Comparison of Simultaneous Prompting and Constant Time Delay Procedures in Teaching Children with Autism the Responses to Questions about Personal Information

ERIC Educational Resources Information Center

Akmanoglu, Nurgul; Kurt, Onur; Kapan, Alper

2015-01-01

The aim of the current study was to compare simultaneous prompting (SP) and constant time delay (CTD) in terms of their effectiveness and efficiency in teaching children with autism how to respond to questions about personal information. The adapted alternating treatments model was used in the study. Three male students with autism aged 4, 6, and…

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

PubMed

Thurm, Audrey; Himelstein, Daniel; DʼSouza, Precilla; Rennert, Owen; Jiang, Susanqi; Olatunji, Damilola; Longo, Nicola; Pasquali, Marzia; Swedo, Susan; Salomons, Gajja S; Carrillo, Nuria

2016-05-01

Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders. Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability. We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD. Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

Acquisition of Content Area Vocabulary for Students with Learning Disabilities.

ERIC Educational Resources Information Center

Keel, Marie C.; Slaton, Deborah Bott; Blackhurt, A. Edward

2001-01-01

This study compared effects of two variations of the constant-time-delay (CTD) procedure on the observational learning of content area vocabulary by seven primary grade students with learning disabilities in a small group instructional setting. Both conditions (every student writes all words or only target student writes) were equally effective…

Impact of Smart Board Technology: An Investigation of Sight Word Reading and Observational Learning

ERIC Educational Resources Information Center

Mechling, Linda C.; Gast, David L.; Krupa, Kristin

2007-01-01

The effects of SMART Board technology, an interactive electronic whiteboard, and a 3s constant time delay (CTD) procedure was evaluated for teaching sight word reading to students with moderate intellectual disabilties within a small group arrangment. A multiple probe design across three word sets and replicated with three students was used to…

Differential Effects of Two Spelling Procedures on Acquisition, Maintenance and Adaption to Reading

ERIC Educational Resources Information Center

Cates, Gary L.; Dunne, Megan; Erkfritz, Karyn N.; Kivisto, Aaron; Lee, Nicole; Wierzbicki, Jennifer

2007-01-01

An alternating treatments design was used to assess the effects of a constant time delay (CTD) procedure and a cover-copy-compare (CCC) procedure on three students' acquisition, subsequent maintenance, and adaptation (i.e., application) of acquired spelling words to reading passages. Students were randomly presented two trials of word lists from…

Using SMART Board Technology to Teach Young Students with Disabilities and Limited Group Learning Experience to Read Environmental Text

ERIC Educational Resources Information Center

Shepley, Collin; Lane, Justin D.; Gast, David L.

2016-01-01

A multiple probe design across behaviors was used to evaluate the effectiveness of a SMART Board used in conjunction with teacher delivered constant time delay (CTD) to teach environmental text to three young students with disabilities and minimal group learning experience during small group direct instruction. Observational learning, instructive…

Differential Effects of Three Computer-Assisted Instruction Programs on the Development of Math Skills among Primary Grade Students

ERIC Educational Resources Information Center

Erkfritz-Gay, Karyn N.

2009-01-01

Past research has documented that the effectiveness of three different math strategies delivered to students via one-on-one instruction (i.e., cover-copy-compare (CCC); e.g., Skinner, Turco, Beatty, & Rasavage, 1989, traditional drill and practice (TDP); e.g., Cybriwsky & Schuster, 1990, and constant time delay (CTD); Kulik, 1994). This study…

Crystal structure of an HIV assembly and maturation switch

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

Wagner, Jonathan M.; Zadrozny, Kaneil K.; Chrustowicz, Jakub

Virus assembly and maturation proceed through the programmed operation of molecular switches, which trigger both local and global structural rearrangements to produce infectious particles. HIV-1 contains an assembly and maturation switch that spans the C-terminal domain (CTD) of the capsid (CA) region and the first spacer peptide (SP1) of the precursor structural protein, Gag. The crystal structure of the CTD-SP1 Gag fragment is a goblet-shaped hexamer in which the cup comprises the CTD and an ensuing type II β-turn, and the stem comprises a 6-helix bundle. The β-turn is critical for immature virus assembly and the 6-helix bundle regulates proteolysismore » during maturation. This bipartite character explains why the SP1 spacer is a critical element of HIV-1 Gag but is not a universal property of retroviruses. Our results also indicate that HIV-1 maturation inhibitors suppress unfolding of the CA-SP1 junction and thereby delay access of the viral protease to its substrate.« less

Assessing XCTD Fall Rate Errors using Concurrent XCTD and CTD Profiles in the Southern Ocean

NASA Astrophysics Data System (ADS)

Millar, J.; Gille, S. T.; Sprintall, J.; Frants, M.

2010-12-01

Refinements in the fall rate equation for XCTDs are not as well understood as those for XBTs, due in part to the paucity of concurrent and collocated XCTD and CTD profiles. During February and March 2010, the Diapycnal and Isopycnal Mixing Experiment in the Southern Ocean (DIMES) conducted 31 collocated 1000-meter XCTD and CTD casts in the Drake Passage. These XCTD/CTD profile pairs are closely matched in space and time, with a mean distance between casts of 1.19 km and a mean lag time of 39 minutes. The profile pairs are well suited to address the XCTD fall rate problem specifically in higher latitude waters, where existing fall rate corrections have rarely been assessed. Many of these XCTD/CTD profile pairs reveal an observable depth offset in measurements of both temperature and conductivity. Here, the nature and extent of this depth offset is evaluated.

Performances of a date dissemination code on telephone lines using commercial modems

NASA Technical Reports Server (NTRS)

Cordara, F.; Pettiti, V.; Quasso, R.; Rubiola, E.

1993-01-01

A coded time/date information dissemination system (CTD), based on telephone lines and commercial modems, is now in its experimental phase in Italy at IEN. This service, born from a cooperation with other metrological laboratories (TUG, Austria, SNT, Sweden, VSL, The Netherlands), represents an attempt towards an European standardization. Some results of an experimental analysis in which a few modems were tested, both in laboratory conditions and connected to the telephone network, in order to evaluate the timing capability of the system are given. When the system is used in a one-way mode, in many practical cases the modems delay turns out to be the main factor which limits the accuracy, even more than the telephone line delays. If the two-way mode is used, the modems asymmetry, i.e., the delay difference between transmission and reception, is almost always the most important source of uncertainty, provided the link is not including a space segment. Comparing the widely used V.22 modems to the old V.21 ones, the latters turn out to be better both in delay time (30-100 ms V.22, and 7-15 ms V.21) and asymmetry (10-50 micro-s V.22, and 10 ms V.22). Time transfer accuracies of 10 micron-s (same turn) to 100 micro-s (long distance calls) were obtained in two-way mode with commercial V.21 modems.

The RNA polymerase II CTD coordinates transcription and RNA processing

PubMed Central

Hsin, Jing-Ping; Manley, James L.

2012-01-01

The C-terminal domain (CTD) of the RNA polymerase II largest subunit consists of multiple heptad repeats (consensus Tyr1–Ser2–Pro3–Thr4–Ser5–Pro6–Ser7), varying in number from 26 in yeast to 52 in vertebrates. The CTD functions to help couple transcription and processing of the nascent RNA and also plays roles in transcription elongation and termination. The CTD is subject to extensive post-translational modification, most notably phosphorylation, during the transcription cycle, which modulates its activities in the above processes. Therefore, understanding the nature of CTD modifications, including how they function and how they are regulated, is essential to understanding the mechanisms that control gene expression. While the significance of phosphorylation of Ser2 and Ser5 residues has been studied and appreciated for some time, several additional modifications have more recently been added to the CTD repertoire, and insight into their function has begun to emerge. Here, we review findings regarding modification and function of the CTD, highlighting the important role this unique domain plays in coordinating gene activity. PMID:23028141

Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study.

PubMed

Oguz, Ekin Oktay; Kucuksahin, Orhan; Turgay, Murat; Yildizgoren, Mustafa Turgut; Ates, Askin; Demir, Nalan; Kumbasar, Ozlem Ozdemir; Kinikli, Gulay; Duzgun, Nursen

2016-03-01

It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL-6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict progressive ILD.

Bedside talc pleurodesis for malignant pleural effusion: factors affecting success.

PubMed

Aydogmus, Umit; Ozdemir, Servet; Cansever, Levent; Sonmezoglu, Yasar; Kocaturk, Celalettin Ibrahim; Bedirhan, Mehmet Ali

2009-03-01

To determine the factors affecting the success of bedside talc slurry (TS) used for symptomatic treatment of patients with malignant pleural effusion (MPE). Data of 113 effusions in 103 MPE patients treated between 1999 and 2007 were retrospectively evaluated for the study. The study group involved 73 patients whose follow-up information was available out of 81 patients treated by TS. Causes of MPE were lung cancer in 22 patients (30.1%) and breast carcinoma in 21 patients (28.8%). The success rate of TS was significantly higher if the time period between radiological diagnosis of effusion and administration of TS was less than 30 days (P= .02), or spontaneous expansion was attained after chest tube drainage (CTD) (P= .01). Success rate was higher for patients with daily drainage of less than 200 ml before TS than patients with more than 200 ml of daily drainage (P= .01). Dose of talc, either 4 g or above (P= .34), primary cause of MPE (P= .53), time to termination of CTD (P= .57), amount of drainage when CTD was terminated (P= .23), and time period between CTD and administration of TS (P= .20) did not show a statistically significant effect on the success of TS. In the treatment of malignant pleural effusion, patients with daily drainage of less than 200 ml before TS developed less recurrence than patients with daily drainage of more than 200 ml. Longer time period between the diagnosis of MPE and onset of CTD increased recurrence.

Predictive value of nailfold capillaroscopy in patients with Raynaud's phenomenon.

PubMed

Meli, Madeleine; Gitzelmann, Gabriela; Koppensteiner, Renate; Amann-Vesti, Beatrice R

2006-03-01

The objective of this study was to evaluate the long-term follow-up of patients with Raynaud's phenomenon (RP) and pathological nailfold capillaroscopy (NC) in order to analyse the predictive value of specific features of capillaroscopy for the development of a connective tissue disease (CTD). From 1992 to 2002, NC alone or combined with fluorescence videomicroscopy with sodium fluorescein (NaF) was performed in 1024 consecutive patients because of RP. We analysed the follow-up and pathological features of NC in all patients who had neither clinical nor serological signs of a CTD at the time of NC. Of 308 patients with neither serological findings nor clinical signs of CTD but with RP and pathological features in NC suspicious for CTD, follow-up data were available for 133 patients. An additional NaF test had been performed in 51 (38.4%) patients. After a mean follow-up of 6.5 years (range: 1-15 years), 109 patients had developed a CTD and 24 patients did not show any clinical signs or serological markers for a CTD after a mean follow-up of 8.5 years (range: 2-15 years). There were no differences in age, duration of RP or of follow-up in patients who developed a CTD compared to patients who did not. Significantly more giant capillaries (p=0.0001), avascular fields (p=0.02) and irregular architecture (p=0.0001) had been observed in patients who had developed a CTD during the follow-up of 6.5 years. The presence of giant capillaries, avascular fields and irregular architecture of nailfold capillaries is predictive for the development of a CTD in patients with RP.

The key DNA-binding residues in the C-terminal domain of Mycobacterium tuberculosis DNA gyrase A subunit (GyrA)

PubMed Central

Huang, You-Yi; Deng, Jiao-Yu; Gu, Jing; Zhang, Zhi-Ping; Maxwell, Anthony; Bi, Li-Jun; Chen, Yuan-Yuan; Zhou, Ya-Feng; Yu, Zi-Niu; Zhang, Xian-En

2006-01-01

As only the type II topoisomerase is capable of introducing negative supercoiling, DNA gyrase is involved in crucial cellular processes. Although the other domains of DNA gyrase are better understood, the mechanism of DNA binding by the C-terminal domain of the DNA gyrase A subunit (GyrA-CTD) is less clear. Here, we investigated the DNA-binding sites in the GyrA-CTD of Mycobacterium tuberculosis gyrase through site-directed mutagenesis. The results show that Y577, R691 and R745 are among the key DNA-binding residues in M.tuberculosis GyrA-CTD, and that the third blade of the GyrA-CTD is the main DNA-binding region in M.tuberculosis DNA gyrase. The substitutions of Y577A, D669A, R691A, R745A and G729W led to the loss of supercoiling and relaxation activities, although they had a little effect on the drug-dependent DNA cleavage and decatenation activities, and had no effect on the ATPase activity. Taken together, these results showed that the GyrA-CTD is essential to DNA gyrase of M.tuberculosis, and promote the idea that the M.tuberculosis GyrA-CTD is a new potential target for drug design. It is the first time that the DNA-binding sites in GyrA-CTD have been identified. PMID:17038336

Satellite Analysis of Ocean Biogeochemistry and Mesoscale Variability in the Sargasso Sea

NASA Technical Reports Server (NTRS)

Siegel, D. A.; Micheals, A. F.; Nelson, N. B.

1997-01-01

The objective of this study was to analyze the impact of spatial variability on the time-series of biogeochemical measurements made at the U.S. JGOFS Bermuda Atlantic Time-series Study (BATS) site. Originally the study was planned to use SeaWiFS as well as AVHRR high-resolution data. Despite the SeaWiFS delays we were able to make progress on the following fronts: (1) Operational acquisition, processing, and archive of HRPT data from a ground station located in Bermuda; (2) Validation of AVHRR SST data using BATS time-series and spatial validation cruise CTD data; (3) Use of AVHRR sea surface temperature imagery and ancillary data to assess the impact of mesoscale spatial variability on P(CO2) and carbon flux in the Sargasso Sea; (4) Spatial and temporal extent of tropical cyclone induced surface modifications; and (5) Assessment of eddy variability using TOPEX/Poseidon data.

Improved statistical method for temperature and salinity quality control

NASA Astrophysics Data System (ADS)

Gourrion, Jérôme; Szekely, Tanguy

2017-04-01

Climate research and Ocean monitoring benefit from the continuous development of global in-situ hydrographic networks in the last decades. Apart from the increasing volume of observations available on a large range of temporal and spatial scales, a critical aspect concerns the ability to constantly improve the quality of the datasets. In the context of the Coriolis Dataset for ReAnalysis (CORA) version 4.2, a new quality control method based on a local comparison to historical extreme values ever observed is developed, implemented and validated. Temperature, salinity and potential density validity intervals are directly estimated from minimum and maximum values from an historical reference dataset, rather than from traditional mean and standard deviation estimates. Such an approach avoids strong statistical assumptions on the data distributions such as unimodality, absence of skewness and spatially homogeneous kurtosis. As a new feature, it also allows addressing simultaneously the two main objectives of an automatic quality control strategy, i.e. maximizing the number of good detections while minimizing the number of false alarms. The reference dataset is presently built from the fusion of 1) all ARGO profiles up to late 2015, 2) 3 historical CTD datasets and 3) the Sea Mammals CTD profiles from the MEOP database. All datasets are extensively and manually quality controlled. In this communication, the latest method validation results are also presented. The method has already been implemented in the latest version of the delayed-time CMEMS in-situ dataset and will be deployed soon in the equivalent near-real time products.

Rsp5 WW domains interact directly with the carboxyl-terminal domain of RNA polymerase II.

