major amputations (HR, 1.4; 95% CI, 1.2-1.8). This study supports the ability of the SVS WIfI classification system to predict 1-year amputation, RAS events, and wound healing in patients with CLI undergoing endovascular infrapopliteal revascularization procedures. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

A new microsporidium, Apotaspora heleios n. g., n. sp., from the Riverine grass shrimp Palaemonetes paludosus (Decapoda: Caridea: Palaemonidae).

PubMed

Sokolova, Yuliya Y; Overstreet, Robin M

2018-05-19

We report a new microsporidium from a key species of the estuarine communities of the Gulf States, the Riverine grass shrimp, Palaemonetes paludosus. A milky-white shrimp was found in the Mobile Bay Delta, a large, oligohaline-freshwater wetland in Alabama, USA. Light microscopy of smears and thick sections of the abdominal tissues demonstrated infection with microsporidian spores enclosed in sporophorous vesicles (SVs) in sets of eight. Broadly oval spores measured 2.9 ± 0.06 × 1.7 ± 0.03 µm (2.5-3.3 × 1.6-1.9 µm, n = 11). SVs with a persistent membrane ranged from 4.4 to 5.6 µm in diameter. Subcuticular epithelium and underlying musculature were packed with sporonts, sporoblasts, and spores. Electron microscopy demonstrated diplokaryotic meronts that gave rise to sporont mother cells with a large single nucleus. The meront plasma membrane turned into a SV envelope, and the sporont wall segregated internally. The sporont nucleus underwent meiosis followed by two mitotic divisions accompanied by internal budding to produce four sporonts, each dividing in two uninucleate sporoblasts. Eight-spore SVs were filled with fibrillary-tubular secretions. Spores possessed 90-110-nm thick envelopes (exospore, 40-60 nm + endospore, 30-50 nm), a triangle-shaped nucleus, isofilar polar filament of 10-13 coils arranged in two-three rows, bipartite polaroplast, and a mushroom-shaped polar disk. The SSU rDNA sequence of the novel species was deposited in GenBank under Accession number MG 708238. SSU rDNA-based phylogenetic analysis indicated that the Riverine grass shrimp microsporidium was a new species and placed it in one branch with two species of Potaspora, xenoma-forming microsporidia from freshwater perciform fishes. Because morphological and developmental characters of the novel species did not fit the diagnosis of the genus Potaspora, and, based on SSU rDNA-inferred phylogenetic analyses, different host specificity, pathogenesis, and ecological considerations, we erect here the new genus Apotaspora for the Riverine grass shrimp microsporidium and name the new species Apotaspora heleios. Grouping together fish and crustacean parasites on SSU rDNA phylogenetic trees suggests that polyxenous life cycles might be a common feature of extinct and/or extant members of the studied lineage of the Microsporidia. Copyright © 2018 Elsevier Inc. All rights reserved.

Facies architecture of a Triassic rift-related Silicic Volcano-Sedimentary succession in the Tethyan realm, Peonias subzone, Vardar (Axios) Zone, northern Greece; Regional implications

NASA Astrophysics Data System (ADS)

Asvesta, Argyro; Dimitriadis, Sarantis

2010-06-01

In northern Greece, along the western edge of the Paleozoic Vertiscos terrane (Serbomacedonian massif) and within the Peonias subzone - the eastern part of the Vardar (Axios) Zone - a Silicic Volcano-Sedimentary (SVS) succession of Permo(?)-Skythian to Mid Triassic age records the development of a faulted continental margin and the formation of rhyolitic volcanoes along a continental shelf fringed by neritic carbonate accumulations. It represents the early rifting extensional stages that eventually led to the opening of the main oceanic basin in the western part of the Vardar (Axios) Zone (the Almopias Oceanic Basin). Even though the SVS succession is deformed, altered, extensively silicified and metamorphosed in the low greenschist facies, primary textures, original contacts and facies relationships are recognized in some places allowing clues for the facies architecture and the depositional environment. Volcanic and sedimentary facies analysis has been carried out at Nea Santa and Kolchida rhyolitic volcanic centres. Pyroclastic facies, mostly composed of gas-supported lapilli tuffs and locally intercalated accretionary lapilli tuffs, built the early cones which were then overridden by rhyolitic aphyric and minor K-feldspar-phyric lava flows. The characteristics of facies, especially the presence of accretionary lapilli, imply subaerial to coastal emplacement at this early stage. The mature and final stages of volcanism are mostly represented by quartz-feldspar porphyry intrusions that probably occupied the vents. At Nea Santa area, the presence of resedimented hyaloclastite facies indicates subaqueous emplacement of rhyolitic lavas and/or lobes. Moreover, quartz-feldspar-phyric sills and a partly extrusive dome featuring peperites at their margins are inferred to have intruded unconsolidated, wet carbonate sediments of the overlying Triassic Neritic Carbonate Formation, in a shallow submarine environment. The dome had probably reached above wave-base as is indicated by the presence of reworked rhyolitic clasts in the younger mixed rhyolite-carbonate epiclastic sedimentary facies. This facies is interpreted as mass- and debris-flow of mixed provenance, deposited below wave-base. The facies architecture of the SVS succession records a change in volcanic activity from explosive to effusive and then to intrusive. The depositional environment changed from subaerial-coastal to shallow submarine as the silicic volcanism evolved and carbonate sedimentation was progressively taking over, probably compensating for the gradual subsidence of the corresponding basin. Silicic magmatism and carbonate sedimentation were contemporaneous and spatially related. The timing of the rifting, the continental crustal elements involved and the accompanying tectonic, magmatic and sedimentary processes are features of the spatially and temporally evolving western peri-Tethyan region.

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

PubMed Central

Homburger, Julian R.; Green, Eric M.; Caleshu, Colleen; Sunitha, Margaret S.; Taylor, Rebecca E.; Ruppel, Kathleen M.; Metpally, Raghu Prasad Rao; Colan, Steven D.; Michels, Michelle; Day, Sharlene M.; Olivotto, Iacopo; Bustamante, Carlos D.; Dewey, Frederick E.; Ho, Carolyn Y.; Spudich, James A.; Ashley, Euan A.

2016-01-01

Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease. PMID:27247418

Functional and Structural Consequence of Rare Exonic Single Nucleotide Polymorphisms: One Story, Two Tales

PubMed Central

Gu, Wanjun; Gurguis, Christopher I.; Zhou, Jin J.; Zhu, Yihua; Ko, Eun-A.; Ko, Jae-Hong; Wang, Ting; Zhou, Tong

2015-01-01

Genetic variation arising from single nucleotide polymorphisms (SNPs) is ubiquitously found among human populations. While disease-causing variants are known in some cases, identifying functional or causative variants for most human diseases remains a challenging task. Rare SNPs, rather than common ones, are thought to be more important in the pathology of most human diseases. We propose that rare SNPs should be divided into two categories dependent on whether the minor alleles are derived or ancestral. Derived alleles are less likely to have been purified by evolutionary processes and may be more likely to induce deleterious effects. We therefore hypothesized that the rare SNPs with derived minor alleles would be more important for human diseases and predicted that these variants would have larger functional or structural consequences relative to the rare variants for which the minor alleles are ancestral. We systematically investigated the consequences of the exonic SNPs on protein function, mRNA structure, and translation. We found that the functional and structural consequences are more significant for the rare exonic variants for which the minor alleles are derived. However, this pattern is reversed when the minor alleles are ancestral. Thus, the rare exonic SNPs with derived minor alleles are more likely to be deleterious. Age estimation of rare SNPs confirms that these potentially deleterious SNPs are recently evolved in the human population. These results have important implications for understanding the function of genetic variations in human exonic regions and for prioritizing functional SNPs in genome-wide association studies of human diseases. PMID:26454016

Computational Redesign of Acyl-ACP Thioesterase with Improved Selectivity toward Medium-Chain-Length Fatty Acids

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

Grisewood, Matthew J.; Hernández-Lozada, Néstor J.; Thoden, James B.

Enzyme and metabolic engineering offer the potential to develop biocatalysts for converting natural resources to a wide range of chemicals. To broaden the scope of potential products beyond natural metabolites, methods of engineering enzymes to accept alternative substrates and/or perform novel chemistries must be developed. DNA synthesis can create large libraries of enzyme-coding sequences, but most biochemistries lack a simple assay to screen for promising enzyme variants. Our solution to this challenge is structure-guided mutagenesis, in which optimization algorithms select the best sequences from libraries based on specified criteria (i.e., binding selectivity). We demonstrate this approach by identifying medium-chain (C8–C12)more » acyl-ACP thioesterases through structure-guided mutagenesis. Medium-chain fatty acids, which are products of thioesterase-catalyzed hydrolysis, are limited in natural abundance, compared to long-chain fatty acids; the limited supply leads to high costs of C6–C10 oleochemicals such as fatty alcohols, amines, and esters. Here, we applied computational tools to tune substrate binding of the highly active ‘TesA thioesterase in Escherichia coli. We used the IPRO algorithm to design thioesterase variants with enhanced C12 or C8 specificity, while maintaining high activity. After four rounds of structure-guided mutagenesis, we identified 3 variants with enhanced production of dodecanoic acid (C12) and 27 variants with enhanced production of octanoic acid (C8). The top variants reached up to 49% C12 and 50% C8 while exceeding native levels of total free fatty acids. A comparably sized library created by random mutagenesis failed to identify promising mutants. The chain length-preference of ‘TesA and the best mutant were confirmed in vitro using acyl-CoA substrates. Molecular dynamics simulations, confirmed by resolved crystal structures, of ‘TesA variants suggest that hydrophobic forces govern ‘TesA substrate specificity. Finally, we expect the design rules that we uncovered and the thioesterase variants that we identified will be useful to metabolic engineering projects aimed at sustainable production of medium-chain-length oleochemicals.« less

Computational Redesign of Acyl-ACP Thioesterase with Improved Selectivity toward Medium-Chain-Length Fatty Acids

DOE PAGES

Grisewood, Matthew J.; Hernández-Lozada, Néstor J.; Thoden, James B.; ...

2017-04-20

Enzyme and metabolic engineering offer the potential to develop biocatalysts for converting natural resources to a wide range of chemicals. To broaden the scope of potential products beyond natural metabolites, methods of engineering enzymes to accept alternative substrates and/or perform novel chemistries must be developed. DNA synthesis can create large libraries of enzyme-coding sequences, but most biochemistries lack a simple assay to screen for promising enzyme variants. Our solution to this challenge is structure-guided mutagenesis, in which optimization algorithms select the best sequences from libraries based on specified criteria (i.e., binding selectivity). We demonstrate this approach by identifying medium-chain (C8–C12)more » acyl-ACP thioesterases through structure-guided mutagenesis. Medium-chain fatty acids, which are products of thioesterase-catalyzed hydrolysis, are limited in natural abundance, compared to long-chain fatty acids; the limited supply leads to high costs of C6–C10 oleochemicals such as fatty alcohols, amines, and esters. Here, we applied computational tools to tune substrate binding of the highly active ‘TesA thioesterase in Escherichia coli. We used the IPRO algorithm to design thioesterase variants with enhanced C12 or C8 specificity, while maintaining high activity. After four rounds of structure-guided mutagenesis, we identified 3 variants with enhanced production of dodecanoic acid (C12) and 27 variants with enhanced production of octanoic acid (C8). The top variants reached up to 49% C12 and 50% C8 while exceeding native levels of total free fatty acids. A comparably sized library created by random mutagenesis failed to identify promising mutants. The chain length-preference of ‘TesA and the best mutant were confirmed in vitro using acyl-CoA substrates. Molecular dynamics simulations, confirmed by resolved crystal structures, of ‘TesA variants suggest that hydrophobic forces govern ‘TesA substrate specificity. Finally, we expect the design rules that we uncovered and the thioesterase variants that we identified will be useful to metabolic engineering projects aimed at sustainable production of medium-chain-length oleochemicals.« less

Three-dimensional structure of a variant `Termamyl-like' Geobacillus stearothermophilus α-amylase at 1.9 Å resolution.

PubMed

Offen, Wendy A; Viksoe-Nielsen, Anders; Borchert, Torben V; Wilson, Keith S; Davies, Gideon J

2015-01-01

The enzyme-catalysed degradation of starch is central to many industrial processes, including sugar manufacture and first-generation biofuels. Classical biotechnological platforms involve steam explosion of starch followed by the action of endo-acting glycoside hydrolases termed α-amylases and then exo-acting α-glucosidases (glucoamylases) to yield glucose, which is subsequently processed. A key enzymatic player in this pipeline is the `Termamyl' class of bacterial α-amylases and designed/evolved variants thereof. Here, the three-dimensional structure of one such Termamyl α-amylase variant based upon the parent Geobacillus stearothermophilus α-amylase is presented. The structure has been solved at 1.9 Å resolution, revealing the classical three-domain fold stabilized by Ca2+ and a Ca2+-Na+-Ca2+ triad. As expected, the structure is similar to the G. stearothermophilus α-amylase but with main-chain deviations of up to 3 Å in some regions, reflecting both the mutations and differing crystal-packing environments.

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

Wu, Hong; Zeng, Hong; Lam, Robert

Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in theMLH1gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. Lastly, the structure shares a high degree of similarity with previously determined prokaryoticMLH1homologs; however, this structure affords a more accurate platform for the classification ofMLH1variants.

Variant Review with the Integrative Genomics Viewer.

PubMed

Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

2017-11-01

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

Solubilization of a membrane protein by combinatorial supercharging.

PubMed

Hajduczki, Agnes; Majumdar, Sudipta; Fricke, Marie; Brown, Isola A M; Weiss, Gregory A

2011-04-15

Hydrophobic and aggregation-prone, membrane proteins often prove too insoluble for conventional in vitro biochemical studies. To engineer soluble variants of human caveolin-1, a phage-displayed library of caveolin variants targeted the hydrophobic intramembrane domain with substitutions to charged residues. Anti-selections for insolubility removed hydrophobic variants, and positive selections for binding to the known caveolin ligand HIV gp41 isolated functional, folded variants. Assays with several caveolin binding partners demonstrated the successful folding and functionality by a solubilized, full-length caveolin variant selected from the library. This caveolin variant allowed assay of the direct interaction between caveolin and cavin. Clustered along one face of a putative helix, the solubilizing mutations suggest a structural model for the intramembrane domain of caveolin. The approach provides a potentially general method for solubilization and engineering of membrane-associated proteins by phage display.

Meta-analysis of gene-level tests for rare variant association.

PubMed

Liu, Dajiang J; Peloso, Gina M; Zhan, Xiaowei; Holmen, Oddgeir L; Zawistowski, Matthew; Feng, Shuang; Nikpay, Majid; Auer, Paul L; Goel, Anuj; Zhang, He; Peters, Ulrike; Farrall, Martin; Orho-Melander, Marju; Kooperberg, Charles; McPherson, Ruth; Watkins, Hugh; Willer, Cristen J; Hveem, Kristian; Melander, Olle; Kathiresan, Sekar; Abecasis, Gonçalo R

2014-02-01

The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.