PubMed

Chang, A; Cheang, S; Espanel, X; Sudol, M

2000-07-07

RSP5 is an essential gene in Saccharomyces cerevisiae and was recently shown to form a physical and functional complex with RNA polymerase II (RNA pol II). The amino-terminal half of Rsp5 consists of four domains: a C2 domain, which binds membrane phospholipids; and three WW domains, which are protein interaction modules that bind proline-rich ligands. The carboxyl-terminal half of Rsp5 contains a HECT (homologous to E6-AP carboxyl terminus) domain that catalytically ligates ubiquitin to proteins and functionally classifies Rsp5 as an E3 ubiquitin-protein ligase. The C2 and WW domains are presumed to act as membrane localization and substrate recognition modules, respectively. We report that the second (and possibly third) Rsp5 WW domain mediates binding to the carboxyl-terminal domain (CTD) of the RNA pol II large subunit. The CTD comprises a heptamer (YSPTSPS) repeated 26 times and a PXY core that is critical for interaction with a specific group of WW domains. An analysis of synthetic peptides revealed a minimal CTD sequence that is sufficient to bind to the second Rsp5 WW domain (Rsp5 WW2) in vitro and in yeast two-hybrid assays. Furthermore, we found that specific "imperfect" CTD repeats can form a complex with Rsp5 WW2. In addition, we have shown that phosphorylation of this minimal CTD sequence on serine, threonine and tyrosine residues acts as a negative regulator of the Rsp5 WW2-CTD interaction. In view of the recent data pertaining to phosphorylation-driven interactions between the RNA pol II CTD and the WW domain of Ess1/Pin1, we suggest that CTD dephosphorylation may be a prerequisite for targeted RNA pol II degradation.

Addison's disease secondary to connective tissue diseases: a report of six cases.

PubMed

Zhang, Zhuo-li; Wang, Yu; Zhou, Wei; Hao, Yan-jie

2009-04-01

Addison's disease is an autoimmune process. However, Addison's disease associated with connective tissue diseases (CTD) is only occasionally reported. Here, we report six cases of Addison's disease secondary to a variety of CTD, which include systemic lupus erythematosus, Takayasu arteritis, systemic sclerosis, ankylosing spondylitis (AS) and antiphospholipid antibody syndrome. The association of Addison's disease with Takayasu arteritis and AS is reported for the first time. We also found high prevalence of hypothyroidism as concomitant autoimmune disorder. Our case series highlight the autoimmune features of Addison's disease. Therefore, we suggest considering adrenal dysfunction in patients with CTD.

An analysis of the clinical features of lung cancer in patients with connective tissue diseases.

PubMed

Saijo, Atsuro; Hanibuchi, Masaki; Goto, Hisatsugu; Toyoda, Yuko; Tezuka, Toshifumi; Nishioka, Yasuhiko

2017-03-01

Patients with connective tissue diseases (CTDs) are at increased risk for lung cancer (LC); interstitial lung disease (ILD) is a common form of organ dysfunction in cases of CTD. However, the influence of ILD on the treatment and prognosis in LC patients with CTD is unclear. Between January 2010 and December 2014, 27 patients among all patients with CTD at our institution were diagnosed with primary LC. We retrospectively analyzed the clinical features, treatment modalities, and outcomes of these patients, and evaluated the potential prognostic factors. Forty-four LC patients without CTD were also analyzed as a control cohort. LC patients with CTD had a significantly higher incidence of ILD as a complication compared with those without CTD (52% and 14%, respectively). CTD-associated ILD (CTD-ILD) at diagnosis was associated with significantly worse survival in LC patients with CTD. Multivariate analysis demonstrated that the complication of CTD-ILD was an independent poor prognostic factor in LC patients with CTD. The incidence of acute exacerbation (AE) of CTD-ILD was 21% among LC patients with CTD, and all of these patients died despite intensive treatment including high-dose corticosteroids. The restrictions in curative therapy for LC due to the presence of ILD and AE of CTD-ILD were thought to be the major reasons for the poor outcome. LC patients with CTD had a high prevalence of ILD, and the presence of CTD-ILD was significantly associated with poor prognosis. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Pulmonary Function and Survival in Idiopathic vs Secondary Usual Interstitial Pneumonia

PubMed Central

Strand, Matthew J.; Sprunger, David; Cosgrove, Gregory P.; Fernandez-Perez, Evans R.; Frankel, Stephen K.; Huie, Tristan J.; Olson, Amy L.; Solomon, Joshua; Brown, Kevin K.

2014-01-01

BACKGROUND: The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. METHODS: We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups. RESULTS: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses. CONCLUSIONS: Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF—an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF. PMID:24700149

Measurement of antinuclear antibodies and their fine specificities: time for a change in strategy?

PubMed

Otten, Henny G; Brummelhuis, Walter J; Fritsch-Stork, Ruth; Leavis, Helen L; Wisse, Bram W; van Laar, Jacob M; Derksen, Ronald H W M

2017-01-01

The current strategy for antinuclear antibody (ANA) analysis involves screening for presence with a subsequent detailed analysis of their specificity. The aim of this study is to compare the clinical and financial efficacy of this strategy between different commercial tests in a large cohort of unselected patients. In all consecutive 1030 patients associations were defined between results from different ANA test systems and the pre-test probability for connective tissue disease (CTDs). Test systems were used for screening (ANA-IIF vs. CTD screen) and definition of their fine specificity (profile 3 line blot vs. CTD single analytes). Positive ANA-IIF and/or CTD screen results were found in 304 sera. Further analysis for ANA-specificity by profile 3 line blot and CTD single analytes showed 86 discrepant results of which more than a third are clinically relevant, with the CTD single analyte assay performing better than the line blot in supporting or confirming the presence of a CTD. Autoantigens present in one test but absent in the other were of minor practical use. The ANA screening and identification strategies currently employed are not cost-effective as 83% of tests were performed in order to find specific autoantibodies in patients without the fitting clinical signs or symptoms. This causes many unexpected positive results and subsequent confusion with regard to interpretation. We advocate that some autoantigens should be excluded from the line blot and CTD assays and propose the use of a cost-effective and selective ANA specificity testing purely based on clinical guidance.

Fission yeast RNA triphosphatase reads an Spt5 CTD code

DOE PAGES

Doamekpor, Selom K.; Schwer, Beate; Sanchez, Ana M.; ...

2014-11-20

mRNA capping enzymes are directed to nascent RNA polymerase II (Pol2) transcripts via interactions with the carboxy-terminal domains (CTDs) of Pol2 and transcription elongation factor Spt5. Fission yeast RNA triphosphatase binds to the Spt5 CTD, comprising a tandem repeat of nonapeptide motif TPAWNSGSK. Here we report the crystal structure of a Pct1·Spt5-CTD complex, which revealed two CTD docking sites on the Pct1 homodimer that engage TPAWN segments of the motif. Each Spt5 CTD interface, composed of elements from both subunits of the homodimer, is dominated by van der Waals contacts from Pct1 to the tryptophan of the CTD. The boundmore » CTD adopts a distinctive conformation in which the peptide backbone makes a tight U-turn so that the proline stacks over the tryptophan. We show that Pct1 binding to Spt5 CTD is antagonized by threonine phosphorylation. Our results fortify an emerging concept of an “Spt5 CTD code” in which (i) the Spt5 CTD is structurally plastic and can adopt different conformations that are templated by particular cellular Spt5 CTD receptor proteins; and (ii) threonine phosphorylation of the Spt5 CTD repeat inscribes a binary on–off switch that is read by diverse CTD receptors, each in its own distinctive manner.« less

Fission yeast RNA triphosphatase reads an Spt5 CTD code

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

Doamekpor, Selom K.; Schwer, Beate; Sanchez, Ana M.

mRNA capping enzymes are directed to nascent RNA polymerase II (Pol2) transcripts via interactions with the carboxy-terminal domains (CTDs) of Pol2 and transcription elongation factor Spt5. Fission yeast RNA triphosphatase binds to the Spt5 CTD, comprising a tandem repeat of nonapeptide motif TPAWNSGSK. Here we report the crystal structure of a Pct1·Spt5-CTD complex, which revealed two CTD docking sites on the Pct1 homodimer that engage TPAWN segments of the motif. Each Spt5 CTD interface, composed of elements from both subunits of the homodimer, is dominated by van der Waals contacts from Pct1 to the tryptophan of the CTD. The boundmore » CTD adopts a distinctive conformation in which the peptide backbone makes a tight U-turn so that the proline stacks over the tryptophan. We show that Pct1 binding to Spt5 CTD is antagonized by threonine phosphorylation. Our results fortify an emerging concept of an “Spt5 CTD code” in which (i) the Spt5 CTD is structurally plastic and can adopt different conformations that are templated by particular cellular Spt5 CTD receptor proteins; and (ii) threonine phosphorylation of the Spt5 CTD repeat inscribes a binary on–off switch that is read by diverse CTD receptors, each in its own distinctive manner.« less

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

PubMed Central

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-01-01

Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results. PMID:28039187

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

PubMed

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-07-01

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. NCT01178073, post results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Tadalafil in idiopathic or heritable pulmonary arterial hypertension (PAH) compared to PAH associated with connective tissue disease.

PubMed

Galiè, Nazzareno; Denton, Christopher P; Dardi, Fabio; Manes, Alessandra; Mazzanti, Gaia; Li, Baohui; Varanese, Lucio; Esler, Anne; Harmon, Cathi; Palazzini, Massimiliano

2017-05-15

The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40mg in PHIRST-2. Patients taking 20mg in PHIRST without demonstrating clinical worsening continued on 20mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH. The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH. Copyright © 2017. Published by Elsevier B.V.

A Superhelical Spiral in the Escherichia coli DNA Gyrase A C-terminal Domain Imparts Unidirectional Supercoiling Bias

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

Ruthenburg,A.; Graybosch, D.; Huetsch, J.

DNA gyrase is unique among type II topoisomerases in that its DNA supercoiling activity is unidirectional. The C-terminal domain of the gyrase A subunit (GyrA-CTD) is required for this supercoiling bias. We report here the x-ray structure of the Escherichia coli GyrA-CTD (Protein Data Bank code 1ZI0). The E. coli GyrA-CTD adopts a circular-shaped {beta}-pinwheel fold first seen in the Borrelia burgdorferi GyrA-CTD. However, whereas the B. burgdorferi GyrA-CTD is flat, the E. coli GyrA-CTD is spiral. DNA relaxation assays reveal that the E. coli GyrA-CTD wraps DNA inducing substantial (+) superhelicity, while the B. burgdorferi GyrA-CTD introduces a moremore » modest (+) superhelicity. The observation of a superhelical spiral in the present structure and that of the Bacillus stearothermophilus ParC-CTD structure suggests unexpected similarities in substrate selectivity between gyrase and Topo IV enzymes. We propose a model wherein the right-handed ((+) solenoidal) wrapping of DNA around the E. coli GyrA-CTD enforces unidirectional (-) DNA supercoiling.« less

Structural dynamics of native and V260E mutant C-terminal domain of HIV-1 integrase

NASA Astrophysics Data System (ADS)

Sangeetha, Balasubramanian; Muthukumaran, Rajagopalan; Amutha, Ramaswamy

2015-04-01

The C-terminal domain (CTD) of HIV-1 integrase is a five stranded β-barrel resembling an SH3 fold. Mutational studies on isolated CTD and full-length IN have reported V260E mutant as either homo-dimerization defective or affecting the stability and folding of CTD. In this study, molecular dynamics simulation techniques were used to unveil the effect of V260E mutation on isolated CTD monomer and dimer. Both monomeric and dimeric forms of wild type and V260E mutant are highly stable during the simulated period. However, the stabilizing π-stacking interaction between Trp243 and Trp243' at the dimer interface is highly disturbed in CTD-V260E (>6 Å apart). The loss in entropy for dimerization is -30 and -25 kcal/mol for CTD-wt and CTD-V260E respectively signifying a weak hydrophobic interaction and its perturbation in CTD-V260E. The mutant Glu260 exhibits strong attraction/repulsion with all the basic/acidic residues of CTD. In addition to this, the dynamics of CTD-wild type and V260E monomers at 498 K was analyzed to elucidate the effect of V260E mutation on CTD folding. Increase in SASA and reduction in the number of contacts in CTD-V260E during simulation highlights the instability caused by the mutation. In general, V260E mutation affects both multimerization and protein folding with a pronounced effect on protein folding rather than multimerization. This study emphasizes the importance of the hydrophobic nature and SH3 fold of CTD in proper functioning of HIV integrase and perturbing this nature would be a rational approach toward designing more selective and potent allosteric anti-HIV inhibitors.

Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group.

PubMed

Khanna, Dinesh; Mittoo, Shikha; Aggarwal, Rohit; Proudman, Susanna M; Dalbeth, Nicola; Matteson, Eric L; Brown, Kevin; Flaherty, Kevin; Wells, Athol U; Seibold, James R; Strand, Vibeke

2015-11-01

Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research. The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants. OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO. There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

Significance of myositis autoantibody in patients with idiopathic interstitial lung disease.

PubMed

Song, Ju Sun; Hwang, Jiwon; Cha, Hoon-Suk; Jeong, Byeong-Ho; Suh, Gee Young; Chung, Man Pyo; Kang, Eun-Suk

2015-05-01

Some patients with interstitial lung disease (ILD) related to connective tissue disease (CTD) have a delayed diagnosis of the underlying CTD when the ILD is categorized as idiopathic. In this study, we evaluated the frequency of myositis autoantibodies in patients diagnosed with idiopathic ILD and investigated the clinical significance stemming from the presence of the antibodies. A total 32 patients diagnosed with idiopathic ILD were enrolled in this study. We analyzed a panel of 11 myositis autoantibody specificities in the patients using a line blot immunoassay. Then, we divided them into myositis autoantibody-positive and -negative groups and compared the clinical features and laboratory data between the two groups. Of the 32 idiopathic ILD patients, 12 patients had myositis autoantibodies encompassing 9 specificities, except for anti-Mi-2 and anti-PM-Scl 100 (12/32, 38%). Anti-synthetase autoantibodies including Jo-1, EJ, OJ, PL-7, and PL-12 were present in 7 patients (7/32, 22%). The group with myositis autoantibodies presented more frequently with the symptom of mechanic's hand and showed abnormal pulmonary function test results with low forced vital capacity, diffusing capacity for carbon monoxide, total lung capacity, and high lactate dehydrogenase values in blood when compared with the group without myositis antibodies. We strongly suggest that patients undergo an evaluation of myositis autoantibodies, if they are diagnosed with idiopathic ILD in the presence of clinical characteristics including mechanic's hand, arthralgia, and autoantibodies which are insufficient to make a diagnosis of a specific CTD category.

Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain

PubMed Central

Villeneuve, Louis; Demers, Annie; Mayer, Gaétan

2016-01-01

PCSK9 is a secreted ligand and negative post-translational regulator of low-density lipoprotein receptor (LDLR) in hepatocytes. Gain-of-function (GOF) or loss-of-function (LOF) mutations in PCSK9 are directly correlated with high or low plasma LDL-cholesterol levels, respectively. Therefore, PCSK9 is a prevailing lipid-lowering target to prevent coronary heart diseases and stroke. Herein, we fused monomeric fluorescent proteins to PCSK9 and LDLR to visualize their intra- and extracellular trafficking dynamics by live confocal microscopy. Fluorescence recovery after photobleaching (FRAP) showed that PCSK9 LOF R46L mutant and GOF mutations S127R and D129G, but not the LDLR high-affinity mutant D374Y, significantly accelerate PCSK9 exit from the endoplasmic reticulum (ER). Quantitative analysis of inverse FRAP revealed that only R46L presented a much slower trafficking from the trans-Golgi network (TGN) to the plasma membrane and a lower mobile fraction likely suggesting accumulation or delayed exit at the TGN as an underlying mechanism. While not primarily involved in LDLR binding, PCSK9 C-terminal domain (CTD) was found to be essential to induce LDLR degradation both upon its overexpression in cells or via the extracellular pathway. Our data revealed that PCSK9 CTD is required for the localization of PCSK9 at the TGN and increases its LDLR-mediated endocytosis. Interestingly, intracellular lysosomal targeting of PCSK9-ΔCTD was able to rescue its capacity to induce LDLR degradation emphasizing a role of the CTD in the sorting of PCSK9-LDLR complex towards late endocytic compartments. Finally, we validated our dual fluorescence system as a cell based-assay by preventing PCSK9 internalization using a PCSK9-LDLR blocking antibody, which may be expended to identify protein, peptide or small molecule inhibitors of PCSK9. PMID:27280970

Pulmonary MR imaging with ultra-short TEs: utility for disease severity assessment of connective tissue disease patients.