Mass Spectrometric Determination of ILPR G-quadruplex Binding Sites in Insulin and IGF-2

PubMed Central

Xiao, JunFeng

2009-01-01

The insulin-linked polymorphic region (ILPR) of the human insulin gene promoter region forms G-quadruplex structures in vitro. Previous studies show that insulin and insulin-like growth factor-2 (IGF-2) exhibit high affinity binding in vitro to 2-repeat sequences of ILPR variants a and h, but negligible binding to variant i. Two-repeat sequences of variants a and h form intramolecular G-quadruplex structures that are not evidenced for variant i. Here we report on the use of protein digestion combined with affinity capture and MALDI-MS detection to pinpoint ILPR binding sites in insulin and IGF-2. Peptides captured by ILPR variants a and h were sequenced by MALDI-MS/MS, LC-MS and in silico digestion. On-bead digestion of insulin-ILPR variant a complexes supported the conclusions. The results indicate that the sequence VCG(N)RGF is generally present in the captured peptides and is likely involved in the affinity binding interactions of the proteins with the ILPR G-quadruplexes. The significance of arginine in the interactions was studied by comparing the affinities of synthesized peptides VCGERGF and VCGEAGF with ILPR variant a. Peptides from other regions of the proteins that are connected through disulfide linkages were also detected in some capture experiments. Identification of binding sites could facilitate design of DNA binding ligands for capture and detection of insulin and IGF-2. The interactions may have biological significance as well. PMID:19747845

Cap-independent translation of human SP-A 5′-UTR variants: a double-loop structure and cis-element contribution

PubMed Central

Wang, Guirong; Guo, Xiaoxuan; Silveyra, Patricia; Kimball, Scot R.; Floros, Joanna

2009-01-01

Human surfactant protein A (hSP-A), a molecule of innate immunity and surfactant-related functions, consists of two functional genes, SP-A1 and SP-A2. SP-A expression is regulated by several factors including environmental stressors. SP-A1 and SP-A2 5′-untranslated region (5′-UTR) splice variants have a differential impact on translation efficiency and mRNA stability. To study whether these variants mediate internal ribosome entry site (IRES) activity (i.e., cap-independent translation), we performed transient transfection experiments in H441 cells with constructs containing one SP-A1 (A′D′, AB′D′, or A′CD′) or SP-A2 (ABD) 5′-UTR splice variant between the Renilla and firefly luciferase genes of a bicistronic reporter vector. We found that 1) variants A′D′, ABD, and AB′D′ exhibit significantly higher IRES activities than negative control (no SP-A 5′-UTR) and A′CD′ has no activity; the order of highest IRES activity was ABD > A′D′ > AB′D; 2) IRES activity of ABD significantly increased in response to diesel particulate matter (20 μg/ml) but not in response to ozone (1 ppm for 1 h); 3) deletion mutants of ABD revealed regulatory elements associated with IRES activity; one at the end of exon A attenuated activity, whereas a region containing a short adenosine-rich motif in the second half of exon B and the start of exon D enhanced activity; 4) elimination of a predicted double-loop structure or increase in free energy significantly reduced IRES activity; 5) elimination of one or both double-loop structures in A′D′ did not affect cap-dependent translation activity. Thus several factors, including cis-elements and secondary structure type and stability, are required for hSP-A 5′-UTR variant-mediated cap-independent translation. PMID:19181744

Characterization and Expression of the Lucina pectinata Oxygen and Sulfide Binding Hemoglobin Genes

PubMed Central

López-Garriga, Juan; Cadilla, Carmen L.

2016-01-01

The clam Lucina pectinata lives in sulfide-rich muds and houses intracellular symbiotic bacteria that need to be supplied with hydrogen sulfide and oxygen. This clam possesses three hemoglobins: hemoglobin I (HbI), a sulfide-reactive protein, and hemoglobin II (HbII) and III (HbIII), which are oxygen-reactive. We characterized the complete gene sequence and promoter regions for the oxygen reactive hemoglobins and the partial structure and promoters of the HbI gene from Lucina pectinata. We show that HbI has two mRNA variants, where the 5’end had either a sequence of 96 bp (long variant) or 37 bp (short variant). The gene structure of the oxygen reactive Hbs is defined by having 4-exons/3-introns with conservation of intron location at B12.2 and G7.0 and the presence of pre-coding introns, while the partial gene structure of HbI has the same intron conservation but appears to have a 5-exon/ 4-intron structure. A search for putative transcription factor binding sites (TFBSs) was done with the promoters for HbII, HbIII, HbI short and HbI long. The HbII, HbIII and HbI long promoters showed similar predicted TFBSs. We also characterized MITE-like elements in the HbI and HbII gene promoters and intronic regions that are similar to sequences found in other mollusk genomes. The gene expression levels of the clam Hbs, from sulfide-rich and sulfide-poor environments showed a significant decrease of expression in the symbiont-containing tissue for those clams in a sulfide-poor environment, suggesting that the sulfide concentration may be involved in the regulation of these proteins. Gene expression evaluation of the two HbI mRNA variants indicated that the longer variant is expressed at higher levels than the shorter variant in both environments. PMID:26824233

Design of a radiator shade for testing in a simulated lunar environment

NASA Technical Reports Server (NTRS)

Huff, Jaimi; Remington, Randy; Tang, Toan

1992-01-01

The National Aeronautics and Space Administration (NASA) and The Universities Space Research Association (USRA) have chosen the parabolic/catenary concept from their sponsored Fall 1991 lunar radiation shade project for further testing and development. NASA asked the design team to build a shading device and support structure for testing in a vacuum chamber. Besides the support structure for the catenary shading device, the design team was asked to develop a system for varying the shade shape so that the device can be tested at different focal lengths. The design team developed concept variants and combined the concept variants to form overall designs. Using a decision matrix, an overall design was selected by the team from several overall design alternatives. Concept variants were developed for three primary functions. The three functions were structural support, shape adjustments, and end shielding. The shade adjustment function was divided into two sub-functions, arc length adjustment, and width adjustment.

NMR backbone resonance assignments of the prodomain variants of BDNF in the urea denatured state.

PubMed

Wang, Jing; Bains, Henrietta; Anastasia, Agustin; Bracken, Clay

2018-04-01

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family of proteins which plays a central role in neuronal survival, growth, plasticity and memory. A single Val66Met variant has been identified in the prodomain of human BDNF that is associated with anxiety, depression and memory disorders. The structural differences within the full-length prodomain Val66 and Met66 isoforms could shed light on the mechanism of action of the Met66 and its impact on the development of neuropsychiatric-associated disorders. In the present study, we report the backbone 1 H, 13 C, and 15 N NMR assignments of both full-length Val66 and Met66 prodomains in the presence of 2 M urea. These conditions were utilized to suppress residual structure and aid subsequent native state structural investigations aimed at mapping and identifying variant-dependent conformational differences under native-state conditions.

A case of hirsutism due to bilateral diffuse ovarian Leydig cell hyperplasia in a post-menopausal woman.

PubMed

Ali, F S.M.; Stanaway, S E.R.S.; Zakhour, H D.; Spearing, G; Bowen-Jones, D

2003-11-01

Hyperandrogenism in females usually results from ovarian or adrenal pathology. We present a case of virilizaton due to very rare bilateral ovarian diffuse interstitial proliferation of Leydig cells with no tumour or hilar cell hyperplasia identified. Interestingly, the case was further complicated by the finding of high levels of testosterone in one adrenal vein on selective venous sampling (SVS), resulting in an unnecessary unilateral adrenalectomy. Further sampling found high levels also in the ovarian veins, and the condition was finally cured by bilateral oophorectomy.

Modifying and Testing ATC Controller Interface (CI) for Data Link Clearances

NASA Technical Reports Server (NTRS)

2001-01-01

The Controller-Pilot Data Link Communications (CPDLC) and Air Traffic Control workstation research was conducted as part of the 1997 NASA Low Visibility Landing and Surface Operations (LVLASO) demonstration program at Atlanta Hartsfield airport. Research activity under this grant increased the sophistication of the Controllers' Communication and Situational Awareness Terminal (C-CAST) and developed a VHF Data Link -Mode 2 communications platform. The research culminated with participation in the 2000 NASA Aviation Safety Program's Synthetic Vision System (SVS) / Runway Incursion Prevention System (RIPS) flight demonstration at Dallas-Fort Worth Airport.

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

DOE PAGES

Wu, Hong; Zeng, Hong; Lam, Robert; ...

2015-08-01

Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in theMLH1gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. Lastly, the structure shares a high degree of similarity with previously determined prokaryoticMLH1homologs; however, this structure affords a more accurate platform for the classification ofMLH1variants.

Discovery, genotyping and characterization of structural variation and novel sequence at single nucleotide resolution from de novo genome assemblies on a population scale.

PubMed

Liu, Siyang; Huang, Shujia; Rao, Junhua; Ye, Weijian; Krogh, Anders; Wang, Jun

2015-01-01

Comprehensive recognition of genomic variation in one individual is important for understanding disease and developing personalized medication and treatment. Many tools based on DNA re-sequencing exist for identification of single nucleotide polymorphisms, small insertions and deletions (indels) as well as large deletions. However, these approaches consistently display a substantial bias against the recovery of complex structural variants and novel sequence in individual genomes and do not provide interpretation information such as the annotation of ancestral state and formation mechanism. We present a novel approach implemented in a single software package, AsmVar, to discover, genotype and characterize different forms of structural variation and novel sequence from population-scale de novo genome assemblies up to nucleotide resolution. Application of AsmVar to several human de novo genome assemblies captures a wide spectrum of structural variants and novel sequences present in the human population in high sensitivity and specificity. Our method provides a direct solution for investigating structural variants and novel sequences from de novo genome assemblies, facilitating the construction of population-scale pan-genomes. Our study also highlights the usefulness of the de novo assembly strategy for definition of genome structure.

Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion.

PubMed

Tse, Longping Victor; Klinc, Kelli A; Madigan, Victoria J; Castellanos Rivera, Ruth M; Wells, Lindsey F; Havlik, L Patrick; Smith, J Kennon; Agbandje-McKenna, Mavis; Asokan, Aravind

2017-06-13

Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure-guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy.

Analysis of the [RNQ+] Prion Reveals Stability of Amyloid Fibers as the Key Determinant of Yeast Prion Variant Propagation*

PubMed Central

Kalastavadi, Tejas; True, Heather L.

2010-01-01

Variation in pathology of human prion disease is believed to be caused, in part, by distinct conformations of aggregated protein resulting in different prion strains. Several prions also exist in yeast and maintain different self-propagating structures, referred to as prion variants. Investigation of the yeast prion [PSI+] has been instrumental in deciphering properties of prion variants and modeling the physical basis of their formation. Here, we describe the generation of specific variants of the [RNQ+] prion in yeast transformed with fibers formed in vitro in different conditions. The fibers of the Rnq1p prion-forming domain (PFD) that induce different variants in vivo have distinct biochemical properties. The physical basis of propagation of prion variants has been previously correlated to rates of aggregation and disaggregation. With [RNQ+] prion variants, we found that the prion variant does not correlate with the rate of aggregation as anticipated but does correlate with stability. Interestingly, we found that there are differences in the ability of the [RNQ+] prion variants to faithfully propagate themselves and to template the aggregation of other proteins. Incorporating the mechanism of variant formation elucidated in this study with that previously proposed for [PSI+] variants has provided a framework to separate general characteristics of prion variant properties from those specific to individual prion proteins. PMID:20442412

De novo design of the hydrophobic core of ubiquitin.

PubMed Central

Lazar, G. A.; Desjarlais, J. R.; Handel, T. M.

1997-01-01

We have previously reported the development and evaluation of a computational program to assist in the design of hydrophobic cores of proteins. In an effort to investigate the role of core packing in protein structure, we have used this program, referred to as Repacking of Cores (ROC), to design several variants of the protein ubiquitin. Nine ubiquitin variants containing from three to eight hydrophobic core mutations were constructed, purified, and characterized in terms of their stability and their ability to adopt a uniquely folded native-like conformation. In general, designed ubiquitin variants are more stable than control variants in which the hydrophobic core was chosen randomly. However, in contrast to previous results with 434 cro, all designs are destabilized relative to the wild-type (WT) protein. This raises the possibility that beta-sheet structures have more stringent packing requirements than alpha-helical proteins. A more striking observation is that all variants, including random controls, adopt fairly well-defined conformations, regardless of their stability. This result supports conclusions from the cro studies that non-core residues contribute significantly to the conformational uniqueness of these proteins while core packing largely affects protein stability and has less impact on the nature or uniqueness of the fold. Concurrent with the above work, we used stability data on the nine ubiquitin variants to evaluate and improve the predictive ability of our core packing algorithm. Additional versions of the program were generated that differ in potential function parameters and sampling of side chain conformers. Reasonable correlations between experimental and predicted stabilities suggest the program will be useful in future studies to design variants with stabilities closer to that of the native protein. Taken together, the present study provides further clarification of the role of specific packing interactions in protein structure and stability, and demonstrates the benefit of using systematic computational methods to predict core packing arrangements for the design of proteins. PMID:9194177

Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency

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

Xia, Chuanwu; Panda, Satya P.; Marohnic, Christopher C.

2012-03-15

NADPH-cytochrome P450 oxidoreductase (CYPOR) is essential for electron donation to microsomal cytochrome P450-mediated monooxygenation in such diverse physiological processes as drug metabolism (approximately 85-90% of therapeutic drugs), steroid biosynthesis, and bioactive metabolite production (vitamin D and retinoic acid metabolites). Expressed by a single gene, CYPOR's role with these multiple redox partners renders it a model for understanding protein-protein interactions at the structural level. Polymorphisms in human CYPOR have been shown to lead to defects in bone development and steroidogenesis, resulting in sexual dimorphisms, the severity of which differs significantly depending on the degree of CYPOR impairment. The atomic structure ofmore » human CYPOR is presented, with structures of two naturally occurring missense mutations, V492E and R457H. The overall structures of these CYPOR variants are similar to wild type. However, in both variants, local disruption of H bonding and salt bridging, involving the FAD pyrophosphate moiety, leads to weaker FAD binding, unstable protein, and loss of catalytic activity, which can be rescued by cofactor addition. The modes of polypeptide unfolding in these two variants differ significantly, as revealed by limited trypsin digestion: V492E is less stable but unfolds locally and gradually, whereas R457H is more stable but unfolds globally. FAD addition to either variant prevents trypsin digestion, supporting the role of the cofactor in conferring stability to CYPOR structure. Thus, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy in utero, if predicted prenatally, or rescued postnatally in less severe cases.« less

Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia

PubMed Central

Georgiadou, Dimitra; Chroni, Angeliki; Vezeridis, Alexander; Zannis, Vassilis I.; Stratikos, Efstratios

2011-01-01

Background Apolipoprotein E (apoE) is a major protein of the lipoprotein transport system that plays important roles in lipid homeostasis and protection from atherosclerosis. ApoE is characterized by structural plasticity and thermodynamic instability and can undergo significant structural rearrangements as part of its biological function. Mutations in the 136–150 region of the N-terminal domain of apoE, reduce its low density lipoprotein (LDL) receptor binding capacity and have been linked with lipoprotein disorders, such as type III hyperlipoproteinemia (HLP) in humans. However, the LDL-receptor binding defects for these apoE variants do not correlate well with the severity of dyslipidemia, indicating that these variants may carry additional properties that contribute to their pathogenic potential. Methodology/Principal Findings In this study we examined whether three type III HLP predisposing apoE3 variants, namely R136S, R145C and K146E affect the biophysical properties of the protein. Circular dichroism (CD) spectroscopy revealed that these mutations do not significantly alter the secondary structure of the protein. Thermal and chemical unfolding analysis revealed small thermodynamic alterations in each variant compared to wild-type apoE3, as well as effects in the reversibility of the unfolding transition. All variants were able to remodel multillamelar 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) vesicles, but R136S and R145C had reduced kinetics. Dynamic light scattering analysis indicated that the variant R136S exists in a higher-order oligomerization state in solution. Finally, 1-anilinonaphthalene-8-sulfonic acid (ANS) binding suggested that the variant R145C exposes a larger amount of hydrophobic surface to the solvent. Conclusions/Significance Overall, our findings suggest that single amino acid changes in the functionally important region 136–150 of apoE3 can affect the molecule's stability and conformation in solution and may underlie functional consequences. However, the magnitude and the non-concerted nature of these changes, make it unlikely that they constitute a distinct unifying mechanism leading to type III HLP pathogenesis. PMID:22069485

Evaluation: A Qualitative Pilot Study of Novel Information Technology Infrastructure to Communicate Genetic Variant Updates.