PubMed

Ohno, Yoshiharu; Nishio, Mizuho; Koyama, Hisanobu; Takenaka, Daisuke; Takahashi, Masaya; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Obara, Makoto; van Cauteren, Marc; Sugimura, Kazuro

2013-08-01

To evaluate the utility of pulmonary magnetic resonance (MR) imaging with ultra-short echo times (UTEs) at a 3.0 T MR system for pulmonary functional loss and disease severity assessments of connective tissue disease (CTD) patients with interstitial lung disease (ILD). This prospective study was approved by the institutional review board, and written informed consent was obtained from 18 CTD patients (eight men and ten women) and eight normal subjects with suspected chest disease (three men and five women). All subjects underwent thin-section MDCT, pulmonary MR imaging with UTEs, pulmonary function test and serum KL-6. Regional T2 maps were generated from each MR data set, and mean T2 values were determined from ROI measurements. From each thin-section MDCT data set, CT-based disease severity was evaluated with a visual scoring system. Mean T2 values for normal and CTD subjects were statistically compared by using Student's t-test. To assess capability for pulmonary functional loss and disease severity assessments, mean T2 values were statistically correlated with pulmonary functional parameters, serum KL-6 and CT-based disease severity. Mean T2 values for normal and CTD subjects were significantly different (p=0.0019) and showed significant correlations with %VC, %DLCO, serum KL-6 and CT-based disease severity of CTD patients (p<0.05). Pulmonary MR imaging with UTEs is useful for pulmonary functional loss and disease severity assessments of CTD patients with ILD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo.

PubMed

Li, Chi-Chuan; Yu, Fu-Shun; Fan, Ming-Jen; Chen, Ya-Yin; Lien, Jin-Cherng; Chou, Yu-Cheng; Lu, Hsu-Feng; Tang, Nou-Ying; Peng, Shu-Fen; Huang, Wen-Wen; Chung, Jing-Gung

2017-03-01

Cantharidin (CTD), a potential anticancer agent of Traditional Chinese Medicine has cytotxic effects in different human cancer cell lines. The cytotoxic effects of CTD on A431 human skin cancer (epidermoid carcinoma) cells in vitro and in A431 cell xenograft mouse model were examined. In vitro, A431 human skin cell were treated with CTD for 24 and 48 h. Cell phase distribution, ROS production, Ca 2+ release, Caspase activity and the level of apoptosis associated proteins were measured. In vivo, A431 cell xenograft mouse model were examined. CTD-induced cell morphological changes and decreased percentage of viable A431 cells via G0/G1 phase arrest and induced apoptosis. CTD-induced G0/G1 phase arrest through the reduction of protein levels of cyclin E, CDK6, and cyclin D in A431 cells. CTD-induced cell apoptosis of A431 cells also was confirm by DNA gel electrophoresis showed CTD-induced DNA fragmentation. CTD reduced the mitochondrial membrane potential and stimulated release of cytochrome c, AIF and Endo G in A431 cells. Flow cytometry demonstrated that CTD increased activity of caspase-8, -9 and -3. However, when cells were pretreated with specific caspase inhibitors activity was reduced and cell viability increased. CTD increased protein levels of death receptors such as DR4, DR5, TRAIL and levels of the active form of caspase-8, -9 and -3 in A431 cells. AIF and Endo G proteins levels were also enhanced by CTD. In vivo studies showed that CTD significantly inhibited A431 cell xenograft tumors in mice. Taken together, these in vitro and in vivo results provide insight into the mechanisms of CTD on cell growth and tumor production. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 723-738, 2017. © 2016 Wiley Periodicals, Inc.

Developing a low-cost open-source CTD for research and outreach

NASA Astrophysics Data System (ADS)

Thaler, A. D.; Sturdivant, K.

2013-12-01

Developing a low-cost open-source CTD for research and outreach Andrew David Thaler and Kersey Sturdivant Conductivity, temperature, and depth (CTD). With these three measurements, marine scientists can unlock ocean patterns hidden beneath the waves. The ocean is not uniform, it its filled with swirling eddies, temperature boundaries, layers of high and low salinity, changing densities, and many other physical characteristics. To reveal these patterns, oceanographers use a tool called the CTD. A CTD is found on almost every major research vessel. Rare is the scientific expedition-whether it be coastal work in shallow estuaries or journeys to the deepest ocean trenches-that doesn't begin with the humble CTD cast. The CTD is not cheap. Commercial CTD's start at more the 5,000 and can climb as high as 25,000 or more. We believe that the prohibitive cost of a CTD is an unacceptable barrier to open science. The price tag excludes individuals and groups who lack research grants or significant private funds from conducting oceanographic research. We want to make this tool-the workhorse of oceanographic research-available to anyone with an interest in the oceans. The OpenCTD is a low-cost, open-source CTD suitable for both educators and scientists. The platform is built using readily available parts and is powered by an Arduino-based microcontroller. Our goal is to create a device that is accurate enough to be used for scientific research and can be constructed for less than $200. Source codes, circuit diagrams, and building plans will be freely available. The final instrument will be effective to 200 meters depth. Why 200 meters? For many coastal regions, 200 meters of water depth covers the majority of the ocean that is accessible by small boat. The OpenCTD is targeted to people working in this niche, where entire research projects can be conducted for less than the cost of a commercial CTD. However, the Open CTD is scalable, and anyone with the inclination can adapt our plans to operate in deeper waters. Through a crowdfunding initiative and collaboration with numerous interested scientists, researchers, educators, and developers, we developed the framework for a low-cost, open-source, CTD that is appropriate for both scientific research and public outreach. We envision a network or researchers and educators using the OpenCTD to contribute to local and region scientific programs through open-source databases.

78 FR 9098 - Self-Regulatory Organizations; Miami International Securities Exchange LLC; Notice of Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-07

... executed contract for the MIAX Clearing Trade Drop (``CTD''), a messaging interface that will provide real... proposes to establish a new Port Fee for the MIAX CTD. CTD provides Exchange Members, their clearing firms... are routed to a CTD connection containing certain information. The information includes, among other...

77 FR 35691 - Update to Electronic Common Technical Document Module 1

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-14

... Electronic Common Technical Document (eCTD) Module 1, which is used for electronic submission of... they are received with a limit of 350. SUPPLEMENTARY INFORMATION: The eCTD is an International... Research (CBER) have been receiving submissions in the eCTD format since 2003, and the eCTD has been the...

Role of Autoantibodies in the Diagnosis of Connective-Tissue Disease ILD (CTD-ILD) and Interstitial Pneumonia with Autoimmune Features (IPAF)

PubMed Central

Jee, Adelle S.; Adelstein, Stephen; Bleasel, Jane; Keir, Gregory J.; Nguyen, MaiAnh; Sahhar, Joanne; Youssef, Peter; Corte, Tamera J.

2017-01-01

The diagnosis of interstitial lung disease (ILD) requires meticulous evaluation for an underlying connective tissue disease (CTD), with major implications for prognosis and management. CTD associated ILD (CTD-ILD) occurs most commonly in the context of an established CTD, but can be the first and/or only manifestation of an occult CTD or occur in patients who have features suggestive of an autoimmune process, but not meeting diagnostic criteria for a defined CTD—recently defined as “interstitial pneumonia with autoimmune features” (IPAF). The detection of specific autoantibodies serves a critical role in the diagnosis of CTD-ILD, but there remains a lack of data to guide clinical practice including which autoantibodies should be tested on initial assessment and when or in whom serial testing should be performed. The implications of detecting autoantibodies in patients with IPAF on disease behaviour and management remain unknown. The evaluation of CTD-ILD is challenging due to the heterogeneity of presentations and types of CTD and ILD that may be encountered, and thus it is imperative that immunologic tests are interpreted in conjunction with a detailed rheumatologic history and examination and multidisciplinary collaboration between respiratory physicians, rheumatologists, immunologists, radiologists and pathologists. PMID:28471413

Deletion of the COOH-Terminal Domain of CXC Chemokine Receptor 4 Leads to the Down-regulation of Cell-to-Cell Contact, Enhanced Motility and Proliferation in Breast Carcinoma Cells

PubMed Central

Ueda, Yukiko; Neel, Nicole F.; Schutyser, Evemie; Raman, Dayanidhi; Richmond, Ann

2009-01-01

The CXC chemokine receptor 4 (CXCR4) contributes to the metastasis of human breast cancer cells. The CXCR4 COOH-terminal domain (CTD) seems to play a major role in regulating receptor desensitization and down-regulation. We expressed either wild-type CXCR4 (CXCR4-WT) or CTD-truncated CXCR4 (CXCR4-ΔCTD) in MCF-7 human mammary carcinoma cells to determine whether the CTD is involved in CXCR4-modulated proliferation of mammary carcinoma cells. CXCR4-WT-transduced MCF-7 cells (MCF-7/CXCR4-WT cells) do not differ from vector-transduced MCF-7 control cells in morphology or growth rate. However, CXCR4-ΔCTD-transduced MCF-7 cells (MCF-7/CXCR4-ΔCTD cells) exhibit a higher growth rate and altered morphology, potentially indicating an epithelial-to-mesenchymal transition. Furthermore, extracellular signal-regulated kinase (ERK) activation and cell motility are increased in these cells. Ligand induces receptor association with β-arrestin for both CXCR4-WT and CXCR4-ΔCTD in these MCF-7 cells. Overexpressed CXCR4-WT localizes predominantly to the cell surface in unstimulated cells, whereas a significant portion of overexpressed CXCR4-ΔCTD resides intracellularly in recycling endosomes. Analysis with human oligomicroarray, Western blot, and immunohistochemistry showed that E-cadherin and Zonula occludens are down-regulated in MCF-7/CXCR4-ΔCTD cells. The array analysis also indicates that mesenchymal marker proteins and certain growth factor receptors are up-regulated in MCF-7/CXCR4-ΔCTD cells. These observations suggest that (a) the overexpression of CXCR4-ΔCTD leads to a gain-of-function of CXCR4-mediated signaling and (b) the CTD of CXCR4-WT may perform a feedback repressor function in this signaling pathway. These data will contribute to our understanding of how CXCR4-ΔCTD may promote progression of breast tumors to metastatic lesions. PMID:16740704

Long-Term Observations of Nitrogen and Phosphorus Export in Paired-Agricultural Watersheds under Controlled and Conventional Tile Drainage.

PubMed

Sunohara, M D; Gottschall, N; Wilkes, G; Craiovan, E; Topp, E; Que, Z; Seidou, O; Frey, S K; Lapen, D R

2015-09-01

Controlled tile drainage (CTD) regulates water and nutrient export from tile drainage systems. Observations of the effects of CTD imposed en masse at watershed scales are needed to determine the effect on downstream receptors. A paired-watershed approach was used to evaluate the effect of field-to-field CTD at the watershed scale on fluxes and flow-weighted mean concentrations (FWMCs) of N and P during multiple growing seasons. One watershed (467-ha catchment area) was under CTD management (treatment [CTD] watershed); the other (250-ha catchment area) had freely draining or uncontrolled tile drainage (UCTD) (reference [UCTD] watershed). The paired agricultural watersheds are located in eastern Ontario, Canada. Analysis of covariance and paired tests were used to assess daily fluxes and FWMCs during a calibration period when CTD intervention on the treatment watershed was minimal (2005-2006, when only 4-10% of the tile-drained area was under CTD) and a treatment period when the treatment (CTD) watershed had prolific CTD intervention (2007-2011 when 82% of tile drained fields were controlled, occupying >70% of catchment area). Significant linear regression slope changes assessed using ANCOVA ( ≤ 0.1) for daily fluxes from upstream and downstream monitoring sites pooled by calibration and treatment period were -0.06 and -0.20 (stream water) (negative values represent flux declines in CTD watershed), -0.59 and -0.77 (NH-N), -0.14 and -0.15 (NO-N), -1.77 and -2.10 (dissolved reactive P), and -0.28 and 0.45 (total P). Total P results for one site comparison contrasted with other findings likely due to unknown in-stream processes affecting total P loading, not efficacy of CTD. The FWMC results were mixed and inconclusive but suggest physical abatement by CTD is the means by which nutrient fluxes are predominantly reduced at these scales. Overall, our study results indicate that CTD is an effective practice for reducing watershed scale fluxes of stream water, N, and P during the growing season. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Web services-based text-mining demonstrates broad impacts for interoperability and process simplification.

PubMed

Wiegers, Thomas C; Davis, Allan Peter; Mattingly, Carolyn J

2014-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation tasks collectively represent a community-wide effort to evaluate a variety of text-mining and information extraction systems applied to the biological domain. The BioCreative IV Workshop included five independent subject areas, including Track 3, which focused on named-entity recognition (NER) for the Comparative Toxicogenomics Database (CTD; http://ctdbase.org). Previously, CTD had organized document ranking and NER-related tasks for the BioCreative Workshop 2012; a key finding of that effort was that interoperability and integration complexity were major impediments to the direct application of the systems to CTD's text-mining pipeline. This underscored a prevailing problem with software integration efforts. Major interoperability-related issues included lack of process modularity, operating system incompatibility, tool configuration complexity and lack of standardization of high-level inter-process communications. One approach to potentially mitigate interoperability and general integration issues is the use of Web services to abstract implementation details; rather than integrating NER tools directly, HTTP-based calls from CTD's asynchronous, batch-oriented text-mining pipeline could be made to remote NER Web services for recognition of specific biological terms using BioC (an emerging family of XML formats) for inter-process communications. To test this concept, participating groups developed Representational State Transfer /BioC-compliant Web services tailored to CTD's NER requirements. Participants were provided with a comprehensive set of training materials. CTD evaluated results obtained from the remote Web service-based URLs against a test data set of 510 manually curated scientific articles. Twelve groups participated in the challenge. Recall, precision, balanced F-scores and response times were calculated. Top balanced F-scores for gene, chemical and disease NER were 61, 74 and 51%, respectively. Response times ranged from fractions-of-a-second to over a minute per article. We present a description of the challenge and summary of results, demonstrating how curation groups can effectively use interoperable NER technologies to simplify text-mining pipeline implementation. Database URL: http://ctdbase.org/ © The Author(s) 2014. Published by Oxford University Press.

Web services-based text-mining demonstrates broad impacts for interoperability and process simplification

PubMed Central

Wiegers, Thomas C.; Davis, Allan Peter; Mattingly, Carolyn J.

2014-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation tasks collectively represent a community-wide effort to evaluate a variety of text-mining and information extraction systems applied to the biological domain. The BioCreative IV Workshop included five independent subject areas, including Track 3, which focused on named-entity recognition (NER) for the Comparative Toxicogenomics Database (CTD; http://ctdbase.org). Previously, CTD had organized document ranking and NER-related tasks for the BioCreative Workshop 2012; a key finding of that effort was that interoperability and integration complexity were major impediments to the direct application of the systems to CTD's text-mining pipeline. This underscored a prevailing problem with software integration efforts. Major interoperability-related issues included lack of process modularity, operating system incompatibility, tool configuration complexity and lack of standardization of high-level inter-process communications. One approach to potentially mitigate interoperability and general integration issues is the use of Web services to abstract implementation details; rather than integrating NER tools directly, HTTP-based calls from CTD's asynchronous, batch-oriented text-mining pipeline could be made to remote NER Web services for recognition of specific biological terms using BioC (an emerging family of XML formats) for inter-process communications. To test this concept, participating groups developed Representational State Transfer /BioC-compliant Web services tailored to CTD's NER requirements. Participants were provided with a comprehensive set of training materials. CTD evaluated results obtained from the remote Web service-based URLs against a test data set of 510 manually curated scientific articles. Twelve groups participated in the challenge. Recall, precision, balanced F-scores and response times were calculated. Top balanced F-scores for gene, chemical and disease NER were 61, 74 and 51%, respectively. Response times ranged from fractions-of-a-second to over a minute per article. We present a description of the challenge and summary of results, demonstrating how curation groups can effectively use interoperable NER technologies to simplify text-mining pipeline implementation. Database URL: http://ctdbase.org/ PMID:24919658

Significance of Myositis Autoantibody in Patients with Idiopathic Interstitial Lung Disease

PubMed Central

Song, Ju Sun; Hwang, Jiwon; Cha, Hoon-Suk; Jeong, Byeong-Ho; Suh, Gee Young; Chung, Man Pyo

2015-01-01

Purpose Some patients with interstitial lung disease (ILD) related to connective tissue disease (CTD) have a delayed diagnosis of the underlying CTD when the ILD is categorized as idiopathic. In this study, we evaluated the frequency of myositis autoantibodies in patients diagnosed with idiopathic ILD and investigated the clinical significance stemming from the presence of the antibodies. Materials and Methods A total 32 patients diagnosed with idiopathic ILD were enrolled in this study. We analyzed a panel of 11 myositis autoantibody specificities in the patients using a line blot immunoassay. Then, we divided them into myositis autoantibody-positive and -negative groups and compared the clinical features and laboratory data between the two groups. Results Of the 32 idiopathic ILD patients, 12 patients had myositis autoantibodies encompassing 9 specificities, except for anti-Mi-2 and anti-PM-Scl 100 (12/32, 38%). Anti-synthetase autoantibodies including Jo-1, EJ, OJ, PL-7, and PL-12 were present in 7 patients (7/32, 22%). The group with myositis autoantibodies presented more frequently with the symptom of mechanic's hand and showed abnormal pulmonary function test results with low forced vital capacity, diffusing capacity for carbon monoxide, total lung capacity, and high lactate dehydrogenase values in blood when compared with the group without myositis antibodies. Conclusion We strongly suggest that patients undergo an evaluation of myositis autoantibodies, if they are diagnosed with idiopathic ILD in the presence of clinical characteristics including mechanic's hand, arthralgia, and autoantibodies which are insufficient to make a diagnosis of a specific CTD category. PMID:25837172

[Impaired endometrial receptivity in primary infertility in women with undifferentiated connective tissue dysplasia and hereditary thrombophilia].

PubMed

Zanozin, A S; Demura, T A; Kolosovsky, D Yu; Faizullina, N M; Kogan, E A

The concurrence of undifferentiated connective tissue dysplasia (uCTD) and hereditary thrombophilia (HT) often accompanies female infertility, in the pathogenesis of which impaired endometrial receptivity plays an important role. to investigate endometrial morphological and immunophenotypic features in patients with primary infertility in the presence of uCTD and HT. The pipelle endometrial biopsy specimens taken in the implantation window were examined in 81 patients, including 13 women with a clinical diagnosis of uCTD, 40 with HT, 19 with uCTD concurrent with HT, and in a control group of 9 heathy surrogate mothers. Morphological, immunohistochemical, and morphometric examinations were done to study the paraffin-embedded endometrial biopsy sections stained with hematoxylin and eosin, pikrofuksin by van Gieson, and with toluidine blue. Immunohistochemical tests were carried out using primary antibodies against ER, PgR, LIF, PAI-1, VEGF, Collagen I, Collagen III, fibronectin, laminin, MMP-2, and MMP-9. The uCTD, HT, and uCTD + HT groups were found to have signs of decreased endometrial receptivity as dramatically lower counts of mature pinopodes, slower endometrial maturation, reduced expression of the receptivity marker LIF, and deviations of the stromal progesterone-estrogen index from the normal value. Sclerotic foci with type III collagen accumulation were detected in the endometrial stroma. uCTD and HT and especially their concurrence are commonly a concomitant disease and risk factors for infertility in women due to impaired endometrial receptivity. In uCTD, connective tissue remodeling processes are substantially retarded, which ultimately leads to increased processes of endometrial stromal sclerosis, reduced endometrial receptivity, and infertility. The most pronounced morphological and immunophenotypical changes have been ascertained to develop in the uCTD + NT group. The findings may be used to predict and devise new infertility treatments in patients with uCTD + NT.

Suppression Analysis Reveals a Functional Difference between the Serines in Positions Two and Five in the Consensus Sequence of the C-Terminal Domain of Yeast RNA Polymerase II

PubMed Central

Yuryev, A.; Corden, J. L.

1996-01-01

The largest subunit of RNA polymerase II contains a repetitive C-terminal domain (CTD) consisting of tandem repeats of the consensus sequence Tyr(1)Ser(2)Pro(3)Thr(4) Ser(5)Pro(6) Ser(7). Substitution of nonphosphorylatable amino acids at positions two or five of the Saccharomyces cerevisiae CTD is lethal. We developed a selection ssytem for isolating suppressors of this lethal phenotype and cloned a gene, SCA1 (suppressor of CTD alanine), which complements recessive suppressors of lethal multiple-substitution mutations. A partial deletion of SCA1 (sca1Δ::hisG) suppresses alanine or glutamate substitutions at position two of the consensus CTD sequence, and a lethal CTD truncation mutation, but SCA1 deletion does not suppress alanine or glutamate substitutions at position five. SCA1 is identical to SRB9, a suppressor of a cold-sensitive CTD truncation mutation. Strains carrying dominant SRB mutations have the same suppression properties as a sca1Δ::hisG strain. These results reveal a functional difference between positions two and five of the consensus CTD heptapeptide repeat. The ability of SCA1 and SRB mutant alleles to suppress CTD truncation mutations suggest that substitutions at position two, but not at position five, cause a defect in RNA polymerase II function similar to that introduced by CTD truncation. PMID:8725217

Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin

PubMed Central

Ihara, Makoto; Okajima, Toshihide; Yamashita, Atsuko; Oda, Takuma; Hirata, Koichi; Nishiwaki, Hisashi; Morimoto, Takako; Akamatsu, Miki; Ashikawa, Yuji; Kuroda, Shun’ichi; Mega, Ryosuke; Kuramitsu, Seiki; Sattelle, David B.

2008-01-01

Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR–neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH–π interactions in the Ls-AChBP–CTD complex than in the Ls-AChBP–IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs. PMID:18338186

The Cancer Target Discovery and Development Network Dashboard Allows Users to Search for Interesting Data and Results | Office of Cancer Genomics

Cancer.gov

The CTD2 Dashboard hosts analyzed data and other evidence generated by the CTD2 Network. It is a web interface for the research community to browse and search CTD2 Network data related to genes, proteins, and compounds from individual CTD2 Centers, or explore observations across multiple Centers.

Critical Thinking Disposition of Nurse Practitioners in Taiwan.

PubMed

Hsu, Hsiu-Ying; Chang, Shu-Chen; Chang, Ai-Ling; Chen, Shiah-Lian

2017-09-01

Critical thinking disposition (CTD) is crucial for nurse practitioners who face complex patient care scenarios. This study explored the CTD of nurse practitioners and related factors. The study was a cross-sectional descriptive design. A purposive sample was recruited from a medical center and its hospital branches in central Taiwan. A structured questionnaire was used to collect data from 210 nurse practitioners. The participants obtained the highest average score on systematicity and analyticity. CTD had a significant positive correlation with fundamental knowledge readiness, professional knowledge readiness, and confidence in making clinical decisions. Professional knowledge readiness, education level, and on-the-job training predicted the score of the participants on overall CTD. On-the-job training and education level may influence the CTD of nurse practitioners. Providing formal or on-the-job continuing education training to nurse practitioners may help enhance their CTD. J Contin Educ Nurs. 2017;48(9):425-430. Copyright 2017, SLACK Incorporated.

Lung cancer in connective tissue disease-associated interstitial lung disease: clinical features and impact on outcomes.

PubMed

Watanabe, Satoshi; Saeki, Keigo; Waseda, Yuko; Murata, Akari; Takato, Hazuki; Ichikawa, Yukari; Yasui, Masahide; Kimura, Hideharu; Hamaguchi, Yasuhito; Matsushita, Takashi; Yamada, Kazunori; Kawano, Mitsuhiro; Furuichi, Kengo; Wada, Takashi; Kasahara, Kazuo

2018-02-01

Lung cancer (LC) adversely impacts survival in patients with idiopathic pulmonary fibrosis. However, little is known about LC in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The aim of this study was to evaluate the prevalence of and risk factors for LC in CTD-ILD, and the clinical characteristics and survival of CTD-ILD patients with LC. We conducted a single-center, retrospective review of patients with CTD-ILD from 2003 to 2016. Patients with pathologically diagnosed LC were identified. The prevalence, risk factors, and clinical features of LC and the impact of LC on CTD-ILD patient outcomes were observed. Of 266 patients with CTD-ILD, 24 (9.0%) had LC. CTD-ILD with LC was more likely in patients who were older, male, and smokers; had rheumatoid arthritis, a usual interstitial pneumonia pattern, emphysema on chest computed tomography scan, and lower diffusing capacity of the lung carbon monoxide (DLco)% predicted; and were not receiving immunosuppressive therapy. Multivariate analysis indicated that the presence of emphysema [odds ratio (OR), 8.473; 95% confidence interval (CI), 2.241-32.033] and nonuse of immunosuppressive therapy (OR, 8.111; 95% CI, 2.457-26.775) were independent risk factors for LC. CTD-ILD patients with LC had significantly worse survival than patients without LC (10-year survival rate: 28.5% vs. 81.8%, P<0.001). LC is associated with the presence of emphysema and nonuse of immunosuppressive therapy, and contributes to increased mortality in patients with CTD-ILD.

Role of the RNA polymerase α subunits in CII-dependent activation of the bacteriophage λ pE promoter: identification of important residues and positioning of the α C-terminal domains

PubMed Central

Kedzierska, Barbara; Lee, David J.; Węgrzyn, Grzegorz; Busby, Stephen J. W.; Thomas, Mark S.

2004-01-01

The bacteriophage λ CII protein stimulates the activity of three phage promoters, pE, pI and paQ, upon binding to a site overlapping the –35 element at each promoter. Here we used preparations of RNA polymerase carrying a DNA cleavage reagent attached to specific residues in the C-terminal domain of the RNA polymerase α subunit (αCTD) to demonstrate that one αCTD binds near position –41 at pE, whilst the other αCTD binds further upstream. The αCTD bound near position –41 is oriented such that its 261 determinant is in close proximity to σ70. The location of αCTD in CII-dependent complexes at the pE promoter is very similar to that found at many activator-independent promoters, and represents an alternative configuration for αCTD at promoters where activators bind sites overlapping the –35 region. We also used an in vivo alanine scan analysis to show that the DNA-binding determinant of αCTD is involved in stimulation of the pE promoter by CII, and this was confirmed by in vitro transcription assays. We also show that whereas the K271E substitution in αCTD results in a drastic decrease in CII-dependent activation of pE, the pI and paQ promoters are less sensitive to this substitution, suggesting that the role of αCTD at the three lysogenic promoters may be different. PMID:14762211

CTD2 Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network

PubMed Central

Aksoy, Bülent Arman; Dančík, Vlado; Smith, Kenneth; Mazerik, Jessica N.; Ji, Zhou; Gross, Benjamin; Nikolova, Olga; Jaber, Nadia; Califano, Andrea; Schreiber, Stuart L.; Gerhard, Daniela S.; Hermida, Leandro C.; Jagu, Subhashini

2017-01-01

Abstract The Cancer Target Discovery and Development (CTD2) Network aims to use functional genomics to accelerate the translation of high-throughput and high-content genomic and small-molecule data towards use in precision oncology. As part of this goal, and to share its conclusions with the research community, the Network developed the ‘CTD2 Dashboard’ [https://ctd2-dashboard.nci.nih.gov/], which compiles CTD2 Network-generated conclusions, termed ‘observations’, associated with experimental entities, collected by its member groups (‘Centers’). Any researcher interested in learning about a given gene, protein, or compound (a ‘subject’) studied by the Network can come to the CTD2 Dashboard to quickly and easily find, review, and understand Network-generated experimental results. In particular, the Dashboard allows visitors to connect experiments about the same target, biomarker, etc., carried out by multiple Centers in the Network. The Dashboard’s unique knowledge representation allows information to be compiled around a subject, so as to become greater than the sum of the individual contributions. The CTD2 Network has broadly defined levels of validation for evidence (‘Tiers’) pertaining to a particular finding, and the CTD2 Dashboard uses these Tiers to indicate the extent to which results have been validated. Researchers can use the Network’s insights and tools to develop a new hypothesis or confirm existing hypotheses, in turn advancing the findings towards clinical applications. Database URL: https://ctd2-dashboard.nci.nih.gov/ PMID:29220450

Challenges for the registration of vaccines in emerging countries: Differences in dossier requirements, application and evaluation processes.

PubMed

Dellepiane, Nora; Pagliusi, Sonia

2018-06-07

The divergence of regulatory requirements and processes in developing and emerging countries contributes to hamper vaccines' registration, and therefore delay access to high-quality, safe and efficacious vaccines for their respective populations. This report focuses on providing insights on the heterogeneity of registration requirements in terms of numbering structure and overall content of dossiers for marketing authorisation applications for vaccines in different areas of the world. While it also illustrates the divergence of regulatory processes in general, as well as the need to avoid redundant reviews, it does not claim to provide a comprehensive view of all processes nor existing facilitating mechanisms, nor is it intended to touch upon the differences in assessments made by different regulatory authorities. This report describes the work analysed by regulatory experts from vaccine manufacturing companies during a meeting held in Geneva in May 2017, in identifying and quantifying differences in the requirements for vaccine registration in three aspects for comparison: the dossier numbering structure and contents, the application forms, and the evaluation procedures, in different countries and regions. The Module 1 of the Common Technical Document (CTD) of 10 countries were compared. Modules 2-5 of the CTDs of two regions and three countries were compared to the CTD of the US FDA. The application forms of eight countries were compared and the registration procedures of 134 importing countries were compared as well. The analysis indicates a high degree of divergence in numbering structure and content requirements. Possible interventions that would lead to significant improvements in registration efficiency include alignment in CTD numbering structure, a standardised model-application form, and better convergence of evaluation procedures. Copyright © 2018.

The C-terminal cytidine deaminase domain of APOBEC3G itself undergoes intersegmental transfer for a target search, as revealed by real-time NMR monitoring.

PubMed

Kamba, Keisuke; Nagata, Takashi; Katahira, Masato

2018-01-31

APOBEC3G (A3G), an anti-human immunodeficiency virus 1 factor, deaminates cytidines. We examined deamination of two cytidines located separately on substrate ssDNA by the C-terminal domain (CTD) of A3G using real-time NMR monitoring. The deamination preference between the two cytidines was lost when either the substrate or non-substrate ssDNA concentration increased. When the non-substrate ssDNA concentration increased, the deamination activity first increased, but then decreased. This indicates that even a single domain, A3G-CTD, undergoes intersegmental transfer for a target search.

Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases.

PubMed

Zhang, Yongfeng; Zheng, Yi

2014-12-01

The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/µL, we should be care of occurrence of PJP.

Revisiting the co-existence of Attention-Deficit/Hyperactivity Disorder and Chronic Tic Disorder in childhood-The case of colour discrimination, sustained attention and interference control.

PubMed

Uebel-von Sandersleben, Henrik; Albrecht, Björn; Rothenberger, Aribert; Fillmer-Heise, Anke; Roessner, Veit; Sergeant, Joseph; Tannock, Rosemary; Banaschewski, Tobias

2017-01-01

Attention Deficit / Hyperactivity Disorder (ADHD) and Chronic Tic Disorder (CTD) are two common and frequently co-existing disorders, probably following an additive model. But this is not yet clear for the basic sensory function of colour processing sensitive to dopaminergic functioning in the retina and higher cognitive functions like attention and interference control. The latter two reflect important aspects for psychoeducation and behavioural treatment approaches. Colour discrimination using the Farnsworth-Munsell 100-hue Test, sustained attention during the Frankfurt Attention Inventory (FAIR), and interference liability during Colour- and Counting-Stroop-Tests were assessed to further clarify the cognitive profile of the co-existence of ADHD and CTD. Altogether 69 children were classified into four groups: ADHD (N = 14), CTD (N = 20), ADHD+CTD (N = 20) and healthy Controls (N = 15) and compared in cognitive functioning in a 2×2-factorial statistical model. Difficulties with colour discrimination were associated with both ADHD and CTD factors following an additive model, but in ADHD these difficulties tended to be more pronounced on the blue-yellow axis. Attention problems were characteristic for ADHD but not CTD. Interference load was significant in both Colour- and Counting-Stroop-Tests and unrelated to colour discrimination. Compared to Controls, interference load in the Colour-Stroop was higher in pure ADHD and in pure CTD, but not in ADHD+CTD, following a sub-additive model. In contrast, interference load in the Counting-Stroop did not reveal ADHD or CTD effects. The co-existence of ADHD and CTD is characterized by additive as well as sub-additive performance impairments, suggesting that their co-existence may show simple additive characteristics of both disorders or a more complex interaction, depending on demand. The equivocal findings on interference control may indicate limited validity of the Stroop-Paradigm for clinical assessments.