PubMed

Klinkenberg-Ramirez, Stephanie; Neri, Pamela M; Volk, Lynn A; Samaha, Sara J; Newmark, Lisa P; Pollard, Stephanie; Varugheese, Matthew; Baxter, Samantha; Aronson, Samuel J; Rehm, Heidi L; Bates, David W

2016-01-01

Partners HealthCare Personalized Medicine developed GeneInsight Clinic (GIC), a tool designed to communicate updated variant information from laboratory geneticists to treating clinicians through automated alerts, categorized by level of variant interpretation change. The study aimed to evaluate feedback from the initial users of the GIC, including the advantages and challenges to receiving this variant information and using this technology at the point of care. Healthcare professionals from two clinics that ordered genetic testing for cardiomyopathy and related disorders were invited to participate in one-hour semi-structured interviews and/ or a one-hour focus group. Using a Grounded Theory approach, transcript concepts were coded and organized into themes. Two genetic counselors and two physicians from two treatment clinics participated in individual interviews. Focus group participants included one genetic counselor and four physicians. Analysis resulted in 8 major themes related to structuring and communicating variant knowledge, GIC's impact on the clinic, and suggestions for improvements. The interview analysis identified longitudinal patient care, family data, and growth in genetic testing content as potential challenges to optimization of the GIC infrastructure. Participants agreed that GIC implementation increased efficiency and effectiveness of the clinic through increased access to genetic variant information at the point of care. Development of information technology (IT) infrastructure to aid in the organization and management of genetic variant knowledge will be critical as the genetic field moves towards whole exome and whole genome sequencing. Findings from this study could be applied to future development of IT support for genetic variant knowledge management that would serve to improve clinicians' ability to manage and care for patients.

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy

PubMed Central

Blesneac, Iulia; Themistocleous, Andreas C.; Fratter, Carl; Conrad, Linus J.; Ramirez, Juan D.; Cox, James J.; Tesfaye, Solomon; Shillo, Pallai R.; Rice, Andrew S.C.; Tucker, Stephen J.

2018-01-01

Abstract Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively. PMID:29176367

Common 5S rRNA variants are likely to be accepted in many sequence contexts

NASA Technical Reports Server (NTRS)

Zhang, Zhengdong; D'Souza, Lisa M.; Lee, Youn-Hyung; Fox, George E.

2003-01-01

Over evolutionary time RNA sequences which are successfully fixed in a population are selected from among those that satisfy the structural and chemical requirements imposed by the function of the RNA. These sequences together comprise the structure space of the RNA. In principle, a comprehensive understanding of RNA structure and function would make it possible to enumerate which specific RNA sequences belong to a particular structure space and which do not. We are using bacterial 5S rRNA as a model system to attempt to identify principles that can be used to predict which sequences do or do not belong to the 5S rRNA structure space. One promising idea is the very intuitive notion that frequently seen sequence changes in an aligned data set of naturally occurring 5S rRNAs would be widely accepted in many other 5S rRNA sequence contexts. To test this hypothesis, we first developed well-defined operational definitions for a Vibrio region of the 5S rRNA structure space and what is meant by a highly variable position. Fourteen sequence variants (10 point changes and 4 base-pair changes) were identified in this way, which, by the hypothesis, would be expected to incorporate successfully in any of the known sequences in the Vibrio region. All 14 of these changes were constructed and separately introduced into the Vibrio proteolyticus 5S rRNA sequence where they are not normally found. Each variant was evaluated for its ability to function as a valid 5S rRNA in an E. coli cellular context. It was found that 93% (13/14) of the variants tested are likely valid 5S rRNAs in this context. In addition, seven variants were constructed that, although present in the Vibrio region, did not meet the stringent criteria for a highly variable position. In this case, 86% (6/7) are likely valid. As a control we also examined seven variants that are seldom or never seen in the Vibrio region of 5S rRNA sequence space. In this case only two of seven were found to be potentially valid. The results demonstrate that changes that occur multiple times in a local region of RNA sequence space in fact usually will be accepted in any sequence context in that same local region.

Retarded protein folding of deficient human α1-antitrypsin D256V and L41P variants

PubMed Central

Jung, Chan-Hun; Na, Yu-Ran; Im, Hana

2004-01-01

α1-Antitrypsin is the most abundant protease inhibitor in plasma and is the archetype of the serine protease inhibitor superfamily. Genetic variants of human α1-antitrypsin are associated with early-onset emphysema and liver cirrhosis. However, the detailed molecular mechanism for the pathogenicity of most variant α1-antitrypsin molecules is not known. Here we examined the structural basis of a dozen deficient α1-antitrypsin variants. Unlike most α1-antitrypsin variants, which were unstable, D256V and L41P variants exhibited extremely retarded protein folding as compared with the wild-type molecule. Once folded, however, the stability and inhibitory activity of these variant proteins were comparable to those of the wild-type molecule. Retarded protein folding may promote protein aggregation by allowing the accumulation of aggregation-prone folding intermediates. Repeated observations of retarded protein folding indicate that it is an important mechanism causing α1-antitrypsin deficiency by variant molecules, which have to fold into the metastable native form to be functional. PMID:14767073

Filtering genetic variants and placing informative priors based on putative biological function.

PubMed

Friedrichs, Stefanie; Malzahn, Dörthe; Pugh, Elizabeth W; Almeida, Marcio; Liu, Xiao Qing; Bailey, Julia N

2016-02-03

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.

Three-Dimensional High-Order Spectral Volume Method for Solving Maxwell's Equations on Unstructured Grids

NASA Technical Reports Server (NTRS)

Liu, Yen; Vinokur, Marcel; Wang, Z. J.

2004-01-01

A three-dimensional, high-order, conservative, and efficient discontinuous spectral volume (SV) method for the solutions of Maxwell's equations on unstructured grids is presented. The concept of discontinuous 2nd high-order loca1 representations to achieve conservation and high accuracy is utilized in a manner similar to the Discontinuous Galerkin (DG) method, but instead of using a Galerkin finite-element formulation, the SV method is based on a finite-volume approach to attain a simpler formulation. Conventional unstructured finite-volume methods require data reconstruction based on the least-squares formulation using neighboring cell data. Since each unknown employs a different stencil, one must repeat the least-squares inversion for every cell at each time step, or to store the inversion coefficients. In a high-order, three-dimensional computation, the former would involve impractically large CPU time, while for the latter the memory requirement becomes prohibitive. In the SV method, one starts with a relatively coarse grid of triangles or tetrahedra, called spectral volumes (SVs), and partition each SV into a number of structured subcells, called control volumes (CVs), that support a polynomial expansion of a desired degree of precision. The unknowns are cell averages over CVs. If all the SVs are partitioned in a geometrically similar manner, the reconstruction becomes universal as a weighted sum of unknowns, and only a few universal coefficients need to be stored for the surface integrals over CV faces. Since the solution is discontinuous across the SV boundaries, a Riemann solver is thus necessary to maintain conservation. In the paper, multi-parameter and symmetric SV partitions, up to quartic for triangle and cubic for tetrahedron, are first presented. The corresponding weight coefficients for CV face integrals in terms of CV cell averages for each partition are analytically determined. These discretization formulas are then applied to the integral form of the Maxwell equations. All numerical procedures for outer boundary, material interface, zonal interface, and interior SV face are unified with a single characteristic formulation. The load balancing in a massive parallel computing environment is therefore easier to achieve. A parameter is introduced in the Riemann solver to control the strength of the smoothing term. Important aspects of the data structure and its effects to communication and the optimum use of cache memory are discussed. Results will be presented for plane TE and TM waves incident on a perfectly conducting cylinder for up to fifth order of accuracy, and a plane wave incident on a perfectly conducting sphere for up to fourth order of accuracy. Comparisons are made with exact solutions for these cases.

Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome

PubMed Central

Huang, Cheng Ran Lisa; Schneider, Anna M.; Lu, Yunqi; Niranjan, Tejasvi; Shen, Peilin; Robinson, Matoya A.; Steranka, Jared P.; Valle, David; Civin, Curt I.; Wang, Tao; Wheelan, Sarah J.; Ji, Hongkai; Boeke, Jef D.; Burns, Kathleen H.

2010-01-01

Summary Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further. PMID:20602999

Fine structure characterization of martensite/austenite constituent in low-carbon low-alloy steel by transmission electron forward scatter diffraction.

PubMed

Li, C W; Han, L Z; Luo, X M; Liu, Q D; Gu, J F

2016-11-01

Transmission electron forward scatter diffraction and other characterization techniques were used to investigate the fine structure and the variant relationship of the martensite/austenite (M/A) constituent of the granular bainite in low-carbon low-alloy steel. The results demonstrated that the M/A constituents were distributed in clusters throughout the bainitic ferrite. Lath martensite was the main component of the M/A constituent, where the relationship between the martensite variants was consistent with the Nishiyama-Wassermann orientation relationship and only three variants were found in the M/A constituent, suggesting that the variants had formed in the M/A constituent according to a specific mechanism. Furthermore, the Σ3 boundaries in the M/A constituent were much longer than their counterparts in the bainitic ferrite region. The results indicate that transmission electron forward scatter diffraction is an effective method of crystallographic analysis for nanolaths in M/A constituents. © 2016 The Authors Journal of Microscopy © 2016 Royal Microscopical Society.

Role of H1 Linker Histones in Mammalian Development and Stem Cell Differentiation

PubMed Central

Pan, Chenyi; Fan, Yuhong

2016-01-01

H1 linker histones are key chromatin architectural proteins facilitating the formation of higher order chromatin structures. The H1 family constitutes the most heterogeneous group of histone proteins, with eleven non-allelic H1 variants in mammals. H1 variants differ in their biochemical properties and exhibit significant sequence divergence from one another, yet most of them are highly conserved during evolution from mouse to human. H1 variants are differentially regulated during development and their cellular compositions undergo dramatic changes in embryogenesis, gametogenesis, tissue maturation and cellular differentiation. As a group, H1 histones are essential for mouse development and proper stem cell differentiation. Here we summarize our current knowledge on the expression and functions of H1 variants in mammalian development and stem cell differentiation. Their diversity, sequence conservation, complex expression and distinct functions suggest that H1s mediate chromatin reprogramming and contribute to the large variations and complexity of chromatin structure and gene expression in the mammalian genome. PMID:26689747

Spatially variant periodic structures in electromagnetics.

PubMed

Rumpf, Raymond C; Pazos, Javier J; Digaum, Jennefir L; Kuebler, Stephen M

2015-08-28

Spatial transforms are a popular technique for designing periodic structures that are macroscopically inhomogeneous. The structures are often required to be anisotropic, provide a magnetic response, and to have extreme values for the constitutive parameters in Maxwell's equations. Metamaterials and photonic crystals are capable of providing these, although sometimes only approximately. The problem still remains about how to generate the geometry of the final lattice when it is functionally graded, or spatially varied. This paper describes a simple numerical technique to spatially vary any periodic structure while minimizing deformations to the unit cells that would weaken or destroy the electromagnetic properties. New developments in this algorithm are disclosed that increase efficiency, improve the quality of the lattices and provide the ability to design aplanatic metasurfaces. The ability to spatially vary a lattice in this manner enables new design paradigms that are not possible using spatial transforms, three of which are discussed here. First, spatially variant self-collimating photonic crystals are shown to flow unguided waves around very tight bends using ordinary materials with low refractive index. Second, multi-mode waveguides in spatially variant band gap materials are shown to guide waves around bends without mixing power between the modes. Third, spatially variant anisotropic materials are shown to sculpt the near-field around electric components. This can be used to improve electromagnetic compatibility between components in close proximity. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Spatially variant periodic structures in electromagnetics

PubMed Central

Rumpf, Raymond C.; Pazos, Javier J.; Digaum, Jennefir L.; Kuebler, Stephen M.

2015-01-01

Spatial transforms are a popular technique for designing periodic structures that are macroscopically inhomogeneous. The structures are often required to be anisotropic, provide a magnetic response, and to have extreme values for the constitutive parameters in Maxwell's equations. Metamaterials and photonic crystals are capable of providing these, although sometimes only approximately. The problem still remains about how to generate the geometry of the final lattice when it is functionally graded, or spatially varied. This paper describes a simple numerical technique to spatially vary any periodic structure while minimizing deformations to the unit cells that would weaken or destroy the electromagnetic properties. New developments in this algorithm are disclosed that increase efficiency, improve the quality of the lattices and provide the ability to design aplanatic metasurfaces. The ability to spatially vary a lattice in this manner enables new design paradigms that are not possible using spatial transforms, three of which are discussed here. First, spatially variant self-collimating photonic crystals are shown to flow unguided waves around very tight bends using ordinary materials with low refractive index. Second, multi-mode waveguides in spatially variant band gap materials are shown to guide waves around bends without mixing power between the modes. Third, spatially variant anisotropic materials are shown to sculpt the near-field around electric components. This can be used to improve electromagnetic compatibility between components in close proximity. PMID:26217058

Recurrent emergence of structural variants of LTR retrotransposon CsRn1 evolving novel expression strategy and their selective expansion in a carcinogenic liver fluke, Clonorchis sinensis.

PubMed

Kim, Seon-Hee; Kong, Yoon; Bae, Young-An

2017-06-01

Autonomous retrotransposons, in which replication and transcription are coupled, encode the essential gag and pol genes as a fusion or separate overlapping form(s) that are expressed in single transcripts regulated by a common upstream promoter. The element-specific expression strategies have driven development of relevant translational recoding mechanisms including ribosomal frameshifting to satisfy the protein stoichiometry critical for the assembly of infectious virus-like particles. Retrotransposons with different recoding strategies exhibit a mosaic distribution pattern across the diverse families of reverse transcribing elements, even though their respective distributions are substantially skewed towards certain family groups. However, only a few investigations to date have focused on the emergence of retrotransposons evolving novel expression strategy and causal genetic drivers of the structural variants. In this study, the bulk of genomic and transcribed sequences of a Ty3/gypsy-like CsRn1 retrotransposon in Clonorchis sinensis were analyzed for the comprehensive examination of its expression strategy. Our results demonstrated that structural variants with single open reading frame (ORF) have recurrently emerged from precedential CsRn1 copies encoding overlapping gag-pol ORFs by a single-nucleotide insertion in an upstream region of gag stop codon. In the parasite genome, some of the newly evolved variants appeared to undergo proliferative burst as active master lineages together with their ancestral copies. The genetic event was similarly observed in Opisthorchis viverrini, the closest neighbor of C. sinensis, whereas the resulting structural variants might have failed to overcome purifying selection and comprised minor remnant copies in the Opisthorchis genome. Copyright © 2017 Elsevier B.V. All rights reserved.

Structure-Function Analysis of Friedreich's Ataxia Mutants Reveals Determinants of Frataxin Binding and Activation of the Fe-S Assembly Complex

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

Bridwell-Rabb, Jennifer; Winn, Andrew M; Barondeau, David P

2012-08-01

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease associated with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a GAA triplet repeat expansion or, occasionally, from missense mutations in the FXN gene. Here biochemical and structural properties of FXN variants, including three FRDA missense mutations (N146K, Q148R, and R165C) and three related mutants (N146A, Q148G, and Q153A), were determined in an effort to understand the structural basis for the loss of function. In vitro assays revealed that although the three FRDA missense mutations exhibited similar losses of cysteine desulfurase and Fe-Smore » cluster assembly activities, the causes for these activation defects were distinct. The R165C variant exhibited a k cat/K M higher than that of native FXN but weak binding to the NFS1, ISD11, and ISCU2 (SDU) complex, whereas the Q148R variant exhibited the lowest k cat/K M of the six tested FXN variants and only a modest binding deficiency. The order of the FXN binding affinities for the SDU Fe-S assembly complex was as follows: FXN > Q148R > N146A > Q148G > N146K > Q153A > R165C. Four different classes of FXN variants were identified on the basis of their biochemical properties. Together, these structure-function studies reveal determinants for the binding and allosteric activation of the Fe-S assembly complex and provide insight into how FRDA missense mutations are functionally compromised.« less

[Antigen differences of genetic variants Abent+ and Abent- poliovirus vaccine strain of III type].

PubMed

Shyrobokov, V P; Kostenko, I H; Nikolaienko, I V

2003-01-01

Hybridomes--producers of monoclonal antibodies (MAB) were obtained able to differentiate the variants Abent+ and Abent- poliovirus vaccine strain in the virus neutralizing reaction. Using the obtained panel the changes of the epitope structure of capsid proteins of poliovirus variants (dissociants) were found which appeared during reproduction in cell culture. It proves the fact that there exist essential antigenic differences of superficial virion's proteins, which appear during the process of dissociation.

Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing.

PubMed

Horai, Makiko; Mishima, Hiroyuki; Hayashida, Chisa; Kinoshita, Akira; Nakane, Yoshibumi; Matsuo, Tatsuki; Tsuruda, Kazuto; Yanagihara, Katsunori; Sato, Shinya; Imanishi, Daisuke; Imaizumi, Yoshitaka; Hata, Tomoko; Miyazaki, Yasushi; Yoshiura, Koh-Ichiro

2018-03-01

Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic-bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors.