Quantum chemical calculations and molecular docking studies of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione(CTD) and its mannich product 5-(4-chlorobenzylidene)-3-(morpholinomethyl)thiazolidine-2,4-dione (CMTD)

NASA Astrophysics Data System (ADS)

Fatma, Shaheen; Bishnoi, Abha; Verma, Anil Kumar; Singh, Vineeta; Srivastava, Krishna

2018-04-01

This work presents the synthesis of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione (CTD) by Claisen condensation of thiazolidine-2,4-dione and mannich product of CTD, 5-(4-chlorobenzylidene)-3-(morpholinomethyl)thiazolidine-2,4-dione (CMTD). The static first hyperpolarizability values for thiazolidine-2,4-dione derivatives have been calculated as 10.28 × 10-30 esu for CTD and 19.42 × 10-30 esu for CMTD. The gradual increase in hyperpolarizability values of synthesized thiazolidine-2,4-dione derivatives from CTD to CMTD is due to the blockage of sbnd NH group on CTD by mannich reaction. The structures of these compounds have been derived by spectroscopic(IR, UV, Mass, 1H and 13C NMR) analysis as well as with the help of theoretical studies. The high values of first static hyperpolarizability indicate that the synthesized derivatives are suitable as non-linear optical (NLO) material. CTD with MIC value of 12.5 μg/mL can be developed as an alternative drug for the treatment of enteric fever. Calculated frontier orbital gap values suggest that the CMTD is a soft molecule with high chemical reactivity and is more polarizable as compared to the CTD. Molecular electrostatic potential is calculated for the optimized geometry of the molecules to estimate their chemical reactivity. The inhibitor CTD forms a stable complex with 3-dehydroquinase enzyme of Salmonella typhi. It is evident from the ligand receptor interactions and a binding affinity value of -5.88 kcal/mol and an inhibition constant of 49.22 μM. This is further confirmed by the experimental biological data. The molecular docking studies are supportive of the antibacterial activity of CTD exhibiting high inhibition constant and binding energy.

Revisiting the co-existence of Attention-Deficit/Hyperactivity Disorder and Chronic Tic Disorder in childhood—The case of colour discrimination, sustained attention and interference control

PubMed Central

Rothenberger, Aribert; Fillmer-Heise, Anke; Roessner, Veit; Sergeant, Joseph; Tannock, Rosemary; Banaschewski, Tobias

2017-01-01

Objective Attention Deficit / Hyperactivity Disorder (ADHD) and Chronic Tic Disorder (CTD) are two common and frequently co-existing disorders, probably following an additive model. But this is not yet clear for the basic sensory function of colour processing sensitive to dopaminergic functioning in the retina and higher cognitive functions like attention and interference control. The latter two reflect important aspects for psychoeducation and behavioural treatment approaches. Methods Colour discrimination using the Farnsworth-Munsell 100-hue Test, sustained attention during the Frankfurt Attention Inventory (FAIR), and interference liability during Colour- and Counting-Stroop-Tests were assessed to further clarify the cognitive profile of the co-existence of ADHD and CTD. Altogether 69 children were classified into four groups: ADHD (N = 14), CTD (N = 20), ADHD+CTD (N = 20) and healthy Controls (N = 15) and compared in cognitive functioning in a 2×2-factorial statistical model. Results Difficulties with colour discrimination were associated with both ADHD and CTD factors following an additive model, but in ADHD these difficulties tended to be more pronounced on the blue-yellow axis. Attention problems were characteristic for ADHD but not CTD. Interference load was significant in both Colour- and Counting-Stroop-Tests and unrelated to colour discrimination. Compared to Controls, interference load in the Colour-Stroop was higher in pure ADHD and in pure CTD, but not in ADHD+CTD, following a sub-additive model. In contrast, interference load in the Counting-Stroop did not reveal ADHD or CTD effects. Conclusion The co-existence of ADHD and CTD is characterized by additive as well as sub-additive performance impairments, suggesting that their co-existence may show simple additive characteristics of both disorders or a more complex interaction, depending on demand. The equivocal findings on interference control may indicate limited validity of the Stroop-Paradigm for clinical assessments. PMID:28594866

Reward enhances tic suppression in children within months of tic disorder onset.

PubMed

Greene, Deanna J; Koller, Jonathan M; Robichaux-Viehoever, Amy; Bihun, Emily C; Schlaggar, Bradley L; Black, Kevin J

2015-02-01

Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

REWARD ENHANCES TIC SUPPRESSION IN CHILDREN WITHIN MONTHS OF TIC DISORDER ONSET

PubMed Central

Greene, Deanna J.; Koller, Jonathan M.; Robichaux-Viehoever, Amy; Bihun, Emily C.; Schlaggar, Bradley L.; Black, Kevin J.

2014-01-01

Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of how tics develop and how behavior therapy for tics works. We investigated tic suppression in school-age children as close to the time of tic onset as possible, and no later than six months after onset. Children were asked to suppress their tics both in the presence and absence of a contingent reward. Results demonstrated that these children, like children with TS/CTD, have some capacity to suppress tics, and that immediate reward enhances that capacity. These findings demonstrate that the modulating effect of reward on inhibitory control of tics is present within months of tic onset, before tics have become chronic. PMID:25220075

Ergonomics: CTD management evaluation tool.

PubMed

Ostendorf, J S; Rogers, B; Bertsche, P K

2000-01-01

Cumulative trauma disorder (CTD) occurrences peaked in number in 1994 and although decreasing in 1995, still accounted for 62% of all illness cases reported. A CTD Management Evaluation Tool was developed to assist Occupational Safety and Health Compliance Officers (CSHOs) in program evaluation and documentation of the occupational health management component and the need for an ergonomics program. Occupational and environmental health nurses may use the tool not only to reduce and prevent CTD occurrences, but also as a benchmark for program evaluation.

The distal C-terminal region of the KcsA potassium channel is a pH-dependent tetramerization domain.

PubMed

Kamnesky, Guy; Shaked, Hadassa; Chill, Jordan H

2012-05-04

The intracellular C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is a 40-residue-long segment that natively adopts a helical bundle conformation with 4-fold symmetry. A hallmark of KcsA behavior is pH-induced conformational change, which leads to the opening of the channel at acidic pH. Previous studies have reached conflicting conclusions as to the role of the CTD in this transition. Here, we investigate the involvement of this domain in pH-mediated channel opening by NMR using a soluble peptide corresponding to residues 128-160 of the CTD (CTD34). At neutral pH, CTD34 exhibits concentration-dependent spectral changes consistent with oligomer formation. We prove this slowly tumbling species to be a tetramer with a dissociation constant of (2.0±0.5)×10(-)(11) M(3) by NMR and sedimentation equilibrium experiments. Whereas monomeric CTD34 is only mildly helical, secondary chemical shifts prove that the tetrameric species adopts a tight native-like helical bundle conformation. The tetrameric species undergoes pH-dependent dissociation, and CTD34 is fully monomeric below pH 5.0. The structural basis for this phenomenon is the destabilization of the tetrameric CTD34 by protonation of residue H145 in the monomeric form of the peptide. We conclude that (i) the CTD34 peptide is independently capable of forming a tetrameric helical bundle, and (ii) this structurally significant conformational shift is modulated by the effects of solution pH on residue H145. Therefore, the involvement of this domain in the pH gating of the channel is strongly suggested. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - A subgroup analysis of the ARIES-E clinical trial.

PubMed

Fischer, Aryeh; Denton, Christopher P; Matucci-Cerinic, Marco; Gillies, Hunter; Blair, Christiana; Tislow, James; Nathan, Steven D

2016-08-01

Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Interpreting & Biomechanics. PEPNet Tipsheet

ERIC Educational Resources Information Center

PEPNet-Northeast, 2001

2001-01-01

Cumulative trauma disorder (CTD) refers to a collection of disorders associated with nerves, muscles, tendons, bones, and the neurovascular (nerves and related blood vessels) system. CTD symptoms may involve the neck, back, shoulders, arms, wrists, or hands. Interpreters with CTD may experience a variety of symptoms including: pain, joint…

Korean Nursing Students' Acquisition of Evidence-Based Practice and Critical Thinking Skills.

PubMed

Kim, Sang Suk; Kim, Eun Joo; Lim, Ji Young; Kim, Geun Myun; Baek, Hee Chong

2018-01-01

Evidence-based practice (EBP) is essential for enhancing nurses' quality of care. We identified Korean nursing students' practices, attitudes, and knowledge concerning EBP, as well as their critical thinking disposition (CTD). The EBP Questionnaire (EBPQ) was administered to a convenience sample of 266 nursing students recruited from four nursing schools in Seoul and its metropolitan area. Average EBPQ and CTD total scores were 4.69 ± 0.64 and 3.56 ± 0.32, respectively. Students who were ages ⩾23 years, male, and satisfied with their major demonstrated higher EBPQ and CTD scores. EBPQ scores were significantly correlated with CTD scores (r = .459, p < .01), and CTD was an explanatory factor of EBP (adjusted R 2 = 0.200). It is necessary to develop comprehensive teaching strategies to help nursing students improve their CTD and information utilization skills, as well as integrate EBP in undergraduate programs to enhance nurses' EBP abilities. [J Nurs Educ. 2018;57(1):21-27.]. Copyright 2018, SLACK Incorporated.

Sustained-release microsphere formulation containing an agrochemical by polyurethane polymerization during an agitation granulation process.

PubMed

Terada, Takatoshi; Tagami, Manabu; Ohtsubo, Toshiro; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

2016-07-25

In this report, a new solventless microencapsulation method by synthesizing polyurethane (PU) from polyol and isocyanate during an agglomeration process in a high-speed mixing apparatus was developed. Clothianidin (CTD), which is a neonicotinoid insecticide and highly effective against a wide variety of insect pests, was used as the model compound. The microencapsulated samples covered with PU (CTD microspheres) had a median diameter of <75μm and sustained-release properties. The CTD microspheres were analyzed by synchrotron X-ray computed tomography measurements. Multiple cores of CTD and other solid excipient were dispersed in PU. Although voids appeared in the CTD microspheres after CTD release, the spherical shape of the microspheres remained stable and no change in its framework was observed. The experimental release data were highly consistent with the Baker-Lonsdale model derived from drug release of spherical monolithic dispersions and consistent with the computed tomography measurements. Copyright © 2016 Elsevier B.V. All rights reserved.

Comprehensive nitrogen budgets for controlled tile drainage fields in eastern ontario, Canada.

PubMed

Sunohara, M D; Craiovan, E; Topp, E; Gottschall, N; Drury, C F; Lapen, D R

2014-03-01

Excessive N loading from subsurface tile drainage has been linked to water quality degradation. Controlled tile drainage (CTD) has the potential to reduce N losses via tile drainage and boost crop yields. While CTD can reduce N loss from tile drainage, it may increase losses through other pathways. A multiple-year field-scale accounting of major N inputs and outputs during the cropping season was conducted on freely drained and controlled tile drained agricultural fields under corn ( L.)-soybean [ (L.) Merr.] production systems in eastern Ontario, Canada. Greater predicted gaseous N emissions for corn and soybean and greater observed lateral seepage N losses were observed for corn and soybean fields under CTD relative to free-draining fields. However, observed N losses from tile were significantly lower for CTD fields, in relation to freely drained fields. Changes in residual soil N were essentially equivalent between drainage treatments, while mass balance residual terms were systematically negative (slightly more so for CTD). Increases in plant N uptake associated with CTD were observed, probably resulting in higher grain yields for corn and soybean. This study illustrates the benefits of CTD in decreasing subsurface tile drainage N losses and boosting crop yields, while demonstrating the potential for CTD to increase N losses via other pathways related to gaseous emissions and groundwater seepage. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases

PubMed Central

Jeong, Seri; Yang, Heeyoung; Hwang, Hyunyong

2017-01-01

This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF) methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCT). The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6), including SLE (24.3 vs. 10.7). The areas under the receiver operating characteristic curves (ROC-AUCs) of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72) and MCT (0.85) than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE. PMID:28273146

Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases.

PubMed

Jeong, Seri; Yang, Heeyoung; Hwang, Hyunyong

2017-01-01

This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF) methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCT). The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6), including SLE (24.3 vs. 10.7). The areas under the receiver operating characteristic curves (ROC-AUCs) of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72) and MCT (0.85) than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE.

Catching the Dream Annual Report, 2002.

ERIC Educational Resources Information Center

Chavers, Dean, Ed.

2002-01-01

In 2002, Catching the Dream (CTD) provided college scholarships to 208 American Indian students as well as grants to improve education in schools that serve Native students. This annual report describes CTD's programs and activities in 2002. Contents include short descriptions of CTD's scholarship, fellowship, and internship programs; describe…

A multi-sensor land mine detection system: hardware and architectural outline of the Australian RRAMNS CTD system

NASA Astrophysics Data System (ADS)

Abeynayake, Canicious; Chant, Ian; Kempinger, Siegfried; Rye, Alan

2005-06-01

The Rapid Route Area and Mine Neutralisation System (RRAMNS) Capability Technology Demonstrator (CTD) is a countermine detection project undertaken by DSTO and supported by the Australian Defence Force (ADF). The limited time and budget for this CTD resulted in some difficult strategic decisions with regard to hardware selection and system architecture. Although the delivered system has certain limitations arising from its experimental status, many lessons have been learned which illustrate a pragmatic path for future development. RRAMNS a similar sensor suite to other systems, in that three complementary sensors are included. These are Ground Probing Radar, Metal Detector Array, and multi-band electro-optic sensors. However, RRAMNS uses a unique imaging system and a network based real-time control and sensor fusion architecture. The relatively simple integration of each of these components could be the basis for a robust and cost-effective operational system. The RRAMNS imaging system consists of three cameras which cover the visible spectrum, the mid-wave and long-wave infrared region. This subsystem can be used separately as a scouting sensor. This paper describes the system at its mid-2004 status, when full integration of all detection components was achieved.

Measuring and modeling the effects of drainage water management on soil greenhouse gas fluxes from corn and soybean fields.

PubMed

Nangia, V; Sunohara, M D; Topp, E; Gregorich, E G; Drury, C F; Gottschall, N; Lapen, D R

2013-11-15

Controlled tile drainage can boost crop yields and improve water quality, but it also has the potential to increase GHG emissions. This study compared in-situ chamber-based measures of soil CH4, N2O, and CO2 fluxes for silt loam soil under corn and soybean cropping with conventional tile drainage (UTD) and controlled tile drainage (CTD). A semi-empirical model (NEMIS-NOE) was also used to predict soil N2O fluxes from soils using observed soil data. Observed N2O and CH4 fluxes between UTD and CTD fields during the farming season were not significantly different at 0.05 level. Soils were primarily a sink for CH4 but in some cases a source (sources were associated exclusively with CTD). The average N2O fluxes measured ranged between 0.003 and 0.028 kg N ha(-1) day(-1). There were some significantly higher (p ≤ 0.05) CO2 fluxes associated with CTD relative to UTD during some years of study. Correlation analyses indicated that the shallower the water table, the greater the CO2 fluxes. Higher corn plant C for CTD tended to offset estimated higher CTD CO2 C losses via soil respiration by ∼100-300 kg C ha(-1). There were good fits between observed and predicted (NEMIS-NOE) N2O fluxes for corn (R(2) = 0.70) and soybean (R(2) = 0.53). Predicted N2O fluxes were higher for CTD for approximately 70% of the paired-field study periods suggesting that soil physical factors, such as water-filled pore space, imposed by CTD have potentially strong impacts on net N fluxes. Model predictions of daily cumulative N2O fluxes for the agronomically-active study period for corn-CTD and corn-UTD, as a percentage of total N fertilizer applied, were 3.1% and 2.6%, respectively. For predicted N2O fluxes on basis of yield units, indices were 0.0005 and 0.0004 (kg N kg(-1) crop grain yield) for CTD and UTD corn fields, respectively, and 0.0011 and 0.0005 for CTD and UTD soybean fields, respectively. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease.

PubMed

Oldham, Justin M; Lee, Cathryn; Valenzi, Eleanor; Witt, Leah J; Adegunsoye, Ayodeji; Hsu, Scully; Chen, Lena; Montner, Steven; Chung, Jonathan H; Noth, Imre; Vij, Rekha; Strek, Mary E

2016-12-01

Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of nailfold capillaroscopy in interstitial lung diseases - can it differentiate idiopathic cases from collagen tissue disease associated interstitial lung diseases?

PubMed

Çakmakçı Karadoğan, Dilek; Balkarlı, Ayşe; Önal, Özgür; Altınışık, Göksel; Çobankara, Veli

2015-01-01

Nailfold capillaroscopy (NFC) is a non-invasive diagnostic test that is mostly used for early diagnosis of collagen tissue diseases (CTDs). We aimed to evaluate whether NFC findings could be a clue for discriminating idiopathic interstitial lung diseases (ILD) from CTD associated ILDs (CTD-ILD). Additionally it was aimed to determine whether NFC could be helpful in discriminating usual interstitial pneumonia (UIP) pattern from non-specific interstitial pneumonia (NSIP) pattern. We grouped patients into three main groups: 15 CTD-ILD, 18 idiopathic ILD, and 17 patients in the control group. The CTD-ILD group was split into two subgroups: 8 patients with Sjögren's syndrome (SJS)-associated ILD and 7 with rheumatoid arthritis (RA)-associated ILD. The idiopathic-ILD group consisted of 10 idiopathic NSIP and 8 IPF patients. The control group consisted of 10 SJS and 7 RA patients without lung disease. None of the patients were on acute exacerbation at the time of examination, and none had Reynaud's phenomenon. Mean capillary density was significantly reduced only in the CTD-ILD group as compared to the control group (p= 0.006). In subgroup analysis, it was determined that RA-ILD, IPF, and SJS-ILD subgroups had more severe capillaroscopic abnormalities. Mean capillary density in patients with the UIP pattern was reduced compared to patients with the NSIP pattern and those in the control group; p values were 0.008 and < 0.001, respectively. This study is to be the first describing and comparing the nailfold capillaroscopic findings of patients with NSIP and UIP patterns. NFC findings can be helpful in discriminating UIP patterns from NSIP patterns. But to show its role in differentiating idiopathic disease, more studies with more patients are needed.

Structural conversion of the transformer protein RfaH: new insights derived from protein structure prediction and molecular dynamics simulations.

PubMed

Balasco, Nicole; Barone, Daniela; Vitagliano, Luigi

2015-01-01

Recent structural investigations have shown that the C-terminal domain (CTD) of the transcription factor RfaH undergoes unique structural modifications that have a profound impact into its functional properties. These modifications cause a complete change in RfaH(CTD) topology that converts from an α-hairpin to a β-barrel fold. To gain insights into the determinants of this major structural conversion, we here performed computational studies (protein structure prediction and molecular dynamics simulations) on RfaH(CTD). Although these analyses, in line with literature data, suggest that the isolated RfaH(CTD) has a strong preference for the β-barrel fold, they also highlight that a specific region of the protein is endowed with a chameleon conformational behavior. In particular, the Leu-rich region (residues 141-145) has a good propensity to adopt both α-helical and β-structured states. Intriguingly, in the RfaH homolog NusG, whose CTD uniquely adopts the β-barrel fold, the corresponding region is rich in residues as Val or Ile that present a strong preference for the β-structure. On this basis, we suggest that the presence of this Leu-rich element in RfaH(CTD) may be responsible for the peculiar structural behavior of the domain. The analysis of the sequences of RfaH family (PfamA code PF02357) unraveled that other members potentially share the structural properties of RfaH(CTD). These observations suggest that the unusual conformational behavior of RfaH(CTD) may be rare but not unique.

Interpretacion y Biomecanica. Hoja de consejos de PEPNet (Interpreting and Biomechanics. PEPNet Tipsheet)

ERIC Educational Resources Information Center

DeGroote, Bill; Morrison, Carolyn

2010-01-01

This publication, written in Spanish, describes cumulative trauma disorder (CTD), which refers to a collection of disorders associated with nerves, muscles, tendons, bones, and the neurovascular (nerves and related blood vessels) system. CTD symptoms may involve the neck, back, shoulders, arms, wrists, or hands. Interpreters with CTD may…

78 FR 51192 - Secure Supply Chain Pilot Program

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-20

... (PDF) and using the Electronic Common Technical Document (eCTD) format and the Electronic Submissions.... The PDF file name should contain ``3676'' as part of the file name, and the eCTD leaf title should.... For further information regarding eCTD, please refer to the Web site at http://www.fda.gov/Drugs...

78 FR 34393 - Electronic Submission of Tobacco Product Applications and Other Information; Public Workshop...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-07

... manufacturers experienced with electronic Common Technical Document (eCTD); vendors of software used to support... electronic submission workshop will include discussion on eCTD, which is an International Conference on Harmonization (ICH) specification developed by ICH and its member parties. The eCTD provides an organizational...

Molecular dynamics study of the phosphorylation effect on the conformational states of the C-terminal domain of RNA polymerase II.

PubMed

Yonezawa, Yasushige

2014-05-01

The carboxyl-terminal domain (CTD) of RNA polymerase II in eukaryotes regulates mRNA processing processes by recruiting various regulation factors. A main function of the CTD relies on the heptad consensus sequence (YSPTSPS). The CTD dynamically changes its conformational state to recognize and bind different regulation factors. The dynamical conformation changes are caused by modifications, mainly phosphorylation and dephosphorylation, to the serine residues. In this study, we investigate the conformational states of the unit consensus CTD peptide with various phosphorylation patterns of the serine residues by extended ensemble simulations. The results show that the CTD without phosphorylation has a flexible disordered structure distributed between twisted and extended states, but phosphorylation tends to reduce the conformational space. It was found that phosphorylation induces a β-turn around the phosphorylated serine residue and the cis conformation of the proline residue significantly inhibits the β-turn formation. The β-turn should contribute to specific CTD binding of the different regulation factors by changing the conformation propensity combined with induced fit.

Cytoplasmic tail domain of glycoprotein B is essential for HHV-6 infection

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

Mahmoud, Nora F.; Faculty of Pharmacy, Suez Canal University, Ismailia; Jasirwan, Chyntia

2016-03-15

Human herpesvirus 6 (HHV-6) glycoprotein B (gB) is an abundantly expressed viral glycoprotein required for viral entry and cell fusion, and is highly conserved among herpesviruses. The present study examined the function of HHV-6 gB cytoplasmic tail domain (CTD). A gB CTD deletion mutant was constructed which, in contrast to its revertant, could not be reconstituted. Moreover, deletion of gB cytoplasmic tail impaired the intracellular transport of gB protein to the trans-Golgi network (TGN). Taken together, these results suggest that gB CTD is critical for HHV-6 propagation and important for intracellular transportation. - Highlights: • Glycoprotein B (gB) is highlymore » conserved among herpesviruses. • HHV-6 gB is also abundantly expressed in virions. • In the present study, we showed the function of HHV-6 gB cytoplasmic tail domain (CTD). • We found that deletion of gB CTD impairs the intracellular transport of gB protein to the trans-Golgi network (TGN), and CTD of gB is critical for HHV-6 propagation.« less

The clinical impact of Anti-DFS70 antibodies in undifferentiated connective tissue disease: case reports and a review of the literature.

PubMed

Infantino, M; Meacci, F; Grossi, V; Manfredi, M; Li Gobbi, F; Sarzi-Puttini, P; Atzeni, F; Benucci, M

2017-02-01

Anti-nuclear antibody (ANA) positivity suggests CTD but can also lead to a diagnosis of UCTD when a patient does not fulfill the CTD diagnostic criteria. An anti-dense fine speckled (DFS) immunofluorescence (IIF) pattern can be observed when using an ANA test on HEp-2 cells and is due to the presence of antibodies to the nuclear DFS70 antigen that has rarely found in CTD. Serological testing for anti-DFS70 antibodies could therefore play a very interesting negative predictive role in stratifying patients on the basis of the evolution of UCTD to CTD. We described two patients ANA and anti-DFS70 positive in which the use of new method allowing the immunoadsorption of anti-DFS70 antibodies has permitted to exclude the incorrect diagnosis of CTD.

Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II.

PubMed

Lu, Huasong; Yu, Dan; Hansen, Anders S; Ganguly, Sourav; Liu, Rongdiao; Heckert, Alec; Darzacq, Xavier; Zhou, Qiang

2018-06-01

Hyperphosphorylation of the C-terminal domain (CTD) of the RPB1 subunit of human RNA polymerase (Pol) II is essential for transcriptional elongation and mRNA processing 1-3 . The CTD contains 52 heptapeptide repeats of the consensus sequence YSPTSPS. The highly repetitive nature and abundant possible phosphorylation sites of the CTD exert special constraints on the kinases that catalyse its hyperphosphorylation. Positive transcription elongation factor b (P-TEFb)-which consists of CDK9 and cyclin T1-is known to hyperphosphorylate the CTD and negative elongation factors to stimulate Pol II elongation 1,4,5 . The sequence determinant on P-TEFb that facilitates this action is currently unknown. Here we identify a histidine-rich domain in cyclin T1 that promotes the hyperphosphorylation of the CTD and stimulation of transcription by CDK9. The histidine-rich domain markedly enhances the binding of P-TEFb to the CTD and functional engagement with target genes in cells. In addition to cyclin T1, at least one other kinase-DYRK1A 6 -also uses a histidine-rich domain to target and hyperphosphorylate the CTD. As a low-complexity domain, the histidine-rich domain also promotes the formation of phase-separated liquid droplets in vitro, and the localization of P-TEFb to nuclear speckles that display dynamic liquid properties and are sensitive to the disruption of weak hydrophobic interactions. The CTD-which in isolation does not phase separate, despite being a low-complexity domain-is trapped within the cyclin T1 droplets, and this process is enhanced upon pre-phosphorylation by CDK7 of transcription initiation factor TFIIH 1-3 . By using multivalent interactions to create a phase-separated functional compartment, the histidine-rich domain in kinases targets the CTD into this environment to ensure hyperphosphorylation and efficient elongation of Pol II.

The curation paradigm and application tool used for manual curation of the scientific literature at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; Murphy, Cynthia G.; Mattingly, Carolyn J.

2011-01-01

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and convert free-text information into a structured format using official nomenclature, integrating third party controlled vocabularies for chemicals, genes, diseases and organisms, and a novel controlled vocabulary for molecular interactions. Manual curation produces a robust, richly annotated dataset of highly accurate and detailed information. Currently, CTD describes over 349 000 molecular interactions between 6800 chemicals, 20 900 genes (for 330 organisms) and 4300 diseases that have been manually curated from over 25 400 peer-reviewed articles. This manually curated data are further integrated with other third party data (e.g. Gene Ontology, KEGG and Reactome annotations) to generate a wealth of toxicogenomic relationships. Here, we describe our approach to manual curation that uses a powerful and efficient paradigm involving mnemonic codes. This strategy allows biocurators to quickly capture detailed information from articles by generating simple statements using codes to represent the relationships between data types. The paradigm is versatile, expandable, and able to accommodate new data challenges that arise. We have incorporated this strategy into a web-based curation tool to further increase efficiency and productivity, implement quality control in real-time and accommodate biocurators working remotely. Database URL: http://ctd.mdibl.org PMID:21933848

Overexpression of YB1 C-terminal domain inhibits proliferation, angiogenesis and tumorigenicity in a SK-BR-3 breast cancer xenograft mouse model.

PubMed

Shi, Jian-Hong; Cui, Nai-Peng; Wang, Shuo; Zhao, Ming-Zhi; Wang, Bing; Wang, Ya-Nan; Chen, Bao-Ping

2016-01-01

Y-box-binding protein 1 (YB1) is a multifunctional transcription factor with vital roles in proliferation, differentiation and apoptosis. In this study, we have examined the role of its C-terminal domain (YB1 CTD) in proliferation, angiogenesis and tumorigenicity in breast cancer. Breast cancer cell line SK-BR-3 was infected with GFP-tagged YB1 CTD adenovirus expression vector. An 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) proliferation assay showed that YB1 CTD decreased SK-BR-3 cell proliferation, and down-regulated cyclin B1 and up-regulated p21 levels in SK-BR-3 cells. YB1 CTD overexpression changed the cytoskeletal organization and slightly inhibited the migration of SK-BR-3 cells. YB1 CTD also inhibited secreted VEGF expression in SK-BR-3 cells, which decreased SK-BR-3-induced EA.hy926 endothelial cell angiogenesis in vitro. YB1 CTD overexpression attenuated the ability of SK-BR-3 cells to form tumours in nude mice, and decreased in vivo VEGF levels and angiogenesis in the xenografts in SK-BR-3 tumour-bearing mice. Taken together, our findings demonstrate the vital role of YB1 CTD overexpression in inhibiting proliferation, angiogenesis and tumorigenicity of breast cancer cell line SK-BR-3.

Intact Arabidopsis RPB1 functions in stem cell niches maintenance and cell cycling control.

PubMed

Zhang, Qian-Qian; Li, Ying; Fu, Zhao-Ying; Liu, Xun-Biao; Yuan, Kai; Fang, Ying; Liu, Yan; Li, Gang; Zhang, Xian-Sheng; Chong, Kang; Ge, Lei

2018-05-12

Plant meristem activity depends on accurate execution of transcriptional networks required for establishing optimum functioning of stem cell niches. An Arabidopsis mutant card1-1 (constitutive auxin response with DR5:GFP) that encodes a truncated RPB1 (RNA Polymerase II's largest subunit) with shortened C-terminal domain (CTD) was identified. Phosphorylation of the CTD repeats of RPB1 is coupled to transcription in eukaryotes. Here we uncover that the truncated CTD of RPB1 disturbed cell cycling and enlarged the size of shoot and root meristem. The defects in patterning of root stem cell niche in card1-1 indicates that intact CTD of RPB1 is necessary for fine-tuning the specific expression of genes responsible for cell-fate determination. The gene-edited plants with different CTD length of RPB1, created by CRISPR-CAS9 technology, confirmed that both the full length and the DK-rich tail of RPB1's CTD play roles in the accurate transcription of CYCB1;1 encoding a cell-cycle marker protein in root meristem and hence participate in maintaining root meristem size. Our experiment proves that the intact RPB1 CTD is necessary for stem cell niche maintenance, which is mediated by transcriptional regulation of cell cycling genes. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

Heat-shock inactivation of the TFIIH-associated kinase and change in the phosphorylation sites on the C-terminal domain of RNA polymerase II.

PubMed

Dubois, M F; Vincent, M; Vigneron, M; Adamczewski, J; Egly, J M; Bensaude, O

1997-02-15

The C-terminal domain (CTD) of the RNA polymerase II largest subunit (RPB1) plays a central role in transcription. The CTD is unphosphorylated when the polymerase assembles into a preinitiation complex of transcription and becomes heavily phosphorylated during promoter clearance and entry into elongation of transcription. A kinase associated to the general transcription factor TFIIH, in the preinitiation complex, phosphorylates the CTD. The TFIIH-associated CTD kinase activity was found to decrease in extracts from heat-shocked HeLa cells compared to unstressed cells. This loss of activity correlated with a decreased solubility of the TFIIH factor. The TFIIH-kinase impairment during heat-shock was accompanied by the disappearance of a particular phosphoepitope (CC-3) on the RPB1 subunit. The CC-3 epitope was localized on the C-terminal end of the CTD and generated in vitro when the RPB1 subunit was phosphorylated by the TFIIH-associated kinase but not by another CTD kinase such as MAP kinase. In apparent discrepancy, the overall RPB1 subunit phosphorylation increased during heat-shock. The decreased activity in vivo of the TFIIH kinase might be compensated by a stress-activated CTD kinase such as MAP kinase. These results also suggest that heat-shock gene transcription may have a weak requirement for TFIIH kinase activity.