Rare variation facilitates inferences of fine-scale population structure in humans.

PubMed

O'Connor, Timothy D; Fu, Wenqing; Mychaleckyj, Josyf C; Logsdon, Benjamin; Auer, Paul; Carlson, Christopher S; Leal, Suzanne M; Smith, Joshua D; Rieder, Mark J; Bamshad, Michael J; Nickerson, Deborah A; Akey, Joshua M

2015-03-01

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data

PubMed Central

Zhu, Yun; Fan, Ruzong; Xiong, Momiao

2017-01-01

Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative internal representation and features from high dimensional genotype and phenotype data. To explore correlation information of genetic variants, effectively reduce data dimensions, and overcome critical barriers in advancing the development of novel statistical methods and computational algorithms for genetic pleiotropic analysis, we proposed a new statistic method referred to as a quadratically regularized functional CCA (QRFCCA) for association analysis which combines three approaches: (1) quadratically regularized matrix factorization, (2) functional data analysis and (3) canonical correlation analysis (CCA). Large-scale simulations show that the QRFCCA has a much higher power than that of the ten competing statistics while retaining the appropriate type 1 errors. To further evaluate performance, the QRFCCA and ten other statistics are applied to the whole genome sequencing dataset from the TwinsUK study. We identify a total of 79 genes with rare variants and 67 genes with common variants significantly associated with the 46 traits using QRFCCA. The results show that the QRFCCA substantially outperforms the ten other statistics. PMID:29040274

Protective V127 prion variant prevents prion disease by interrupting the formation of dimer and fibril from molecular dynamics simulations.

PubMed

Zhou, Shuangyan; Shi, Danfeng; Liu, Xuewei; Liu, Huanxiang; Yao, Xiaojun

2016-02-24

Recent studies uncovered a novel protective prion protein variant: V127 variant, which was reported intrinsically resistant to prion conversion and propagation. However, the structural basis of its protective effect is still unknown. To uncover the origin of the protective role of V127 variant, molecular dynamics simulations were performed to explore the influence of G127V mutation on two key processes of prion propagation: dimerization and fibril formation. The simulation results indicate V127 variant is unfavorable to form dimer by reducing the main-chain H-bond interactions. The simulations of formed fibrils consisting of β1 strand prove V127 variant will make the formed fibril become unstable and disorder. The weaker interaction energies between layers and reduced H-bonds number for V127 variant reveal this mutation is unfavorable to the formation of stable fibril. Consequently, we find V127 variant is not only unfavorable to the formation of dimer but also unfavorable to the formation of stable core and fibril, which can explain the mechanism on the protective role of V127 variant from the molecular level. Our findings can deepen the understanding of prion disease and may guide the design of peptide mimetics or small molecule to mimic the protective effect of V127 variant.

Structural characterization of O- and C-glycosylating variants of the landomycin glycosyltransferase LanGT2.

PubMed

Tam, Heng Keat; Härle, Johannes; Gerhardt, Stefan; Rohr, Jürgen; Wang, Guojun; Thorson, Jon S; Bigot, Aurélien; Lutterbeck, Monika; Seiche, Wolfgang; Breit, Bernhard; Bechthold, Andreas; Einsle, Oliver

2015-02-23

The structures of the O-glycosyltransferase LanGT2 and the engineered, C-C bond-forming variant LanGT2S8Ac show how the replacement of a single loop can change the functionality of the enzyme. Crystal structures of the enzymes in complex with a nonhydrolyzable nucleotide-sugar analogue revealed that there is a conformational transition to create the binding sites for the aglycon substrate. This induced-fit transition was explored by molecular docking experiments with various aglycon substrates. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The variant call format and VCFtools.

PubMed

Danecek, Petr; Auton, Adam; Abecasis, Goncalo; Albers, Cornelis A; Banks, Eric; DePristo, Mark A; Handsaker, Robert E; Lunter, Gerton; Marth, Gabor T; Sherry, Stephen T; McVean, Gilean; Durbin, Richard

2011-08-01

The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API. http://vcftools.sourceforge.net

Structural comparisons of two allelic variants of human placental alkaline phosphatase.

PubMed

Millán, J L; Stigbrand, T; Jörnvall, H

1985-01-01

A simple immunosorbent purification scheme based on monoclonal antibodies has been devised for human placental alkaline phosphatase. The two most common allelic variants, S and F, have similar amino acid compositions with identical N-terminal amino acid sequences through the first 13 residues. Both variants have identical lectin binding properties towards concanavalin A, lentil-lectin, wheat germ agglutinin, phytohemagglutinin and soybean agglutinin, and identical carbohydrate contents as revealed by methylation analysis. CNBr fragments of the variants demonstrate identical high performance liquid chromatography patterns. The carbohydrate containing fragment is different from the 32P-labeled active site fragment and the N-terminal fragment.

Coexisting Vocal Fold Polyps and Sulcus Vocalis: Coincidence or Coexistence? Characteristics of 14 Patients.

PubMed

Carmel-Neiderman, Narin Nard; Wasserzug, Oshri; Ziv-Baran, Tomer; Oestreicher-Kedem, Yael

2018-03-01

The study aimed (1) to evaluate the prevalence of sulcus vocalis (SV) coexisting with vocal fold polyp (SV-VFP), and (2) to determine the effect of their coexistence on voice quality. This is a retrospective cohort study in a tertiary referral center. The medical records of all patients who underwent micro direct laryngoscopy due to VFPs between January 2013 and April 2015 were reviewed. Patients with SV-VFP were identified and data of their demographics, medical history, habits, preoperative and intraoperative laryngeal findings, and pre- and postoperative GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) score, and compared with the data of patients with solitary VFPs (S-VFPs). Eighty-nine patients were diagnosed with VFPs, 14 (15.7%) of whom were diagnosed with SV-VFPs. Patients with SV-VFPs had significantly lower incidence of concurrent leukoplakia (P = 0.01), higher incidence of contralateral vocal fold lesions (P = 0.04), increased voice roughness score postoperatively (P = 0.01) on the GRBAS score, and had a lower rate of cigarette smoking (P = 0.02) compared with patients with S-VFPs. The possibility of a hidden SV should be considered when detecting VFPs, particularly in patients with contralateral vocal fold lesions and without cigarette smoking history. Because the group of patients with SV-VFP presented with unique features, we suspect that the coexistence of VFPs and SVs is not incidental and that SVs may contribute to the formation of VFPs, possibly by alternating glottic airflow. Copyright © 2018 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Combination of alkaline and microwave pretreatment for disintegration of meat processing wastewater sludge.

PubMed

Erden, G

2013-01-01

Meat processing wastewater sludge has high organic content but it is very slow to degrade in biological processes. Anaerobic digestion may be a good alternative for this type of sludge when the hydrolysis, known to be the rate-limiting step of biological sludge anaerobic degradation, could be eliminated by disintegration. This investigation deals with disintegration of meat processing wastewater sludge. Microwave (MW) irradiation and combined alkaline pretreatment and MW irradiation were applied to sludge for disintegration purposes. Disintegration performance of the methods was evaluated with disintegration degree based on total and dissolved organic carbon calculations (DD(TOC)), and the solubilization of volatile solids (S(VS)) in the pretreated sludge. Optimum conditions were found to be 140 degrees C and 30 min for MW irradiation using response surface methodology (RSM) and pH = 13 for combined pretreatment. While DD(TOC) was observed as 24.6% and 54.9, S(VS) was determined as 8.54% and 42.5% for MW pretreated and combined pretreated sludge, respectively. The results clearly show that pre-conditioning of sludge with alkaline pretreatment played an important role in enhancing the disintegration efficiency of subsequent MW irradiation. Disintegration methods also affected the anaerobic biodegradability and dewaterability of sludge. An increase of 23.6% in biogas production in MW irradiated sludge was obtained, comparing to the raw sludge at the end of the 35 days of incubation. This increase was observed as 44.5% combined pretreatment application. While MW pretreatment led to a little improvement of the dewatering performance of sludge, in combined pretreatment NaOH deteriorates the sludge dewaterability.

Effect of Human Milk Appetite Hormones, Macronutrients, and Infant Characteristics on Gastric Emptying and Breastfeeding Patterns of Term Fully Breastfed Infants

PubMed Central

Gridneva, Zoya; Kugananthan, Sambavi; Hepworth, Anna R.; Tie, Wan J.; Lai, Ching T.; Ward, Leigh C.; Hartmann, Peter E.; Geddes, Donna T.

2016-01-01

Human milk (HM) components influence infant feeding patterns and nutrient intake, yet it is unclear how they influence gastric emptying (GE), a key component of appetite regulation. This study analyzed GE of a single breastfeed, HM appetite hormones/macronutrients and demographics/anthropometrics/body composition of term fully breastfed infants (n = 41, 2 and/or 5 mo). Stomach volumes (SV) were calculated from pre-/post-feed ultrasound scans, then repeatedly until the next feed. Feed volume (FV) was measured by the test-weigh method. HM samples were analyzed for adiponectin, leptin, fat, lactose, total carbohydrate, lysozyme, and total/whey/casein protein. Linear regression/mixed effect models were used to determine associations between GE/feed variables and HM components/infant anthropometrics/adiposity. Higher FVs were associated with faster (−0.07 [−0.10, −0.03], p < 0.001) GE rate, higher post-feed SVs (0.82 [0.53, 1.12], p < 0.001), and longer GE times (0.24 [0.03, 0.46], p = 0.033). Higher whey protein concentration was associated with higher post-feed SVs (4.99 [0.84, 9.13], p = 0.023). Longer GE time was associated with higher adiponectin concentration (2.29 [0.92, 3.66], p = 0.002) and dose (0.02 [0.01, 0.03], p = 0.005), and lower casein:whey ratio (−65.89 [−107.13, −2.66], p = 0.003). FV and HM composition influence GE and breastfeeding patterns in term breastfed infants. PMID:28036041

Integration of a 3D perspective view in the navigation display: featuring pilot's mental model

NASA Astrophysics Data System (ADS)

Ebrecht, L.; Schmerwitz, S.

2015-05-01

Synthetic vision systems (SVS) appear as spreading technology in the avionic domain. Several studies prove enhanced situational awareness when using synthetic vision. Since the introduction of synthetic vision a steady change and evolution started concerning the primary flight display (PFD) and the navigation display (ND). The main improvements of the ND comprise the representation of colored ground proximity warning systems (EGPWS), weather radar, and TCAS information. Synthetic vision seems to offer high potential to further enhance cockpit display systems. Especially, concerning the current trend having a 3D perspective view in a SVS-PFD while leaving the navigational content as well as methods of interaction unchanged the question arouses if and how the gap between both displays might evolve to a serious problem. This issue becomes important in relation to the transition and combination of strategic and tactical flight guidance. Hence, pros and cons of 2D and 3D views generally as well as the gap between the egocentric perspective 3D view of the PFD and the exocentric 2D top and side view of the ND will be discussed. Further a concept for the integration of a 3D perspective view, i.e., bird's eye view, in synthetic vision ND will be presented. The combination of 2D and 3D views in the ND enables a better correlation of the ND and the PFD. Additionally, this supports the building of pilot's mental model. The authors believe it will improve the situational and spatial awareness. It might prove to further raise the safety margin when operating in mountainous areas.

Fast mapping of the T2 relaxation time of cerebral metabolites using proton echo-planar spectroscopic imaging (PEPSI).

PubMed

Tsai, Shang-Yueh; Posse, Stefan; Lin, Yi-Ru; Ko, Cheng-Wen; Otazo, Ricardo; Chung, Hsiao-Wen; Lin, Fa-Hsuan

2007-05-01

Metabolite T2 is necessary for accurate quantification of the absolute concentration of metabolites using long-echo-time (TE) acquisition schemes. However, lengthy data acquisition times pose a major challenge to mapping metabolite T2. In this study we used proton echo-planar spectroscopic imaging (PEPSI) at 3T to obtain fast T2 maps of three major cerebral metabolites: N-acetyl-aspartate (NAA), creatine (Cre), and choline (Cho). We showed that PEPSI spectra matched T2 values obtained using single-voxel spectroscopy (SVS). Data acquisition for 2D metabolite maps with a voxel volume of 0.95 ml (32 x 32 image matrix) can be completed in 25 min using five TEs and eight averages. A sufficient spectral signal-to-noise ratio (SNR) for T2 estimation was validated by high Pearson's correlation coefficients between logarithmic MR signals and TEs (R2 = 0.98, 0.97, and 0.95 for NAA, Cre, and Cho, respectively). In agreement with previous studies, we found that the T2 values of NAA, but not Cre and Cho, were significantly different between gray matter (GM) and white matter (WM; P < 0.001). The difference between the T2 estimates of the PEPSI and SVS scans was less than 9%. Consistent spatial distributions of T2 were found in six healthy subjects, and disagreement among subjects was less than 10%. In summary, the PEPSI technique is a robust method to obtain fast mapping of metabolite T2. (c) 2007 Wiley-Liss, Inc.

Collaboration and conquest: MTD as viewed by voice teacher (singing voice specialist) and speech-language pathologist.

PubMed

Goffi-Fynn, Jeanne C; Carroll, Linda M

2013-05-01

This study was designed as a qualitative case study to demonstrate the process of diagnosis and treatment between a voice team to manage a singer diagnosed with muscular tension dysphonia (MTD). Traditionally, literature suggests that MTD is challenging to treat and little in the literature directly addresses singers with MTD. Data collected included initial medical screening with laryngologist, referral to speech-language pathologist (SLP) specializing in voice disorders among singers, and adjunctive voice training with voice teacher trained in vocology (singing voice specialist or SVS). Initial target goals with SLP included reducing extrinsic laryngeal tension, using a relaxed laryngeal posture, and effective abdominal-diaphragmatic support for all phonation events. Balance of respiratory forces, laryngeal coordination, and use of optimum filtering of the source signal through resonance and articulatory awareness was emphasized. Further work with SVS included three main goals including a lowered breathing pattern to aid in decreasing subglottic air pressure, vertical laryngeal position to lower to allow for a relaxed laryngeal position, and a top-down singing approach to encourage an easier, more balanced registration, and better resonance. Initial results also emphasize the retraining of subject toward a sensory rather than auditory mode of monitoring. Other areas of consideration include singers' training and vocal use, the psychological effects of MTD, the personalities potentially associated with it, and its relationship with stress. Finally, the results emphasize that a positive rapport with the subject and collaboration between all professionals involved in a singer's care are essential for recovery. Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Mw Systematic Study of Alkaloids: the Distorted Tropane of Scopoline

NASA Astrophysics Data System (ADS)

Ecija, Patricia; Cocinero, Emilio J.; Basterretxea, Francisco J.; Fernandez, Jose A.; Castano, Fernando; Lesarri, Alberto

2013-06-01

Tropane alkaloids have diverse pharmacological uses and are well-known for their neurostimulant activity. Previous structure-activity-relationship established correlations between bioactivity and several aspects of ligand conformation and stereochemistry, including delicate intramolecular effects like nitrogen inversion^{a}. We have initiated a series of structural studies on tropane alkaloids^{b}, aimed to discerning their intrinsic stereochemical properties using rotational spectroscopy in supersonic jets^{c}. Here we extend these studies to the epoxytropanes, initially motivated to interrogate the influence of the epoxy group on nitrogen inversion and ring conformation. The rotational spectrum evidences a single structure in the gas phase, providing a first description of the (three ring) structurally-distorted tropane in scopoline. The determined rotational parameters of scopoline reveal the structural consequences of the intramolecular cyclation of scopine, which breaks the original epoxy group and creates a new ether bridge and a 7β-hydroxytropane configuration. The hydroxyl group further stabilizes the molecule by an O-H \\cdots N intramolecular hydrogen bond, which, in turn, forces the N-methyl group to the less stable axial form^{b}. The experimental work was supported by ab initio and DFT calculations. ^{a} i) S.Singh, Chem. Rev. 100, 925 (2000); ii) A. Krunic, D. Pan, W.J. Dunn III, S.V.S. Miariappan, Bioorg. & Med. Chem. 17, 811 (2009). ^{b} E.J. Cocinero, A. Lesarri, P. écija, J.-U. Grabow, J.A. Fernández, F. Castaño, Phys. Chem. Chem. Phys. 12, 6076 (2010). ^{c} E.J. Cocinero, A. Lesarri, P. écija, J.-U. Grabow, J.A. Fernández, F. Castaño, Phys. Chem. Chem. Phys. 12, 12486 (2010).