Heat-shock inactivation of the TFIIH-associated kinase and change in the phosphorylation sites on the C-terminal domain of RNA polymerase II.

PubMed Central

Dubois, M F; Vincent, M; Vigneron, M; Adamczewski, J; Egly, J M; Bensaude, O

1997-01-01

The C-terminal domain (CTD) of the RNA polymerase II largest subunit (RPB1) plays a central role in transcription. The CTD is unphosphorylated when the polymerase assembles into a preinitiation complex of transcription and becomes heavily phosphorylated during promoter clearance and entry into elongation of transcription. A kinase associated to the general transcription factor TFIIH, in the preinitiation complex, phosphorylates the CTD. The TFIIH-associated CTD kinase activity was found to decrease in extracts from heat-shocked HeLa cells compared to unstressed cells. This loss of activity correlated with a decreased solubility of the TFIIH factor. The TFIIH-kinase impairment during heat-shock was accompanied by the disappearance of a particular phosphoepitope (CC-3) on the RPB1 subunit. The CC-3 epitope was localized on the C-terminal end of the CTD and generated in vitro when the RPB1 subunit was phosphorylated by the TFIIH-associated kinase but not by another CTD kinase such as MAP kinase. In apparent discrepancy, the overall RPB1 subunit phosphorylation increased during heat-shock. The decreased activity in vivo of the TFIIH kinase might be compensated by a stress-activated CTD kinase such as MAP kinase. These results also suggest that heat-shock gene transcription may have a weak requirement for TFIIH kinase activity. PMID:9016617

The risk of cancer in patients with connective tissue diseases but without dermatomyositis or polymyositis: A multicenter cohort study conducted over 15 years in China.

PubMed

Xu, Wei; Guo, Huan; Liu, Zhi; Chen, Chen; Lei, Cong-Cong

2016-09-01

To investigate the relative risk of cancer in Chinese patients with connective tissue diseases (CTD) associated with and without dermatomyositis or polymyositis. A retrospective, multicenter cohort study investigated 32,380 CTD patients (2334 diagnosed with dermatomyositis or polymyositis) without a history of malignancies treated from January 1, 1997, to December 31, 2011. Standardized incidence ratios (SIR) of cancers determined the incidence of malignancies during follow-up. The data was compared with the cancer morbidity of the general population from the Chinese Cancer Registry Annual Report of National Central Cancer Registry. A total of 113 patients (348.98 per 100,000) developed cancer during follow-up, 75 (249.62 per 100,000) were patients with CTD without dermatomyositis or polymyositis. The risk of cancer among patients with CTD was increased (SIR=1.45, 95% confidence interval [CI] 1.22-1.71), and this risk increased with age (<40 years: SIR=1.00 [95%CI 0.45-2.21]; 41-60 years: SIR=1.53 [95%CI 1.17-2.00]; and >60 years SIR=2.34 (95%CI 0.93-2.77]) and the time of follow-up (<1year: SIR=1.22 [95%CI 0.88-1.70]; 1-5 years: SIR=1.14 [95%CI 0.79-1.65]; and 6-10 years SIR=1.70 [95%CI 1.34-2.85]), but was similar between genders (male SIR=1.60 [95%CI 1.10-2.31] and female SIR=1.25 [95%CI 1.01-1.55]). The cancer risk among CTD patients without dermatomyositis or polymyositis was not affected (SIR=0.93, 95%CI 0.75-1.16), regardless of gender, age, or follow-up. The cancer risk for patients with CTD without dermatomyositis or polymyositis was not increased or decreased, but it was increased when patients with dermatomyositis or polymyositis were included. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Using AnnAGNPS to Predict the Effects of Tile Drainage Control on Nutrient and Sediment Loads for a River Basin.

PubMed

Que, Z; Seidou, O; Droste, R L; Wilkes, G; Sunohara, M; Topp, E; Lapen, D R

2015-03-01

Controlled tile drainage (CTD) can reduce pollutant loading. The Annualized Agricultural Nonpoint Source model (AnnAGNPS version 5.2) was used to examine changes in growing season discharge, sediment, nitrogen, and phosphorus loads due to CTD for a ∼3900-km agriculturally dominated river basin in Ontario, Canada. Two tile drain depth scenarios were examined in detail to mimic tile drainage control for flat cropland: 600 mm depth (CTD) and 200 mm (CTD) depth below surface. Summed for five growing seasons (CTD), direct runoff, total N, and dissolved N were reduced by 6.6, 3.5, and 13.7%, respectively. However, five seasons of summed total P, dissolved P, and total suspended solid loads increased as a result of CTD by 0.96, 1.6, and 0.23%. The AnnAGNPS results were compared with mass fluxes observed from paired experimental watersheds (250, 470 ha) in the river basin. The "test" experimental watershed was dominated by CTD and the "reference" watershed by free drainage. Notwithstanding environmental/land use differences between the watersheds and basin, comparisons of seasonal observed and predicted discharge reductions were comparable in 100% of respective cases. Nutrient load comparisons were more consistent for dissolved, relative to particulate water quality endpoints. For one season under corn crop production, AnnAGNPS predicted a 55% decrease (CTD) in dissolved N from the basin. AnnAGNPS v. 5.2 treats P transport from a surface pool perspective, which is appropriate for many systems. However, for assessment of tile drainage management practices for relatively flat tile-dominated systems, AnnAGNPS may benefit from consideration of P and particulate transport in the subsurface. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Psychopathological Profile in Children with Chronic Tic Disorder and Co-Existing ADHD: Additive Effects

ERIC Educational Resources Information Center

Roessner, Veit; Becker, Andreas; Banaschewski, Tobias; Rothenberger, Aribert

2007-01-01

The nature of the co-occurrence of chronic tic disorders (CTD) and attention deficit hyperactivity disorder (ADHD) is unclear. Especially in the field of psychopathology, the relationship of CTD and ADHD remains to be clarified. Thus, the aim of the present chart review study was to specify the contribution of CTD and/or ADHD to the…

Evidence-based diuretics: focus on chlorthalidone and indapamide.

PubMed

DiNicolantonio, James J; Bhutani, Jaikrit; Lavie, Carl J; O'Keefe, James H

2015-03-01

Thiazide and thiazide-like diuretics are cornerstone treatments for hypertension. However, unlike chlorthalidone (CTD) and indapamide (IDP), hydrochlorothiazide (HCTZ) lacks evidence for reducing morbidity and mortality as monotherapy compared with placebo or control. Despite this fact, HCTZ is prescribed much more frequently than CTD or IDP. We believe that all hypertension guidelines should follow the National Institute for Health and Excellence (NICE) and make IDP and CTD first choice 'thiazide-like diuretics.' This article will focus on the available evidence pertaining to HCTZ versus CTD and IDP. We will review the pharmacological differences between these three diuretics, as well as the clinical trial data and important side effects.

Histopathology of lung disease in the connective tissue diseases.

PubMed

Vivero, Marina; Padera, Robert F

2015-05-01

The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD. Copyright © 2015 Elsevier Inc. All rights reserved.

cis-Proline-mediated Ser(P)[superscript 5] Dephosphorylation by the RNA Polymerase II C-terminal Domain Phosphatase Ssu72

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

Werner-Allen, Jon W.; Lee, Chul-Jin; Liu, Pengda

2012-05-16

RNA polymerase II coordinates co-transcriptional events by recruiting distinct sets of nuclear factors to specific stages of transcription via changes of phosphorylation patterns along its C-terminal domain (CTD). Although it has become increasingly clear that proline isomerization also helps regulate CTD-associated processes, the molecular basis of its role is unknown. Here, we report the structure of the Ser(P){sup 5} CTD phosphatase Ssu72 in complex with substrate, revealing a remarkable CTD conformation with the Ser(P){sup 5}-Pro{sup 6} motif in the cis configuration. We show that the cis-Ser(P){sup 5}-Pro{sup 6} isomer is the minor population in solution and that Ess1-catalyzed cis-trans-proline isomerizationmore » facilitates rapid dephosphorylation by Ssu72, providing an explanation for recently discovered in vivo connections between these enzymes and a revised model for CTD-mediated small nuclear RNA termination. This work presents the first structural evidence of a cis-proline-specific enzyme and an unexpected mechanism of isomer-based regulation of phosphorylation, with broad implications for CTD biology« less

Laparoscopic Antireflux Surgery in Patients with Connective Tissue Diseases.

PubMed

Menezes, Mariano A; Herbella, Fernando A M; Patti, Marco G

2016-04-01

Different connective tissue diseases (CTDs), such as dermatomyositis, mixed CTD, rheumatoid arthritis, polymyositis, lupus, and Behçet's, may affect the esophagus, impairing its motor function. The muscular atrophy and fibrosis caused by the autoimmune vasculitis and neuronal dysfunction affect the esophageal body and the lower esophageal sphincter, leading to a clinical presentation of dysphagia and gastroesophageal reflux disease (GERD). The belief that the impaired esophageal motility may negatively affect surgical outcome has led to the common recommendation of avoiding laparoscopic antireflux surgery (LARS) for fear of creating or worsening dysphagia. This review focuses on the evaluation of the outcome of LARS in patients with CTD. Specifically, this review shows that the literature on LARS and CTDs is scarce and most studies have a small number of patients and a short follow-up. Furthermore, a subanalysis of the outcome based on the type of CTD or the manometric profile is still elusive. In the setting of these limitations, it appears that results are good and comparable to those of patients with GERD and without a CTD. Morbidity and mortality are insignificant even considering the systemic manifestations of the CTD. LARS should not be denied to patients with CTD and GERD.

Clinical Correlates and Mediators of Self-Concept in Youth with Chronic Tic Disorders.

PubMed

Hanks, Camille E; McGuire, Joseph F; Lewin, Adam B; Storch, Eric A; Murphy, Tanya K

2016-02-01

This study investigated the clinical correlates and mediators of self-concept in youth with Chronic Tic Disorders (CTD). Ninety-seven youth aged 6-17 (M = 11.1 ± 2.89; 79.4 % male) with CTD were administered the Yale Global Tic Severity Scale, the Piers-Harris Children's Self-Concept Scale-Second Edition, and self-report and clinician-administered measures assessing behavioral and psychological difficulties and comorbid conditions. Youth with CTD had a slightly below average level of self-concept, with 20 % (n = 19) exhibiting low self-concept. Youth with CTD-only had greater self-concept relative to youth with CTD and obsessive-compulsive disorder (OCD) (p = 0.04) or CTD, OCD, and attention deficit hyperactivity disorder (ADHD) combined (p = 0.009). Medium-to-large-sized associations were observed between youth's self-concept and clinical characteristics (e.g., severity of ADHD, OCD and depressive symptoms). Youth's self-concept partially mediated the relationship between tic severity and depressive symptom severity, and the interaction between tic impairment and youth's reliance on avoidant coping strategies moderated youth's self-concept. Implications, limitations, and recommendations for future interventions are discussed.

Clinical Correlates and Mediators of Self-Concept in Youth with Chronic Tic Disorders

PubMed Central

Hanks, Camille E.; McGuire, Joseph F.; Lewin, Adam B.; Storch, Eric A.

2015-01-01

This study investigated the clinical correlates and mediators of self-concept in youth with Chronic Tic Disorders (CTD). Ninety-seven youth aged 6–17 (M = 11.1 ± 2.89; 79.4 % male) with CTD were administered the Yale Global Tic Severity Scale, the Piers-Harris Children’s Self-Concept Scale—Second Edition, and self-report and clinician-administered measures assessing behavioral and psychological difficulties and comorbid conditions. Youth with CTD had a slightly below average level of self-concept, with 20 % (n = 19) exhibiting low self-concept. Youth with CTD-only had greater self-concept relative to youth with CTD and obsessive–compulsive disorder (OCD) (p = 0.04) or CTD, OCD, and attention deficit hyperactivity disorder (ADHD) combined (p = 0.009). Medium-to-large-sized associations were observed between youth’s self-concept and clinical characteristics (e.g., severity of ADHD, OCD and depressive symptoms). Youth’s self-concept partially mediated the relationship between tic severity and depressive symptom severity, and the interaction between tic impairment and youth’s reliance on avoidant coping strategies moderated youth’s self-concept. Implications, limitations, and recommendations for future interventions are discussed. PMID:25791488

Chromatin Condensing Functions of the Linker Histone C-terminal Domain are mediated by Specific Amino Acid Composition and Intrinsic Protein Disorder†

PubMed Central

Lu, Xu; Hamkalo, Barbara; Parseghian, Missag H.; Hansen, Jeffrey C.

2009-01-01

Linker histones bind to the nucleosomes and linker DNA of chromatin fibers, causing changes in linker DNA structure and stabilization of higher order folded and oligomeric chromatin structures. Linker histones affect chromatin structure acting primarily through their ~100 residue C-terminal domain (CTD). We have previously shown that the ability of the linker histone H1° to alter chromatin structure was localized to two discontinuous 24-/25-residue CTD regions (Lu, X., and Hansen, J. C. (2004) J Biol Chem 279, 8701–8707). To determine the biochemical basis for these results, we have characterized chromatin model systems assembled with endogenous mouse somatic H1 isoforms, or recombinant H1° CTD mutants in which the primary sequence has been scrambled, the amino acid composition mutated, or the location of various CTD regions swapped. Our results indicate that specific amino acid composition plays a fundamental role in molecular recognition and function by the H1 CTD. Additionally, these experiments support a new molecular model for CTD function, and provide a biochemical basis for the redundancy observed in H1 isoform knockout experiments in vivo. PMID:19072710

Relationship between cognitive and non-cognitive symptoms of delirium.

PubMed

Rajlakshmi, Aarya Krishnan; Mattoo, Surendra Kumar; Grover, Sandeep

2013-04-01

To study relationship between the cognitive and the non-cognitive symptoms of delirium. Eighty-four patients referred to psychiatry liaison services and met DSM-IVTR criteria of delirium were assessed using the Delirium Rating Scale Revised-1998 (DRSR-98) and Cognitive Test for Delirium (CTD). The mean DRS-R-98 severity score was 17.19 and DRS-R-98 total score was 23.36. The mean total score on CTD was 11.75. The mean scores on CTD were highest for comprehension (3.47) and lowest for vigilance (1.71). Poor attention was associated with significantly higher motor retardation and higher DRS-R-98 severity scores minus the attention scores. There were no significant differences between those with and without poor attention. Higher attention deficits were associated with higher dysfunction on all other domains of cognition on CTD. There was significant correlation between cognitive functions as assessed on CTD and total DRS-R-98 score, DRS-R-98 severity score and DRS-R-98 severity score without the attention item score. However, few correlations emerged between CTD domains and CTD total scores with cognitive symptom total score of DRS-R-98 (items 9-13) and non-cognitive symptom total score of DRS-R-98 (items 1-8). Our study suggests that in delirium, cognitive deficits are quite prevalent and correlate with overall severity of delirium. Attention deficit is a core symptom of delirium. Copyright © 2012 Elsevier B.V. All rights reserved.

Top-Down Charge Transfer Dissociation (CTD) of Gas-Phase Insulin: Evidence of a One-Step, Two-Electron Oxidation Mechanism

NASA Astrophysics Data System (ADS)

Li, Pengfei; Kreft, Iris; Jackson, Glen P.