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

Radhakrishnan, Bala; Gorti, Sarma; Babu, Suresh Sudharsanam

Here, we present phase field simulations incorporating energy contributions due to thermodynamics, and anisotropic interfacial and strain energies, to demonstrate the nucleation and growth of multiple variants of alpha from beta in Ti-6Al-4V under isothermal conditions. The simulations focused on the effect of thermodynamic driving force and nucleation rate on the morphology of the transformed alpha assuming that the partitioning of V between beta and alpha is negligible for short isothermal holds. The results indicate that a high nucleation rate favors the formation of the basket-weave structure. However, at a lower nucleation rate the simulations show the intragranular nucleation ofmore » a colony structure by an autocatalytic nucleation mechanism adjacent to a pre-existing alpha variant. New side-plates of the same variant appear to nucleate progressively and grow to form the colony. The isothermal simulation results are used to offer a possible explanation for the transition from a largely basket weave structure to a colony structure inside narrow layer bands occurring during continuous heating and cooling conditions encountered during laser additive manufacturing of Ti-6Al-4V.« less

regSNPs-splicing: a tool for prioritizing synonymous single-nucleotide substitution.

PubMed

Zhang, Xinjun; Li, Meng; Lin, Hai; Rao, Xi; Feng, Weixing; Yang, Yuedong; Mort, Matthew; Cooper, David N; Wang, Yue; Wang, Yadong; Wells, Clark; Zhou, Yaoqi; Liu, Yunlong

2017-09-01

While synonymous single-nucleotide variants (sSNVs) have largely been unstudied, since they do not alter protein sequence, mounting evidence suggests that they may affect RNA conformation, splicing, and the stability of nascent-mRNAs to promote various diseases. Accurately prioritizing deleterious sSNVs from a pool of neutral ones can significantly improve our ability of selecting functional genetic variants identified from various genome-sequencing projects, and, therefore, advance our understanding of disease etiology. In this study, we develop a computational algorithm to prioritize sSNVs based on their impact on mRNA splicing and protein function. In addition to genomic features that potentially affect splicing regulation, our proposed algorithm also includes dozens structural features that characterize the functions of alternatively spliced exons on protein function. Our systematical evaluation on thousands of sSNVs suggests that several structural features, including intrinsic disorder protein scores, solvent accessible surface areas, protein secondary structures, and known and predicted protein family domains, show significant differences between disease-causing and neutral sSNVs. Our result suggests that the protein structure features offer an added dimension of information while distinguishing disease-causing and neutral synonymous variants. The inclusion of structural features increases the predictive accuracy for functional sSNV prioritization.

Structural redesign of lipase B from Candida antarctica by circular permutation and incremental truncation.

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

Qian, Zhen; Horton, John R.; Cheng, Xiadong

2009-11-02

Circular permutation of Candida antarctica lipase B yields several enzyme variants with substantially increased catalytic activity. To better understand the structural and functional consequences of protein termini reorganization, we have applied protein engineering and x-ray crystallography to cp283, one of the most active hydrolase variants. Our initial investigation has focused on the role of an extended surface loop, created by linking the native N- and C-termini, on protein integrity. Incremental truncation of the loop partially compensates for observed losses in secondary structure and the permutants temperature of unfolding. Unexpectedly, the improvements are accompanied by quaternary-structure changes from monomer to dimer.more » The crystal structures of one truncated variant (cp283{Delta}7) in the apo-form determined at 1.49 {angstrom} resolution and with a bound phosphonate inhibitor at 1.69 {angstrom} resolution confirmed the formation of a homodimer by swapping of the enzyme's 35-residue N-terminal region. Separately, the new protein termini at amino acid positions 282/283 convert the narrow access tunnel to the catalytic triad into a broad crevice for accelerated substrate entry and product exit while preserving the native active-site topology for optimal catalytic turnover.« less

A FRMD7 variant in a Japanese family causes congenital nystagmus.

PubMed

Kohmoto, Tomohiro; Okamoto, Nana; Satomura, Shigeko; Naruto, Takuya; Komori, Takahide; Hashimoto, Toshiaki; Imoto, Issei

2015-01-01

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.

A FRMD7 variant in a Japanese family causes congenital nystagmus

PubMed Central

Kohmoto, Tomohiro; Okamoto, Nana; Satomura, Shigeko; Naruto, Takuya; Komori, Takahide; Hashimoto, Toshiaki; Imoto, Issei

2015-01-01

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN. PMID:27081518

Traits regionaux en protoroman (Regional Traits in Proto-Romance).

ERIC Educational Resources Information Center

De Dardel, Robert

2001-01-01

Every spoken linguistic system shared by a community has structurally related regional variants. For example, the variant of the present day French for "soixante-dix" is "septante" in eastern France, Belgium, and the French-speaking community of Switzerland. This suggests that Proto-Romance has regionalisms. Using the…

Primary structural variation in anaplasma marginale Msp2 efficiently generates immune escape variants

USDA-ARS?s Scientific Manuscript database

Antigenic variation allows microbial pathogens to evade immune clearance and establish persistent infection. Anaplasma marginale utilizes gene conversion of a repertoire of silent msp2 alleles into a single active expression site to encode unique Msp2 variants. As the genomic complement of msp2 alle...

Structure-Based Alteration of Substrate Specificity and Catalytic Activity of Sulfite Oxidase from Sulfite Oxidation to Nitrate Reduction

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

Qiu, James A.; Wilson, Heather L.; Rajagopalan, K.V.

Eukaryotic sulfite oxidase is a dimeric protein that contains the molybdenum cofactor and catalyzes the metabolically essential conversion of sulfite to sulfate as the terminal step in the metabolism of cysteine and methionine. Nitrate reductase is an evolutionarily related molybdoprotein in lower organisms that is essential for growth on nitrate. In this study, we describe human and chicken sulfite oxidase variants in which the active site has been modified to alter substrate specificity and activity from sulfite oxidation to nitrate reduction. On the basis of sequence alignments and the known crystal structure of chicken sulfite oxidase, two residues are conservedmore » in nitrate reductases that align with residues in the active site of sulfite oxidase. On the basis of the crystal structure of yeast nitrate reductase, both positions were mutated in human sulfite oxidase and chicken sulfite oxidase. The resulting double-mutant variants demonstrated a marked decrease in sulfite oxidase activity but gained nitrate reductase activity. An additional methionine residue in the active site was proposed to be important in nitrate catalysis, and therefore, the triple variant was also produced. The nitrate reducing ability of the human sulfite oxidase triple mutant was nearly 3-fold greater than that of the double mutant. To obtain detailed structural data for the active site of these variants, we introduced the analogous mutations into chicken sulfite oxidase to perform crystallographic analysis. The crystal structures of the Mo domains of the double and triple mutants were determined to 2.4 and 2.1 {angstrom} resolution, respectively.« less

Structure-based approach to rationally design a chimeric protein for an effective vaccine against Group B Streptococcus infections.

PubMed

Nuccitelli, Annalisa; Cozzi, Roberta; Gourlay, Louise J; Donnarumma, Danilo; Necchi, Francesca; Norais, Nathalie; Telford, John L; Rappuoli, Rino; Bolognesi, Martino; Maione, Domenico; Grandi, Guido; Rinaudo, C Daniela

2011-06-21

Structural vaccinology is an emerging strategy for the rational design of vaccine candidates. We successfully applied structural vaccinology to design a fully synthetic protein with multivalent protection activity. In Group B Streptococcus, cell-surface pili have aroused great interest because of their direct roles in virulence and importance as protective antigens. The backbone subunit of type 2a pilus (BP-2a) is present in six immunogenically different but structurally similar variants. We determined the 3D structure of one of the variants, and experimentally demonstrated that protective antibodies specifically recognize one of the four domains that comprise the protein. We therefore constructed a synthetic protein constituted by the protective domain of each one of the six variants and showed that the chimeric protein protects mice against the challenge with all of the type 2a pilus-carrying strains. This work demonstrates the power of structural vaccinology and will facilitate the development of an optimized, broadly protective pilus-based vaccine against Group B Streptococcus by combining the uniquely generated chimeric protein with protective pilin subunits from two other previously identified pilus types. In addition, this work describes a template procedure that can be followed to develop vaccines against other bacterial pathogens.

Biochemical properties and atomic resolution structure of a proteolytically processed β-mannanase from cellulolytic Streptomyces sp. SirexAA-E.

PubMed

Takasuka, Taichi E; Acheson, Justin F; Bianchetti, Christopher M; Prom, Ben M; Bergeman, Lai F; Book, Adam J; Currie, Cameron R; Fox, Brian G

2014-01-01

β-Mannanase SACTE_2347 from cellulolytic Streptomyces sp. SirexAA-E is abundantly secreted into the culture medium during growth on cellulosic materials. The enzyme is composed of domains from the glycoside hydrolase family 5 (GH5), fibronectin type-III (Fn3), and carbohydrate binding module family 2 (CBM2). After secretion, the enzyme is proteolyzed into three different, catalytically active variants with masses of 53, 42 and 34 kDa corresponding to the intact protein, loss of the CBM2 domain, or loss of both the Fn3 and CBM2 domains. The three variants had identical N-termini starting with Ala51, and the positions of specific proteolytic reactions in the linker sequences separating the three domains were identified. To conduct biochemical and structural characterizations, the natural proteolytic variants were reproduced by cloning and heterologously expressed in Escherichia coli. Each SACTE_2347 variant hydrolyzed only β-1,4 mannosidic linkages, and also reacted with pure mannans containing partial galactosyl- and/or glucosyl substitutions. Examination of the X-ray crystal structure of the GH5 domain of SACTE_2347 suggests that two loops adjacent to the active site channel, which have differences in position and length relative to other closely related mannanases, play a role in producing the observed substrate selectivity.

Characterization of Alzheimer's Protective and Causative Amyloid-beta Variants Using a Combination of Simulations and Experiments

NASA Astrophysics Data System (ADS)

Das, Payel; Chakraborty, Srirupa; Chacko, Anita; Murray, Brian; Belfort, Georges

The aggregation of amyloid-beta (A β) peptides plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, it has been reported that an A2T mutation in A β can protect from AD. Interestingly, an A2V mutation has been also found to offer protection against AD in the heterozygous state. Structural characterization of these natural A β variants thus offers an intriguing approach to understand the molecular mechanism of AD. Toward this goal, we have characterized the conformational landscapes of the intrinsically disordered WT, A2V, and A2T A β1-42 variant monomers and dimers by using extensive atomistic molecular dynamics (MD) simulations. Simulations reveal markedly different secondary and tertiary structure at the central and C-terminal hydrophobic regions of the peptide, which play a crucial role in A β aggregation and related toxicity. For example, an enhanced double β-hairpin formation was observed in A2V monomer. In contrast, the A2T mutation enhances disorder of the conformational ensemble due to formation of atypical long-range interactions. These structural insights obtained from simulations allow understanding of the differential aggregation, oligomer morphology, and LTP inhibition of the variants observed in the experiments and offer a path toward designing and testing aggregation inhibitors.

Landscape of Pleiotropic Proteins Causing Human Disease: Structural and System Biology Insights.

PubMed

Ittisoponpisan, Sirawit; Alhuzimi, Eman; Sternberg, Michael J E; David, Alessia

2017-03-01

Pleiotropy is the phenomenon by which the same gene can result in multiple phenotypes. Pleiotropic proteins are emerging as important contributors to rare and common disorders. Nevertheless, little is known on the mechanisms underlying pleiotropy and the characteristic of pleiotropic proteins. We analyzed disease-causing proteins reported in UniProt and observed that 12% are pleiotropic (variants in the same protein cause more than one disease). Pleiotropic proteins were enriched in deleterious and rare variants, but not in common variants. Pleiotropic proteins were more likely to be involved in the pathogenesis of neoplasms, neurological, and circulatory diseases and congenital malformations, whereas non-pleiotropic proteins in endocrine and metabolic disorders. Pleiotropic proteins were more essential and had a higher number of interacting partners compared with non-pleiotropic proteins. Significantly more pleiotropic than non-pleiotropic proteins contained at least one intrinsically long disordered region (P < 0.001). Deleterious variants occurring in structurally disordered regions were more commonly found in pleiotropic, rather than non-pleiotropic proteins. In conclusion, pleiotropic proteins are an important contributor to human disease. They represent a biologically different class of proteins compared with non-pleiotropic proteins and a better understanding of their characteristics and genetic variants can greatly aid in the interpretation of genetic studies and drug design. © 2016 WILEY PERIODICALS, INC.

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

PubMed

Loley, Christina; Alver, Maris; Assimes, Themistocles L; Bjonnes, Andrew; Goel, Anuj; Gustafsson, Stefan; Hernesniemi, Jussi; Hopewell, Jemma C; Kanoni, Stavroula; Kleber, Marcus E; Lau, King Wai; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Nelson, Christopher P; Nikpay, Majid; Qu, Liming; Salfati, Elias; Scholz, Markus; Tukiainen, Taru; Willenborg, Christina; Won, Hong-Hee; Zeng, Lingyao; Zhang, Weihua; Anand, Sonia S; Beutner, Frank; Bottinger, Erwin P; Clarke, Robert; Dedoussis, George; Do, Ron; Esko, Tõnu; Eskola, Markku; Farrall, Martin; Gauguier, Dominique; Giedraitis, Vilmantas; Granger, Christopher B; Hall, Alistair S; Hamsten, Anders; Hazen, Stanley L; Huang, Jie; Kähönen, Mika; Kyriakou, Theodosios; Laaksonen, Reijo; Lind, Lars; Lindgren, Cecilia; Magnusson, Patrik K E; Marouli, Eirini; Mihailov, Evelin; Morris, Andrew P; Nikus, Kjell; Pedersen, Nancy; Rallidis, Loukianos; Salomaa, Veikko; Shah, Svati H; Stewart, Alexandre F R; Thompson, John R; Zalloua, Pierre A; Chambers, John C; Collins, Rory; Ingelsson, Erik; Iribarren, Carlos; Karhunen, Pekka J; Kooner, Jaspal S; Lehtimäki, Terho; Loos, Ruth J F; März, Winfried; McPherson, Ruth; Metspalu, Andres; Reilly, Muredach P; Ripatti, Samuli; Sanghera, Dharambir K; Thiery, Joachim; Watkins, Hugh; Deloukas, Panos; Kathiresan, Sekar; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; König, Inke R

2016-10-12

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

MutaBind estimates and interprets the effects of sequence variants on protein-protein interactions.

PubMed

Li, Minghui; Simonetti, Franco L; Goncearenco, Alexander; Panchenko, Anna R

2016-07-08

Proteins engage in highly selective interactions with their macromolecular partners. Sequence variants that alter protein binding affinity may cause significant perturbations or complete abolishment of function, potentially leading to diseases. There exists a persistent need to develop a mechanistic understanding of impacts of variants on proteins. To address this need we introduce a new computational method MutaBind to evaluate the effects of sequence variants and disease mutations on protein interactions and calculate the quantitative changes in binding affinity. The MutaBind method uses molecular mechanics force fields, statistical potentials and fast side-chain optimization algorithms. The MutaBind server maps mutations on a structural protein complex, calculates the associated changes in binding affinity, determines the deleterious effect of a mutation, estimates the confidence of this prediction and produces a mutant structural model for download. MutaBind can be applied to a large number of problems, including determination of potential driver mutations in cancer and other diseases, elucidation of the effects of sequence variants on protein fitness in evolution and protein design. MutaBind is available at http://www.ncbi.nlm.nih.gov/projects/mutabind/. Published by Oxford University Press on behalf of Nucleic Acids Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Stereotypic and complex phrase types provide structural evidence for a multi-message display in humpback whales (Megaptera novaeangliae).

PubMed

Murray, Anita; Dunlop, Rebecca A; Noad, Michael J; Goldizen, Anne W

2018-02-01

Male humpback whales produce a mating display called "song." Behavioral studies indicate song has inter- and/or intra-sexual functionality, suggesting song may be a multi-message display. Multi-message displays often include stereotypic components that convey group membership for mate attraction and/or male-male interactions, and complex components that convey individual quality for courtship. Humpback whale song contains sounds ("units") arranged into sequences ("phrases"). Repetitions of a specific phrase create a "theme." Within a theme, imperfect phrase repetitions ("phrase variants") create variability among phrases of the same type ("phrase type"). The hypothesis that song contains stereotypic and complex phrase types, structural characteristics consistent with a multi-message display, is investigated using recordings of 17 east Australian males (8:2004, 9:2011). Phrase types are categorized as stereotypic or complex using number of unit types, number of phrase variants, and the proportion of phrases that is unique to an individual versus shared amongst males. Unit types are determined using self-organizing maps. Phrase variants are determined by Levenshtein distances between phrases. Stereotypic phrase types have smaller numbers of unit types and shared phrase variants. Complex phrase types have larger numbers of unit types and unique phrase variants. This study supports the hypothesis that song could be a multi-message display.

Localized structural frustration for evaluating the impact of sequence variants

PubMed Central

Kumar, Sushant; Clarke, Declan; Gerstein, Mark

2016-01-01

Population-scale sequencing is increasingly uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions of the genome. The rarity of these variants makes it challenging to evaluate their deleteriousness with conventional phenotype–genotype associations. Protein structures provide a way of addressing this challenge. Previous efforts have focused on globally quantifying the impact of SNVs on protein stability. However, local perturbations may severely impact protein functionality without strongly disrupting global stability (e.g. in relation to catalysis or allostery). Here, we describe a workflow in which localized frustration, quantifying unfavorable local interactions, is employed as a metric to investigate such effects. Using this workflow on the Protein Databank, we find that frustration produces many immediately intuitive results: for instance, disease-related SNVs create stronger changes in localized frustration than non-disease related variants, and rare SNVs tend to disrupt local interactions to a larger extent than common variants. Less obviously, we observe that somatic SNVs associated with oncogenes and tumor suppressor genes (TSGs) induce very different changes in frustration. In particular, those associated with TSGs change the frustration more in the core than the surface (by introducing loss-of-function events), whereas those associated with oncogenes manifest the opposite pattern, creating gain-of-function events. PMID:27915290

Charge heterogeneity: Basic antibody charge variants with increased binding to Fc receptors.

PubMed

Hintersteiner, Beate; Lingg, Nico; Zhang, Peiqing; Woen, Susanto; Hoi, Kong Meng; Stranner, Stefan; Wiederkum, Susanne; Mutschlechner, Oliver; Schuster, Manfred; Loibner, Hans; Jungbauer, Alois

We identified active isoforms of the chimeric anti-GD2 antibody, ch14.18, a recombinant antibody produced in Chinese hamster ovary cells, which is already used in clinical trials. 1,2,3 We separated the antibody by high resolution ion-exchange chromatography with linear pH gradient elution into acidic, main and basic charge variants on a preparative scale yielding enough material for an in-depth study of the sources and the effects of microheterogeneity. The binding affinity of the charge variants toward the antigen and various cell surface receptors was studied by Biacore. Effector functions were evaluated using cellular assays for antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Basic charge variants showed increased binding to cell surface receptor FcγRIIIa, which plays a major role in regulating effector functions. Furthermore, increased binding of the basic fractions to the neonatal receptor was observed. As this receptor mediates the prolonged half-life of IgG in human serum, this data may well hint at an increased serum half-life of these basic variants compared to their more acidic counterparts. Different glycoform patterns, C-terminal lysine clipping and N-terminal pyroglutamate formation were identified as the main structural sources for the observed isoform pattern. Potential differences in structural stability between individual charge variant fractions by nano differential scanning calorimetry could not been detected. Our in-vitro data suggests that the connection between microheterogeneity and the biological activity of recombinant antibody therapeutics deserves more attention than commonly accepted.

IMPACT web portal: oncology database integrating molecular profiles with actionable therapeutics.

PubMed

Hintzsche, Jennifer D; Yoo, Minjae; Kim, Jihye; Amato, Carol M; Robinson, William A; Tan, Aik Choon

2018-04-20

With the advancement of next generation sequencing technology, researchers are now able to identify important variants and structural changes in DNA and RNA in cancer patient samples. With this information, we can now correlate specific variants and/or structural changes with actionable therapeutics known to inhibit these variants. We introduce the creation of the IMPACT Web Portal, a new online resource that connects molecular profiles of tumors to approved drugs, investigational therapeutics and pharmacogenetics associated drugs. IMPACT Web Portal contains a total of 776 drugs connected to 1326 target genes and 435 target variants, fusion, and copy number alterations. The online IMPACT Web Portal allows users to search for various genetic alterations and connects them to three levels of actionable therapeutics. The results are categorized into 3 levels: Level 1 contains approved drugs separated into two groups; Level 1A contains approved drugs with variant specific information while Level 1B contains approved drugs with gene level information. Level 2 contains drugs currently in oncology clinical trials. Level 3 provides pharmacogenetic associations between approved drugs and genes. IMPACT Web Portal allows for sequencing data to be linked to actionable therapeutics for translational and drug repurposing research. The IMPACT Web Portal online resource allows users to query genes and variants to approved and investigational drugs. We envision that this resource will be a valuable database for personalized medicine and drug repurposing. IMPACT Web Portal is freely available for non-commercial use at http://tanlab.ucdenver.edu/IMPACT .

The generation of a 1-hydroxy-2-naphthoate 1,2-dioxygenase by single point mutations of salicylate 1,2-dioxygenase--rational design of mutants and the crystal structures of the A85H and W104Y variants.

PubMed

Ferraroni, Marta; Steimer, Lenz; Matera, Irene; Bürger, Sibylle; Scozzafava, Andrea; Stolz, Andreas; Briganti, Fabrizio

2012-12-01

Key amino acid residues of the salicylate 1,2-dioxygenase (SDO), an iron (II) class III ring cleaving dioxygenase from Pseudaminobacter salicylatoxidans BN12, were selected, based on amino acid sequence alignments and structural analysis of the enzyme, and modified by site-directed mutagenesis to obtain variant forms with altered catalytic properties. SDO shares with 1-hydroxy-2-naphthoate dioxygenase (1H2NDO) its unique ability to oxidatively cleave monohydroxylated aromatic compounds. Nevertheless SDO is more versatile with respect to 1H2NDO and other known gentisate dioxygenases (GDOs) because it cleaves not only gentisate and 1-hydroxy-2-naphthoate (1H2NC) but also salicylate and substituted salicylates. Several enzyme variants of SDO were rationally designed to simulate 1H2NDO. The basic kinetic parameters for the SDO mutants L38Q, M46V, A85H and W104Y were determined. The enzyme variants L38Q, M46V, A85H demonstrated higher catalytic efficiencies toward 1-hydroxy-2-naphthoate (1H2NC) compared to gentisate. Remarkably, the enzyme variant A85H effectively cleaved 1H2NC but did not oxidize gentisate at all. The W104Y SDO mutant exhibited reduced reaction rates for all substrates tested. The crystal structures of the A85H and W104Y variants were solved and analyzed. The substitution of Ala85 with a histidine residue caused significant changes in the orientation of the loop containing this residue which is involved in the active site closing upon substrate binding. In SDO A85H this specific loop shifts away from the active site and thus opens the cavity favoring the binding of bulkier substrates. Since this loop also interacts with the N-terminal residues of the vicinal subunit, the structure and packing of the holoenzyme might be also affected. Copyright © 2012 Elsevier Inc. All rights reserved.

Different structural stability and toxicity of PrP(ARR) and PrP(ARQ) sheep prion protein variants.

PubMed

Paludi, Domenico; Thellung, Stefano; Chiovitti, Katia; Corsaro, Alessandro; Villa, Valentina; Russo, Claudio; Ianieri, Adriana; Bertsch, Uwe; Kretzschmar, Hans A; Aceto, Antonio; Florio, Tullio

2007-12-01

The polymorphisms at amino acid residues 136, 154, and 171 in ovine prion protein (PrP) have been associated with different susceptibility to scrapie: animals expressing PrP(ARQ) [PrP(Ala136/Arg154/Gln171)] show vulnerability, whereas those that express PrP(ARR) [PrP(Ala136/Arg154/Arg171)] are resistant to scrapie. The aim of this study was to evaluate the in vitro toxic effects of PrP(ARR) and PrP(ARQ) variants in relation with their structural characteristics. We show that both peptides cause cell death inducing apoptosis but, unexpectedly, the scrapie resistant PrP(ARR) form was more toxic than the scrapie susceptible PrP(ARQ) variant. Moreover, the alpha-helical conformation of PrP(ARR) was less stable than that of PrP(ARQ) and the structural determinants responsible of these different conformational stabilities were characterized by spectroscopic analysis. We observed that PrP toxicity was inversely related to protein structural stability, being the unfolded conformation more toxic than the native one. However, the PrP(ARQ) variant displays a higher propensity to form large aggregates than PrP(ARR). Interestingly, in the presence of small amounts of PrP(ARR), PrP(ARQ) aggregability was reduced to levels similar to that of PrP(ARR). Thus, in contrast to PrP(ARR) toxicity, scrapie transmissibility seems to reside in the more stable conformation of PrP(ARQ) that allows the formation of large amyloid fibrils.

Deletion mapping of the Aequorea victoria green fluorescent protein.

PubMed

Dopf, J; Horiagon, T M

1996-01-01

Aequorea victoria green fluorescent protein (GFP) is a promising fluorescent marker which is active in a diverse array of prokaryotic and eukaryotic organisms. A key feature underlying the versatility of GFP is its capacity to undergo heterocyclic chromophore formation by cyclization of a tripeptide present in its primary sequence and thereby acquiring fluorescent activity in a variety of intracellular environments. In order to define further the primary structure requirements for chromophore formation and fluorescence in GFP, a series of N- and C-terminal GFP deletion variant expression vectors were created using the polymerase chain reaction. Scanning spectrofluorometric analyses of crude soluble protein extracts derived from eleven GFP expression constructs revealed that amino acid (aa) residues 2-232, of a total of 238 aa in the native protein, were required for the characteristic emission and absorption spectra of native GFP. Heterocyclic chromophore formation was assayed by comparing the absorption spectrum of GFP deletion variants over the 300-500-nm range to the absorption spectra of full-length GFP and GFP deletion variants missing the chromophore substrate domain from the primary sequence. GFP deletion variants lacking fluorescent activity showed no evidence of heterocyclic ring structure formation when the soluble extracts of their bacterial expression hosts were studied at pH 7.9. These observations suggest that the primary structure requirements for the fluorescent activity of GFP are relatively extensive and are compatible with the view that much of the primary structure serves an autocatalytic function.

Extreme Entropy-Enthalpy Compensation in a Drug Resistant Variant of HIV-1 Protease

PubMed Central

King, Nancy M.; Prabu-Jeyabalan, Moses; Bandaranayake, Rajintha M.; Nalam, Madhavi N. L.; Nalivaika, Ellen A.; Özen, Ayşegül; Haliloglu, Türkan; Yılmaz, Neşe Kurt; Schiffer, Celia A.

2012-01-01

The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5–15 kcal/mol, while losing only 1–3 kcal/mol in total binding free energy for any of six FDA approved inhibitors. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wildtype protease and another drug resistant variant that does not exhibit this energetic compensation. Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The finding that drug resistant mutations can profoundly modulate the relative thermodynamic properties of a therapeutic target independent of the inhibitor presents a new challenge for rational drug design. PMID:22712830

GenProBiS: web server for mapping of sequence variants to protein binding sites.

PubMed

Konc, Janez; Skrlj, Blaz; Erzen, Nika; Kunej, Tanja; Janezic, Dusanka

2017-07-03

Discovery of potentially deleterious sequence variants is important and has wide implications for research and generation of new hypotheses in human and veterinary medicine, and drug discovery. The GenProBiS web server maps sequence variants to protein structures from the Protein Data Bank (PDB), and further to protein-protein, protein-nucleic acid, protein-compound, and protein-metal ion binding sites. The concept of a protein-compound binding site is understood in the broadest sense, which includes glycosylation and other post-translational modification sites. Binding sites were defined by local structural comparisons of whole protein structures using the Protein Binding Sites (ProBiS) algorithm and transposition of ligands from the similar binding sites found to the query protein using the ProBiS-ligands approach with new improvements introduced in GenProBiS. Binding site surfaces were generated as three-dimensional grids encompassing the space occupied by predicted ligands. The server allows intuitive visual exploration of comprehensively mapped variants, such as human somatic mis-sense mutations related to cancer and non-synonymous single nucleotide polymorphisms from 21 species, within the predicted binding sites regions for about 80 000 PDB protein structures using fast WebGL graphics. The GenProBiS web server is open and free to all users at http://genprobis.insilab.org. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

Wu, Hong; Zeng, Hong; Lam, Robert

The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree ofmore » similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.« less

Computational design of chimeric protein libraries for directed evolution.

PubMed

Silberg, Jonathan J; Nguyen, Peter Q; Stevenson, Taylor

2010-01-01

The best approach for creating libraries of functional proteins with large numbers of nondisruptive amino acid substitutions is protein recombination, in which structurally related polypeptides are swapped among homologous proteins. Unfortunately, as more distantly related proteins are recombined, the fraction of variants having a disrupted structure increases. One way to enrich the fraction of folded and potentially interesting chimeras in these libraries is to use computational algorithms to anticipate which structural elements can be swapped without disturbing the integrity of a protein's structure. Herein, we describe how the algorithm Schema uses the sequences and structures of the parent proteins recombined to predict the structural disruption of chimeras, and we outline how dynamic programming can be used to find libraries with a range of amino acid substitution levels that are enriched in variants with low Schema disruption.

Structural Characterization of the Histone Variant macroH2A

PubMed Central

Chakravarthy, Srinivas; Gundimella, Sampath Kumar Y.; Caron, Cecile; Perche, Pierre-Yves; Pehrson, John R.; Khochbin, Saadi; Luger, Karolin

2005-01-01

macroH2A is an H2A variant with a highly unusual structural organization. It has a C-terminal domain connected to the N-terminal histone domain by a linker. Crystallographic and biochemical studies show that changes in the L1 loop in the histone fold region of macroH2A impact the structure and potentially the function of nucleosomes. The 1.6-Å X-ray structure of the nonhistone region reveals an α/β fold which has previously been found in a functionally diverse group of proteins. This region associates with histone deacetylases and affects the acetylation status of nucleosomes containing macroH2A. Thus, the unusual domain structure of macroH2A integrates independent functions that are instrumental in establishing a structurally and functionally unique chromatin domain. PMID:16107708

Evidence of trem2 variant associated with triple risk of Alzheimer's disease.

PubMed

Abduljaleel, Zainularifeen; Al-Allaf, Faisal A; Khan, Wajahatullah; Athar, Mohammad; Shahzad, Naiyer; Taher, Mohiuddin M; Elrobh, Mohamed; Alanazi, Mohammed S; El-Huneidi, Waseem

2014-01-01

Alzheimer's disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer's disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His). The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His) through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD) simulation under salvation, the results confirmed that native form of the variant (Arg47His) might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns), which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to "immunoglobulin V-set" and "immunoglobulin-like folds". Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer's disease.

RIC-7 Promotes Neuropeptide Secretion

PubMed Central

Hao, Yingsong; Hu, Zhitao; Sieburth, Derek; Kaplan, Joshua M.

2012-01-01

Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs) respectively. Relatively little is known about factors that differentially regulate SV and DCV secretion. Here we identify a novel protein RIC-7 that is required for neuropeptide secretion in Caenorhabditis elegans. The RIC-7 protein is expressed in all neurons and is localized to presynaptic terminals. Imaging, electrophysiology, and behavioral analysis of ric-7 mutants indicates that acetylcholine release occurs normally, while neuropeptide release is significantly decreased. These results suggest that RIC-7 promotes DCV–mediated secretion. PMID:22275875

MIZEX: A Program for Mesoscale Air-Ice-Ocean Interaction Experiments in Arctic Marginal Ice Zones. VIII. A Science Plan for a Winter Marginal Ice Zone Experiment in the Fram Strait/Greenland Sea: 1987/89,

DTIC Science & Technology

1986-04-01

forward modeling, with the pa- be telemetered via the ARGOS system for real - rameter changes needed to bring the predictions time evaluation, and the...integrated en ’i- rtinnental measurement svs fern. quisition system to the Winter MIZEX in I-ram To control and direct the experiment, real - time Strait...to measure, under- Electromagnetic sensing via aircraft and satellites stand, and model: will be employed in real time to identify eddy " Changes in

VizieR Online Data Catalog: NGC 7129 pre-main sequence stars (Stelzer+, 2009)

NASA Astrophysics Data System (ADS)

Stelzer, B.; Scholz, A.

2010-09-01

We make use of X-ray and IR imaging observations to identify the pre-main sequence stars in NGC 7129. We define a sample of young stellar objects based on color-color diagrams composed from IR photometry between 1.6 and 8um, from 2MASS and Spitzer, and based on X-ray detected sources from a Chandra observation. A 22ks long Chandra observation targeting the Herbig star SVS 12 was carried out on Mar 11, 2006 (start of observation UT 14h29m18s). (5 data files).

A Five-Factor Measure of Schizotypal Personality Traits

ERIC Educational Resources Information Center

Edmundson, Maryanne; Lynam, Donald R.; Miller, Joshua D.; Gore, Whitney L.; Widiger, Thomas A.

2011-01-01

The current study provides convergent, discriminant, and incremental validity data for a new measure of schizotypy from the perspective of the five-factor model (FFM) of general personality structure. Nine schizotypy scales were constructed as maladaptive variants of respective facets of the FFM (e.g., Aberrant Ideas as a maladaptive variant of…

A new β chain hemoglobin variant with increased oxygen affinity: Hb Santa Giusta Sardegna [β93(F9)Cys→Trp; HBB c.282T>G].

PubMed

Fais, Antonella; Sollaino, Maria Carla; Barella, Susanna; Perseu, Lucia; Era, Benedetta; Corda, Marcella

2012-01-01

During a screening program for the identification of β-thalassemia (β-thal) carriers in Sardinia, Italy, we identified two subjects with increased hemoglobin (Hb) levels and an abnormal Hb variant. The same variant was detected in a family member. DNA sequencing revealed a TGT > TGG mutation at codon 93 of the β-globin gene. Structural analysis demonstrated that the cystine residue at position 93 of the β chain was substituted by tryptophan. Since this amino acid substitution had not yet been reported, we designated this variant Hb Santa Giusta Sardegna for the place of birth of the subjects. This amino acid substitution occurs at the tyrosine pocket of the β chain as well as at the α1β2/α2β1 contact of the quaternary structure of the molecule. The presence of this Hb in the hemolysate causes an increased oxygen affinity, a slightly reduced Bohr effect and a reduced heme-heme interaction (n(50), Hill's constant) in comparison with those of Hb A.

Kinetic Resolution of sec-Thiols by Enantioselective Oxidation with Rationally Engineered 5-(Hydroxymethyl)furfural Oxidase.

PubMed

Pickl, Mathias; Swoboda, Alexander; Romero, Elvira; Winkler, Christoph K; Binda, Claudia; Mattevi, Andrea; Faber, Kurt; Fraaije, Marco W

2018-03-05

Various flavoprotein oxidases were recently shown to oxidize primary thiols. Herein, this reactivity is extended to sec-thiols by using structure-guided engineering of 5-(hydroxymethyl)furfural oxidase (HMFO). The variants obtained were employed for the oxidative kinetic resolution of racemic sec-thiols, thus yielding the corresponding thioketones and nonreacted R-configured thiols with excellent enantioselectivities (E≥200). The engineering strategy applied went beyond the classic approach of replacing bulky amino acid residues with smaller ones, as the active site was additionally enlarged by a newly introduced Thr residue. This residue established a hydrogen-bonding interaction with the substrates, as verified in the crystal structure of the variant. These strategies unlocked HMFO variants for the enantioselective oxidation of a range of sec-thiols. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peptidomimetic Escape Mechanisms Arise via Genetic Diversity in the Ligand-Binding Site of the Hepatitis C Virus NS3/4A Serine Protease

PubMed Central

Welsch, Christoph; Shimakami, Tetsuro; Hartmann, Christoph; Yang, Yan; Domingues, Francisco S.; Lengauer, Thomas; Zeuzem, Stefan; Lemon, Stanley M.

2011-01-01

Background & Aims It is a challenge to develop direct-acting antiviral agents (DAAs) that target the NS3/4A protease of hepatitis C virus (HCV) because resistant variants develop. Ketoamide compounds, designed to mimic the natural protease substrate, have been developed as inhibitors. However, clinical trials have revealed rapid selection of resistant mutants, most of which are considered to be pre-existing variants. Methods We identified residues near the ketoamide-binding site in X-ray structures of the genotype 1a protease, co-crystallized with boceprevir or a telaprevir-like ligand, and then identified variants at these positions in 219 genotype 1 sequences from a public database. We used side-chain modeling to assess the potential effects of these variants on the interaction between ketoamide and the protease, and compared these results with the phenotypic effects on ketoamide resistance, RNA replication capacity, and infectious virus yields in a cell culture model of infection. Results Thirteen natural binding-site variants with potential for ketoamide resistance were identified at 10 residues in the protease, near the ketoamide binding site. Rotamer analysis of amino acid side-chain conformations indicated that 2 variants (R155K and D168G) could affect binding of telaprevir more than boceprevir. Measurements of antiviral susceptibility in cell culture studies were consistent with this observation. Four variants (Q41H, I132V, R155K, and D168G) caused low-to-moderate levels of ketoamide resistance; 3 of these were highly fit (Q41H, I132V, and R155K). Conclusions Using a comprehensive sequence and structure-based analysis, we showed how natural variation in the HCV protease NS3/4A sequences might affect susceptibility to first-generation DAAs. These findings increase our understanding of the molecular basis of ketoamide resistance among naturally existing viral variants. PMID:22155364

Cancer-Related Analysis of Variants Toolkit (CRAVAT) | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

CRAVAT is an easy to use web-based tool for analysis of cancer variants (missense, nonsense, in-frame indel, frameshift indel, splice site). CRAVAT provides scores and a variety of annotations that assist in identification of important variants. Results are provided in an interactive, highly graphical webpage and include annotated 3D structure visualization. CRAVAT is also available for local or cloud-based installation as a Docker container. MuPIT provides 3D visualization of mutation clusters and functional annotation and is now integrated with CRAVAT.

Natural genetic variability reduces recalcitrance in poplar

DOE PAGES

Bhagia, Samarthya; Muchero, Wellington; Kumar, Rajeev; ...

2016-05-20

Here, lignin content and structure are known to affect recalcitrance of lignocellulosic biomass to chemical/biochemical conversion. Previously, we identified rare Populus trichocarpa natural variants with significantly reduced lignin content. Because reduced lignin content may lower recalcitrance, 18 rare variants along with 4 comparators, and BESC standard Populus was analyzed for composition of structural carbohydrates and lignin. Sugar yields from these plants were measured at 5 process conditions: one for just enzymatic hydrolysis without pretreatment and four via our combined high-throughput hot water pretreatment and co-hydrolysis (HTPH) technique.

Population structure and genetic variability within isolates of Grapevine fanleaf virus from a naturally infected vineyard in France: evidence for mixed infection and recombination.

PubMed

Vigne, Emmanuelle; Bergdoll, Marc; Guyader, Sébastien; Fuchs, Marc

2004-08-01

The nematode-borne Grapevine fanleaf virus, from the genus Nepovirus in the family Comoviridae, causes severe degeneration of grapevines in most vineyards worldwide. We characterized 347 isolates from transgenic and conventional grapevines from two vineyard sites in the Champagne region of France for their molecular variant composition. The population structure and genetic diversity were examined in the coat protein gene by IC-RT-PCR-RFLP analysis with EcoRI and StyI, and nucleotide sequencing, respectively. RFLP data suggested that 55 % (191 of 347) of the isolates had a population structure consisting of one predominant variant. Sequencing data of 51 isolates representing the different restrictotypes confirmed the existence of mixed infection with a frequency of 33 % (17 of 51) and showed two major predominant haplotypes representing 71 % (60 of 85) of the sequence variants. Comparative nucleotide diversity among population subsets implied a lack of genetic differentiation according to host (transgenic vs conventional) or field site for most restrictotypes (17 of 18 and 13 of 18) and for haplotypes in most phylogenetic groups (seven of eight and six of eight), respectively. Interestingly, five of the 85 haplotypes sequenced had an intermediate divergence (0.036-0.066) between the lower (0.005-0.028) and upper range (0.083-0.138) of nucleotide variability, suggesting the occurrence of homologous RNA recombination. Sequence alignments clearly indicated a mosaic structure for four of these five variants, for which recombination sites were identified and parental lineages proposed. This is the first in-depth characterization of the population structure and genetic diversity in a nepovirus.

Influence of a heptad repeat stutter on the pH-dependent conformational behavior of the central coiled-coil from influenza hemagglutinin HA2.

PubMed

Higgins, Chelsea D; Malashkevich, Vladimir N; Almo, Steven C; Lai, Jonathan R

2014-09-01

The coiled-coil is one of the most common protein structural motifs. Amino acid sequences of regions that participate in coiled-coils contain a heptad repeat in which every third then forth residue is occupied by a hydrophobic residue. Here we examine the consequences of a "stutter," a deviation of the idealized heptad repeat that is found in the central coiled-coil of influenza hemagluttinin HA2. Characterization of a peptide containing the native stutter-containing HA2 sequence, as well as several variants in which the stutter was engineered out to restore an idealized heptad repeat pattern, revealed that the stutter is important for allowing coiled-coil formation in the WT HA2 at both neutral and low pH (7.1 and 4.5). By contrast, all variants that contained idealized heptad repeats exhibited marked pH-dependent coiled-coil formation with structures forming much more stably at low pH. A crystal structure of one variant containing an idealized heptad repeat, and comparison to the WT HA2 structure, suggest that the stutter distorts the optimal interhelical core packing arrangement, resulting in unwinding of the coiled-coil superhelix. Interactions between acidic side chains, in particular E69 and E74 (present in all peptides studied), are suggested to play a role in mediating these pH-dependent conformational effects. This conclusion is partially supported by studies on HA2 variant peptides in which these positions were altered to aspartic acid. These results provide new insight into the structural role of the heptad repeat stutter in HA2. © 2014 Wiley Periodicals, Inc.

HUMAN LIVER FATTY ACID BINDING PROTEIN (L-FABP) T94A VARIANT ALTERS STRUCTURE, STABILITY, AND INTERACTION WITH FIBRATES

PubMed Central

Martin, Gregory G.; McIntosh, Avery L.; Huang, Huan; Gupta, Shipra; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

2014-01-01

Although the human L-FABP T94A variant arises from the most commonly occurring SNP in the entire FABP family, there is a complete lack of understanding regarding the role of this polymorphism in human disease. It has been hypothesized that the T94A substitution results in complete loss of ligand binding ability and function analogous to L-FABP gene ablation. This possibility was addressed using recombinant human WT T94T and T94A variant L-FABP and cultured primary human hepatocytes. Non-conservative replacement of the medium sized, polar, uncharged T residue by a smaller, nonpolar, aliphatic A residue at position 94 of human L-FABP significantly increased L-FABP protein α-helical structure at the expense of β-sheet and concomitantly decreased thermal stability. T94A did not alter binding affinities for PPARα agonist ligands (phytanic acid, fenofibrate, fenofibric acid). While T94A did not alter the impact of phytanic acid and only slightly altered that of fenofibrate on human L-FABP secondary structure, the active metabolite fenofibric acid altered T94A secondary structure much more than that of WT T94T L-FABP. Finally, in cultured primary human hepatocytes the T94A variant exhibited significantly reduced fibrate-mediated induction of PPARα-regulated proteins such as L-FABP, FATP5, and PPARα itself. Thus, while T94A substitution did not alter the affinity of human L-FABP for PPARα agonist ligands, it significantly altered human L-FABP structure, stability, as well as conformational and functional response to fibrate. PMID:24299557

The UK10K project identifies rare variants in health and disease.

PubMed

Walter, Klaudia; Min, Josine L; Huang, Jie; Crooks, Lucy; Memari, Yasin; McCarthy, Shane; Perry, John R B; Xu, ChangJiang; Futema, Marta; Lawson, Daniel; Iotchkova, Valentina; Schiffels, Stephan; Hendricks, Audrey E; Danecek, Petr; Li, Rui; Floyd, James; Wain, Louise V; Barroso, Inês; Humphries, Steve E; Hurles, Matthew E; Zeggini, Eleftheria; Barrett, Jeffrey C; Plagnol, Vincent; Richards, J Brent; Greenwood, Celia M T; Timpson, Nicholas J; Durbin, Richard; Soranzo, Nicole

2015-10-01

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

Nonparaxial propagation and focusing properties of azimuthal-variant vector fields diffracted by an annular aperture.

PubMed

Gu, Bing; Xu, Danfeng; Pan, Yang; Cui, Yiping

2014-07-01

Based on the vectorial Rayleigh-Sommerfeld integrals, the analytical expressions for azimuthal-variant vector fields diffracted by an annular aperture are presented. This helps us to investigate the propagation behaviors and the focusing properties of apertured azimuthal-variant vector fields under nonparaxial and paraxial approximations. The diffraction by a circular aperture, a circular disk, or propagation in free space can be treated as special cases of this general result. Simulation results show that the transverse intensity, longitudinal intensity, and far-field divergence angle of nonparaxially apertured azimuthal-variant vector fields depend strongly on the azimuthal index, the outer truncation parameter and the inner truncation parameter of the annular aperture, as well as the ratio of the waist width to the wavelength. Moreover, the multiple-ring-structured intensity pattern of the focused azimuthal-variant vector field, which originates from the diffraction effect caused by an annular aperture, is experimentally demonstrated.

Rational Modular RNA Engineering Based on In Vivo Profiling of Structural Accessibility.

PubMed

Leistra, Abigail N; Amador, Paul; Buvanendiran, Aishwarya; Moon-Walker, Alex; Contreras, Lydia M

2017-12-15

Bacterial small RNAs (sRNAs) have been established as powerful parts for controlling gene expression. However, development and application of engineered sRNAs has primarily focused on regulating novel synthetic targets. In this work, we demonstrate a rational modular RNA engineering approach that uses in vivo structural accessibility measurements to tune the regulatory activity of a multisubstrate sRNA for differential control of its native target network. Employing the CsrB global sRNA regulator as a model system, we use published in vivo structural accessibility data to infer the contribution of its local structures (substructures) to function and select a subset for engineering. We then modularly recombine the selected substructures, differentially representing those of presumed high or low functional contribution, to build a library of 21 CsrB variants. Using fluorescent translational reporter assays, we demonstrate that the CsrB variants achieve a 5-fold gradient of control of well-characterized Csr network targets. Interestingly, results suggest that less conserved local structures within long, multisubstrate sRNAs may represent better targets for rational engineering than their well-conserved counterparts. Lastly, mapping the impact of sRNA variants on a signature Csr network phenotype indicates the potential of this approach for tuning the activity of global sRNA regulators in the context of metabolic engineering applications.

GALT protein database: querying structural and functional features of GALT enzyme.

PubMed

d'Acierno, Antonio; Facchiano, Angelo; Marabotti, Anna

2014-09-01

Knowledge of the impact of variations on protein structure can enhance the comprehension of the mechanisms of genetic diseases related to that protein. Here, we present a new version of GALT Protein Database, a Web-accessible data repository for the storage and interrogation of structural effects of variations of the enzyme galactose-1-phosphate uridylyltransferase (GALT), the impairment of which leads to classic Galactosemia, a rare genetic disease. This new version of this database now contains the models of 201 missense variants of GALT enzyme, including heterozygous variants, and it allows users not only to retrieve information about the missense variations affecting this protein, but also to investigate their impact on substrate binding, intersubunit interactions, stability, and other structural features. In addition, it allows the interactive visualization of the models of variants collected into the database. We have developed additional tools to improve the use of the database by nonspecialized users. This Web-accessible database (http://bioinformatica.isa.cnr.it/GALT/GALT2.0) represents a model of tools potentially suitable for application to other proteins that are involved in human pathologies and that are subjected to genetic variations. © 2014 WILEY PERIODICALS, INC.

Phase field simulations of autocatalytic formation of alpha lamellar colonies in Ti-6Al-4V

DOE PAGES

Radhakrishnan, Bala; Gorti, Sarma; Babu, Suresh Sudharsanam

2016-09-13

Here, we present phase field simulations incorporating energy contributions due to thermodynamics, and anisotropic interfacial and strain energies, to demonstrate the nucleation and growth of multiple variants of alpha from beta in Ti-6Al-4V under isothermal conditions. The simulations focused on the effect of thermodynamic driving force and nucleation rate on the morphology of the transformed alpha assuming that the partitioning of V between beta and alpha is negligible for short isothermal holds. The results indicate that a high nucleation rate favors the formation of the basket-weave structure. However, at a lower nucleation rate the simulations show the intragranular nucleation ofmore » a colony structure by an autocatalytic nucleation mechanism adjacent to a pre-existing alpha variant. New side-plates of the same variant appear to nucleate progressively and grow to form the colony. The isothermal simulation results are used to offer a possible explanation for the transition from a largely basket weave structure to a colony structure inside narrow layer bands occurring during continuous heating and cooling conditions encountered during laser additive manufacturing of Ti-6Al-4V.« less

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

PubMed

Flannick, Jason; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M; Agarwala, Vineeta; Gaulton, Kyle J; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J; Rivas, Manuel A; Perry, John R B; Sim, Xueling; Blackwell, Thomas W; Robertson, Neil R; Rayner, N William; Cingolani, Pablo; Locke, Adam E; Tajes, Juan Fernandez; Highland, Heather M; Dupuis, Josee; Chines, Peter S; Lindgren, Cecilia M; Hartl, Christopher; Jackson, Anne U; Chen, Han; Huyghe, Jeroen R; van de Bunt, Martijn; Pearson, Richard D; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M; Gamazon, Eric R; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A; Below, Jennifer E; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L; Pasko, Dorota; Parker, Stephen C J; Varga, Tibor V; Green, Todd; Beer, Nicola L; Day-Williams, Aaron G; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F; Han, Bok-Ghee; Jenkinson, Christopher P; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C Y; Palmer, Nicholette D; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D; Neale, Benjamin M; Purcell, Shaun; Butterworth, Adam S; Howson, Joanna M M; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K L; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H T; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E; Rybin, Dennis; Farook, Vidya S; Fowler, Sharon P; Freedman, Barry I; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K; Puppala, Sobha; Scott, William R; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C; Mangino, Massimo; Bonnycastle, Lori L; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L; Herder, Christian; Groves, Christopher J; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A; Doney, Alex S F; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H; Stirrups, Kathleen; Wood, Andrew R; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N A; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M; Syvänen, Ann-Christine; Bergman, Richard N; Bharadwaj, Dwaipayan; Bottinger, Erwin P; Cho, Yoon Shin; Chandak, Giriraj R; Chan, Juliana Cn; Chia, Kee Seng; Daly, Mark J; Ebrahim, Shah B; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A; Lehman, Donna M; Jia, Weiping; Ma, Ronald C W; Pollin, Toni I; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J F; Small, Kerrin S; Ried, Janina S; DeFronzo, Ralph A; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R; Gloyn, Anna L; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D; Hattersley, Andrew T; Bowden, Donald W; Collins, Francis S; Atzmon, Gil; Chambers, John C; Spector, Timothy D; Laakso, Markku; Strom, Tim M; Bell, Graeme I; Blangero, John; Duggirala, Ravindranath; Tai, E Shyong; McVean, Gilean; Hanis, Craig L; Wilson, James G; Seielstad, Mark; Frayling, Timothy M; Meigs, James B; Cox, Nancy J; Sladek, Rob; Lander, Eric S; Gabriel, Stacey; Mohlke, Karen L; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J; Morris, Andrew P; Kang, Hyun Min; Altshuler, David; Burtt, Noël P; Florez, Jose C; Boehnke, Michael; McCarthy, Mark I

2017-12-19

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Genotype–phenotype correlations in individuals with pathogenic RERE variants

PubMed Central

Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

2018-01-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

Genotype-phenotype correlations in individuals with pathogenic RERE variants.

PubMed

Jordan, Valerie K; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J; Balci, Tugce B; Carter, Melissa T; Bernat, John A; Moccia, Amanda N; Srivastava, Anshika; Martin, Donna M; Bielas, Stephanie L; Pappas, John; Svoboda, Melissa D; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M; Scaglia, Fernando; Kohler, Jennefer N; Bernstein, Jonathan A; Dries, Annika M; Rosenfeld, Jill A; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H; Bi, Weimin; Scott, Daryl A

2018-05-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. © 2018 Wiley Periodicals, Inc.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

PubMed Central

Jason, Flannick; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M.; Agarwala, Vineeta; Gaulton, Kyle J.; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J.; Rivas, Manuel A.; Perry, John R. B.; Sim, Xueling; Blackwell, Thomas W.; Robertson, Neil R.; Rayner, N William; Cingolani, Pablo; Locke, Adam E.; Tajes, Juan Fernandez; Highland, Heather M.; Dupuis, Josee; Chines, Peter S.; Lindgren, Cecilia M.; Hartl, Christopher; Jackson, Anne U.; Chen, Han; Huyghe, Jeroen R.; van de Bunt, Martijn; Pearson, Richard D.; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M.; Gamazon, Eric R.; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A.; Below, Jennifer E.; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L.; Pasko, Dorota; Parker, Stephen C. J.; Varga, Tibor V.; Green, Todd; Beer, Nicola L.; Day-Williams, Aaron G.; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J.; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P.; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F.; Han, Bok-Ghee; Jenkinson, Christopher P.; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C. Y.; Palmer, Nicholette D.; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E.; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D.; Neale, Benjamin M.; Purcell, Shaun; Butterworth, Adam S.; Howson, Joanna M. M.; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K. L.; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H. T.; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E.; Rybin, Dennis; Farook, Vidya S.; Fowler, Sharon P.; Freedman, Barry I.; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J.; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K.; Puppala, Sobha; Scott, William R.; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A.; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C.; Mangino, Massimo; Bonnycastle, Lori L.; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L.; Herder, Christian; Groves, Christopher J.; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A.; Doney, Alex S. F.; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J.; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E.; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H.; Stirrups, Kathleen; Wood, Andrew R.; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O.; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P.; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B.; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N. A.; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M.; Syvänen, Ann-Christine; Bergman, Richard N.; Bharadwaj, Dwaipayan; Bottinger, Erwin P.; Cho, Yoon Shin; Chandak, Giriraj R.; Chan, Juliana CN; Chia, Kee Seng; Daly, Mark J.; Ebrahim, Shah B.; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A.; Lehman, Donna M.; Jia, Weiping; Ma, Ronald C. W.; Pollin, Toni I.; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J. F.; Small, Kerrin S.; Ried, Janina S.; DeFronzo, Ralph A.; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J.; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W.; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R.; Gloyn, Anna L.; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D.; Hattersley, Andrew T.; Bowden, Donald W.; Collins, Francis S.; Atzmon, Gil; Chambers, John C.; Spector, Timothy D.; Laakso, Markku; Strom, Tim M.; Bell, Graeme I.; Blangero, John; Duggirala, Ravindranath; Tai, E. Shyong; McVean, Gilean; Hanis, Craig L.; Wilson, James G.; Seielstad, Mark; Frayling, Timothy M.; Meigs, James B.; Cox, Nancy J.; Sladek, Rob; Lander, Eric S.; Gabriel, Stacey; Mohlke, Karen L.; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J.; Morris, Andrew P.; Kang, Hyun Min; Altshuler, David; Burtt, Noël P.; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark I.

2017-01-01

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D. PMID:29257133

A (1)H-NMR study on the effect of high pressures on beta-lactoglobulin.

PubMed

Belloque, J; López-Fandiño, R; Smith, G M

2000-09-01

1H NMR was used to study the effect of high pressure on changes in the structure of beta-lactoglobulin (beta-Lg), particularly the strongly bonded regions, the "core". beta-Lg was exposed to pressures ranging from 100 to 400 MPa at neutral pH. After depressurization and acidification to pH 2.0, (1)H NMR spectra were taken. Pressure-induced unfolding was studied by deuterium exchange. Refolding was also evaluated. Our results showed that the core was unaltered at 100 MPa but increased its conformational flexibility at >/=200 MPa. Even though the core was highly flexible at 400 MPa, its structure was found to be identical to the native structure after equilibration back to atmospheric pressure. It is suggested that pressure-induced aggregates are formed by beta-Lg molecules maintaining most of their structure, and the intermolecular -SS- bonds, formed by -SH/-SS- exchange reaction, are likely to involve C(66)-C(160) rather than C(106)-C(119). In addition, the beta-Lg variants A and B could be distinguished in a (1)H NMR spectrum from a solution made with the AB mixed variant, by the differences in chemical shifts of M(107) and C(106); structural implications are discussed. Under pressure, the core of beta-Lg A seemed to unfold faster than that of beta-LgB. The structural recovery of the core was full for both variants.

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

Bowley, S.; Okumura, N; Lord, S

'A:a' knob-hole interactions and D:D interfacial interactions are important for fibrin polymerization. Previous studies with recombinant ?N308K fibrinogen, a substitution at the D:D interface, showed impaired polymerization. We examined the molecular basis for this loss of function by solving the crystal structure of ?N308K fragment D. In contrast to previous fragment D crystals, the ?N308K crystals belonged to a tetragonal space group with an unusually long unit cell (a = b = 95 Angstroms, c = 448.3 Angstroms). Alignment of the normal and ?N308K structures showed the global structure of the variant was not changed and the knob 'A' peptidemore » GPRP was bound as usual to hole 'a'. The substitution introduced an elongated positively charged patch in the D:D region. The structure showed novel, symmetric D:D crystal contacts between ?N308K molecules, indicating the normal asymmetric D:D interface in fibrin would be unstable in this variant. We examined GPRP binding to ?N308K in solution by plasmin protection assay. The results showed weaker peptide binding, suggesting that 'A:a' interactions were altered. We examined fibrin network structures by scanning electron microscopy and found the variant fibers were thicker and more heterogeneous than normal fibers. Considered together, our structural and biochemical studies indicate both 'A:a' and D:D interactions are weaker. We conclude that stable protofibrils cannot assemble from ?N308K monomers, leading to impaired polymerization.« less

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

PubMed Central

Stein, Kevin C.; True, Heather L.

2014-01-01

Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. PMID:24811344

An in-depth understanding of biomass recalcitrance using natural poplar variants as the feedstock

DOE PAGES

Meng, Xianzhi; Pu, Yunqiao; Yoo, Chang Geun; ...

2016-12-12

Here, in an effort to better understand the biomass recalcitrance, six natural poplar variants were selected as feedstocks based on previous sugar release analysis. Compositional analysis and physicochemical characterizations of these poplars were performed and the correlations between these physicochemical properties and enzymatic hydrolysis yield were investigated. Gel permeation chromatography (GPC) and 13C solid state NMR were used to determine the degree of polymerization (DP) and crystallinity index (CrI) of cellulose, and the results along with the sugar release study indicated that cellulose DP likely played a more important role in enzymatic hydrolysis. Simons’ stain revealed that the accessible surface area of substrate significantly varied among these variants from 17.3 to 33.2 mg gmore » $$–1\\atop{biomass}$$ as reflected by dye adsorption, and cellulose accessibility was shown as one of the major factors governing substrates digestibility. HSQC and 31P NMR analysis detailed the structural features of poplar lignin variants. Overall, cellulose relevant factors appeared to have a stronger correlation with glucose release, if any, than lignin structural features. Lignin structural features, such as a phenolic hydroxyl group and the ratio of syringyl and guaiacyl (S/G), were found to have a more convincing impact on xylose release. Low lignin content, low cellulose DP, and high cellulose accessibility generally favor enzymatic hydrolysis; however, recalcitrance cannot be simply judged on any single substrate factor.« less

An in-depth understanding of biomass recalcitrance using natural poplar variants as the feedstock

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

Meng, Xianzhi; Pu, Yunqiao; Yoo, Chang Geun

Here, in an effort to better understand the biomass recalcitrance, six natural poplar variants were selected as feedstocks based on previous sugar release analysis. Compositional analysis and physicochemical characterizations of these poplars were performed and the correlations between these physicochemical properties and enzymatic hydrolysis yield were investigated. Gel permeation chromatography (GPC) and 13C solid state NMR were used to determine the degree of polymerization (DP) and crystallinity index (CrI) of cellulose, and the results along with the sugar release study indicated that cellulose DP likely played a more important role in enzymatic hydrolysis. Simons’ stain revealed that the accessible surface area of substrate significantly varied among these variants from 17.3 to 33.2 mg gmore » $$–1\\atop{biomass}$$ as reflected by dye adsorption, and cellulose accessibility was shown as one of the major factors governing substrates digestibility. HSQC and 31P NMR analysis detailed the structural features of poplar lignin variants. Overall, cellulose relevant factors appeared to have a stronger correlation with glucose release, if any, than lignin structural features. Lignin structural features, such as a phenolic hydroxyl group and the ratio of syringyl and guaiacyl (S/G), were found to have a more convincing impact on xylose release. Low lignin content, low cellulose DP, and high cellulose accessibility generally favor enzymatic hydrolysis; however, recalcitrance cannot be simply judged on any single substrate factor.« less

Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains

PubMed Central

Cronin, Thomas C; DiNitto, Jonathan P; Czech, Michael P; Lambright, David G

2004-01-01

The pleckstrin homology (PH) domains of the homologous proteins Grp1 (general receptor for phosphoinositides), ARNO (Arf nucleotide binding site opener), and Cytohesin-1 bind phosphatidylinositol (PtdIns) 3,4,5-trisphosphate with unusually high selectivity. Remarkably, splice variants that differ only by the insertion of a single glycine residue in the β1/β2 loop exhibit dual specificity for PtdIns(3,4,5)P3 and PtdIns(4,5)P2. The structural basis for this dramatic specificity switch is not apparent from the known modes of phosphoinositide recognition. Here, we report crystal structures for dual specificity variants of the Grp1 and ARNO PH domains in either the unliganded form or in complex with the head groups of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Loss of contacts with the β1/β2 loop with no significant change in head group orientation accounts for the significant decrease in PtdIns(3,4,5)P3 affinity observed for the dual specificity variants. Conversely, a small increase rather than decrease in affinity for PtdIns(4,5)P2 is explained by a novel binding mode, in which the glycine insertion alleviates unfavorable interactions with the β1/β2 loop. These observations are supported by a systematic mutational analysis of the determinants of phosphoinositide recognition. PMID:15359279

Biochemical Properties and Atomic Resolution Structure of a Proteolytically Processed β-Mannanase from Cellulolytic Streptomyces sp. SirexAA-E

PubMed Central

Takasuka, Taichi E.; Acheson, Justin F.; Bianchetti, Christopher M.; Prom, Ben M.; Bergeman, Lai F.; Book, Adam J.; Currie, Cameron R.; Fox, Brian G.

2014-01-01

β-mannanase SACTE_2347 from cellulolytic Streptomyces sp. SirexAA-E is abundantly secreted into the culture medium during growth on cellulosic materials. The enzyme is composed of domains from the glycoside hydrolase family 5 (GH5), fibronectin type-III (Fn3), and carbohydrate binding module family 2 (CBM2). After secretion, the enzyme is proteolyzed into three different, catalytically active variants with masses of 53, 42 and 34 kDa corresponding to the intact protein, loss of the CBM2 domain, or loss of both the Fn3 and CBM2 domains. The three variants had identical N-termini starting with Ala51, and the positions of specific proteolytic reactions in the linker sequences separating the three domains were identified. To conduct biochemical and structural characterizations, the natural proteolytic variants were reproduced by cloning and heterologously expressed in Escherichia coli. Each SACTE_2347 variant hydrolyzed only β-1,4 mannosidic linkages, and also reacted with pure mannans containing partial galactosyl- and/or glucosyl substitutions. Examination of the X-ray crystal structure of the GH5 domain of SACTE_2347 suggests that two loops adjacent to the active site channel, which have differences in position and length relative to other closely related mannanases, play a role in producing the observed substrate selectivity. PMID:24710170