2018-02-01

Top-down analyses of protonated insulin cations of charge states of 4+, 5+, or 6+ were performed by exposing the isolated precursor ions to a beam of helium cations with kinetic energy of more than 6 keV, in a technique termed charge transfer dissociation (CTD). The 100 ms charge transfer reaction resulted in approximately 20% conversion efficiency to other intact charge exchange products (CTnoD), and a range of low abundance fragment ions. To increase backbone and sulfide cleavages, and to provide better structural information than straightforward MS2 CTD, the CTnoD oxidized products were isolated and subjected to collisional activation at the MS3 level. The MS3 CTD/CID reaction effectively broke the disulfide linkages, separated the two chains, and yielded more structurally informative fragment ions within the inter-chain cyclic region. CTD also provided doubly oxidized intact product ions at the MS2 level, and resonance ejection of the singly oxidized product ion revealed that the doubly oxidized product originates directly from the isolated precursor ion and not from consecutive CTD reactions of a singly oxidized intermediate. MS4 experiments were employed to help identify potential radical cations and diradical cations, but the results were negative or inconclusive. Nonetheless, the two-electron oxidation process is a demonstration of the very large potential energy (>20 eV) available through CTD, and is a notable capability for a 3D ion trap platform.

Better care provided to patients with tuberculosis at county designated TB hospitals (CTD) compared to non-CTDs in rural China.

PubMed

Yuan, Li; Zhang, Hui; Zhou, Changming; Jiang, Weili; Zhao, Qi; Biao, Xu

2017-01-13

The primary unit of tuberculosis (TB) medical care in China is the county TB dispensary or county designated hospital (CTD), where patients can receive free diagnosis and treatment. However, a substantial number of patients seek their anti-TB treatment from general health facilities (Non-CTDs). This study aimed to investigate the first anti-TB treatment experience and choice of health facilities of retreated TB patients and their determinants. A cross-sectional study was conducted in Jiangsu, Shandong and Sichuan provinces. All registered re-treated TB patients were investigated using a structured questionnaire covering information on demographics, socio-economic characteristics, and previous anti-TB treatment experiences. Totally, 75.3% of 544 patients visited CTD directly for initial treatment. Patients who were female (OR:1.71, 95% CI: 1.01-2.87), over 40 years of age (OR:2.80, 95% CI: 1.24-6.33), from Jiangsu (OR:3.07, 95% CI: 1.57-6.01) and Sichuan (OR:4.47, 95% CI: 2.29-8.73) and those diagnosed before 2005 (OR:6.87, 95% CI: 4.24-11.13) had a significant higher risk receiving their initial treatment at a non-CTD. Patients were more likely to have standardized diagnosis and treatment regimens in CTD (89.8%) than in non-CTDs (65.9%). Patients treated in non-CTDs versus in CTD had a lower possibility to complete their treatment course during first TB episode (χ 2  = 3.926, P = 0.048), but there was no significant difference in the cure rate between different facilities (CTD 60.8%, Non-CTDs 59.1%). Patients in non-CTDs incurred higher costs (1,360 CNY) than those treated in CTD (920CNY). CTD play a key role in the National Tuberculosis Control Program. Patients should be guided to seek health care in county designated hospital, where they are more likely to receive appropriate examinations, treatment regimens and rigorous supervision, and to bear a lighter economic burden.

Efficacy and toxicity of the combination chemotherapy of thalidomide, alkylating agent, and steroid for relapsed/refractory myeloma patients: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study.

PubMed

Kwon, Jihyun; Min, Chang-Ki; Kim, Kihyun; Han, Jae-Joon; Moon, Joon Ho; Kang, Hye Jin; Eom, Hyeon-Seok; Kim, Min Kyoung; Kim, Hyo Jung; Yoon, Dok Hyun; Lee, Jeong-Ok; Lee, Won Sik; Lee, Jae Hoon; Lee, Je-Jung; Choi, Yoon-Seok; Kim, Sung Hyun; Yoon, Sung-Soo

2017-01-01

We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35.9%) patients. The response rate overall was 69.4%. Patients who were not treated with bortezomib and lenalidomide before TAS showed a higher response rate compared to those who were exposed to these agents. The estimated median progression-free survival and overall survival times were 10.4 months and 28.0 months, respectively. The adverse events during TAS were generally tolerable, but 39 (10.4%) patients experienced severe infectious complications. There were no differences in terms of efficacy between CTD and MTP, but infectious complications were more common in CTD group. TAS is an effective treatment regimen which induces a high response rate in relapsed or refractory multiple myeloma patients. Due to the high incidence of grade 3 or 4 infection, proper management of infection is necessary during the TAS treatment, especially the CTD. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

[Morphological features of the myometrium in connective tissue dysplasia in women with uterine inertia].

PubMed

Konovalov, P V; Mitrofanova, L B; Gorshkov, A N; Ovsyannikov, F A

2015-01-01

to reveal the morphological features of the lower uterine segment myometrium in connective tissue dysplasia (CTD) in women with uterine inertia. Histological, immunohistochemical (with antibodies against collagen types I and III, matrix metalloproteinases 1 and 9 (MMR-1, MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), fibronectin; fibulin-5, connexin-43), electron microscopic, and electron immunocytochemical studies with morphometry of myometrial fragments from 15 parturient women with CTD and uterine inertia (a study group) and those from 10 women without CTD (a control group). The myometrium in CTD exhibited the decreased expression of connextin-43, fibulin-5, TIMP-1, collagens types I and III with collagen type III predominance and the unchanged levels of fibronectin and MMP-1 and MMP-9. Electron microscopy and immunocytochemistry showed fewer intercellular contacts and the dramatically lower expression of connexin-43 than in the control. A set of found myometrial changes in women with uterine inertia is a manifestation of CTD.

Workplace discrimination and cumulative trauma disorders: the national EEOC ADA research project.

PubMed

Armstrong, Amy J; McMahon, Brian T; West, Steven L; Lewis, Allen

2005-01-01

Employment discrimination of persons with cumulative trauma disorders (CTDs) was explored using the Integrated Mission System dataset of the US Equal Employment Opportunity Commission. Demographic characteristics and merit resolutions of the Charging Parties (persons with CTD) were compared to individuals experiencing other physical, sensory and neurological impairments. Factors compared also included industry designation, geographic region, and size of Respondents against which allegations were filed. Persons with CTD had proportionately greater allegations among large Respondents (greater than 500 workers) engaged in manufacturing, utilities, transportation, finance insurance and real estate. The types of discrimination Issues that were proportionately greater in the CTD group included layoff, failure to reinstate, and failure to provide reasonable accommodation. The CTD group was significantly less likely than the comparison group to be involved in discrimination Issues such as assignment to less desirable duty, shift or work location; demotion; termination, or failure to hire or provide training. Persons with CTD had higher proportions of merit Resolutions where allegations were voluntarily withdrawn by the Charging Party with benefits.

Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases.

PubMed

Saketkoo, Lesley Ann; Mittoo, Shikha; Frankel, Sid; LeSage, Daphne; Sarver, Catherine; Phillips, Kristine; Strand, Vibeke; Matteson, Eric L

2014-04-01

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Analysis of the MRPL3, DNAJC13 and OFCC1 variants in Chinese Han patients with TS-CTD.

PubMed

Guo, Yi; Deng, Xiong; Zhang, Jie; Su, Linyan; Xu, Hongbo; Luo, Ziqiang; Deng, Hao

2012-05-23

Tourette syndrome/chronic tic phenotype (TS-CTD) is a neurological disorder manifested particularly by motor and vocal tics and associated with a variety of behavioral abnormalities. Recently, the mitochondrial ribosomal protein L3 gene (MRPL3) S75N, the DnaJ (Hsp40) homolog subfamily C member 13 gene (DNAJC13) A2057S, the orofacial cleft 1 candidate 1 gene (OFCC1) R129G and c.-5A>G variants are reported to be associated with Tourette syndrome/chronic tic phenotype (TS-CTD) in patients of European ancestry. To evaluate whether these variants are associated with TS-CTD in Chinese Han patients, we screened 132 Chinese Han patients from Mainland China. None of the 132 samples from patients with TS-CTD showed the MRPL3 S75N, DNAJC13 A2057S, OFCC1 R129G and c.-5A>G variants, and these variants probably are a rare cause of TS-CTD in a Chinese Han ethnic group. Genetic heterogeneity of TS should be considered and tests designed to detect these variants in Chinese Han ethnic group probably will not have a diagnostic utility in clinical practice. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Analysis of the antibacterial activity and plaque control benefit of colgate total dentifrice via clinical evaluation and real-time polymerase chain reaction.

PubMed

Xu, Tao; Deshmukh, Meenal; Barnes, Virginia Monsul; Trivedi, Harsh M; Du-Thumm, Laurence; Richter, Rose; Cummins, Diane

2005-01-01

This study analyzed, from a combined clinical and molecular biologic perspective, the antibacterial and antiplaque efficacy of Colgate Total dentifrice (CTD). A single-blind crossover study design utilized 11 healthy human subjects. After a one-week washout period, subjects donated dental plaque, received a dental prophylaxis, and subsequently brushed with a test product. Twenty-four hours postbrushing, dental plaque was collected and a clinical plaque score determined. Dental plaque was submitted for Real-time Polymerase Chain Reaction (Real-time PCR) analysis. The same procedure was repeated in accordance with a crossover design for the use of the second test product. Following a one-week washout, a plaque donation, prophylaxis, and brushing with the test product ensued for each subject. Twenty-four hours post-brushing, the subjects returned for a plaque score and plaque donation. Twenty-four hours after brushing, dental plaque coverage increased 17.88% +/- 8.27% with CTD, compared to 30.42% +/- 9.97% with Colgate Cavity Protection (CCP; p = 0.005). Real-time PCR found plaque collected 24 hours after brushing with CTD exhibited, on average, fewer representative periodontal pathogens (Fusobacterium nucleatum, Actinobacillus actinomycetemcomitans, Tannerella forsythensis, and Porphyromonas gingivalis) and fewer early colonizers (Actinomyces naeslundii) than plaque collected before brushing, whereas CCP showed a moderate effect on oral bacteria. The study provides clinical and molecular biological evidence to substantiate the antibacterial and plaque control benefits of Colgate Total, and suggests the value of combining a molecular biological method with clinical research to corroborate clinical benefits.

Self-esteem in adults with Tourette syndrome and chronic tic disorders: The roles of tic severity, treatment, and comorbidity.

PubMed

Weingarden, Hilary; Scahill, Lawrence; Hoeppner, Susanne; Peterson, Alan L; Woods, Douglas W; Walkup, John T; Piacentini, John; Wilhelm, Sabine

2018-07-01

Tourette syndrome (TS) and chronic tic disorders (CTD) are stigmatizing disorders that may significantly impact self-esteem. Alternatively, comorbid psychiatric illnesses may affect self-esteem more than tics themselves. Extant research on self-esteem in TS/CTD is limited, has inconsistently examined the effect of comorbidities on self-esteem, and yields mixed findings. This study aimed to clarify the roles of tics versus comorbid diagnoses on self-esteem in a large, carefully diagnosed sample of adults with TS/CTD (N = 122) receiving 10 weeks of Comprehensive Behavioral Intervention for Tics (CBIT) or Psychoeducation and Supportive Therapy (PST). Baseline self-esteem did not differ between adults with TS/CTD only and normative means, whereas self-esteem was significantly lower among adults with TS/CTD with a comorbid psychiatric illness. In a multiple regression testing the baseline association between tic severity, presence of comorbid psychiatric illness, and depression severity with self-esteem, comorbidity and depression severity were significantly associated with self-esteem, whereas tic severity was not. Finally, using a generalized linear model, we tested the effects of treatment assignment, comorbidity, and their interaction on changes in self-esteem across treatment, controlling for baseline depression severity. Results showed that for those with a comorbid illness, self-esteem improved significantly more with CBIT than with PST. Comorbid illnesses appear to affect self-esteem more so than tics among adults with TS/CTD. Therapeutic attention should be paid to treating comorbid diagnoses alongside tics when treating TS/CTD. Copyright © 2018 Elsevier Inc. All rights reserved.

A Structured and Unstructured grid Relocatable ocean platform for Forecasting (SURF)

NASA Astrophysics Data System (ADS)

Trotta, Francesco; Fenu, Elisa; Pinardi, Nadia; Bruciaferri, Diego; Giacomelli, Luca; Federico, Ivan; Coppini, Giovanni

2016-11-01

We present a numerical platform named Structured and Unstructured grid Relocatable ocean platform for Forecasting (SURF). The platform is developed for short-time forecasts and is designed to be embedded in any region of the large-scale Mediterranean Forecasting System (MFS) via downscaling. We employ CTD data collected during a campaign around the Elba island to calibrate and validate SURF. The model requires an initial spin up period of a few days in order to adapt the initial interpolated fields and the subsequent solutions to the higher-resolution nested grids adopted by SURF. Through a comparison with the CTD data, we quantify the improvement obtained by SURF model compared to the coarse-resolution MFS model.

Cumulative trauma disorders among apparel manufacturing employees in the southeastern United States.

PubMed

Dignan, M; Hayes, D; Main, H; Parker, K

1996-11-01

Factors associated with cumulative trauma disorders (CTDs) of the upper extremities were studied retrospectively, using data from three apparel manufacturing plants in the southeastern United States. Reported CTDs among the employees at risk during fiscal years 1991 and 1992 were analyzed focusing on individual and plant variables. Results showed that CTD rates increased from 1991 to 1992 and fluctuated in a cyclical pattern each year, peaking during January, March, and August. Employee age and duration of employment were associated with CTD rates. Employees aged 45 to 49 had higher CTD rates than those in any other age groups. Employees with 1 to 3 years' experience had higher CTD rates than employees with more years of service.

Analyzing Conductivity Profiles in Stream Waters Influenced by Mine Water Discharges

NASA Astrophysics Data System (ADS)

Räsänen, Teemu; Hämäläinen, Emmy; Hämäläinen, Matias; Turunen, Kaisa; Pajula, Pasi; Backnäs, Soile

2015-04-01

Conductivity is useful as a general measure of stream water quality. Each stream inclines to have a quite constant range of conductivity that can be used as a baseline for comparing and detecting influence of contaminant sources. Conductivity in natural streams and rivers is affected primarily by the geology of the watershed. Thus discharges from ditches and streams affect not only the flow rate in the river but also the water quality and conductivity. In natural stream waters, the depth and the shape of the river channel change constantly, which changes also the water flow. Thus, an accurate measuring of conductivity or other water quality indicators is difficult. Reliable measurements are needed in order to have holistic view about amount of contaminants, sources of discharges and seasonal variation in mixing and dilution processes controlling the conductivity changes in river system. We tested the utility of CastAway-CTD measuring device (SonTek Inc) to indicate the influence of mine waters as well as mixing and dilution occurring in the recipient river affected by treated dewatering and process effluent water discharges from a Finnish gold mine. The CastAway-CTD measuring device is a small, rugged and designed for profiling of depths of up to 100m. Device measures temperature, salinity, conductivity and sound of speed using 5 Hz response time. It has also built-in GPS which produces location information. CTD casts are normally used to produce vertical conductivity profile for rather deep waters like seas or lakes. We did seasonal multiple Castaway-CTD measurements during 2013 and 2014 and produced scaled vertical and horizontal profiles of conductivity and water temperature at the river. CastAway-CTD measurement pinpoints how possible contaminants behave and locate in stream waters. The conductivity profiles measured by CastAway-CTD device show the variation in maximum conductivity values vertically in measuring locations and horizontally in measured cross-sections. The data from field measurements was combined with detailed water quality analysis and processed by data analysis with Matlab to produce more holistic information about the behavior, mixing and dilution of possible contaminants at the river. Moreover, the results can be used to improve water sampling procedures for more representative sampling and to plan continuous monitoring site locations and measuring device mounting places.

Suicide in Tourette's and Chronic Tic Disorders.

PubMed

Fernández de la Cruz, Lorena; Rydell, Mina; Runeson, Bo; Brander, Gustaf; Rück, Christian; D'Onofrio, Brian M; Larsson, Henrik; Lichtenstein, Paul; Mataix-Cols, David

2017-07-15

Persons with neuropsychiatric disorders are at increased risk of suicide, but there is little data concerning Tourette's and chronic tic disorders (TD/CTD). We aimed to quantify the risk of suicidal behavior in a large nationwide cohort of patients with TD/CTD, establish the contribution of psychiatric comorbidity to this risk, and identify predictors of suicide. Using a validated algorithm, we identified 7736 TD/CTD cases in the Swedish National Patient Register during a 44-year period (1969-2013). Using a matched case-cohort design, patients were compared with general population control subjects (1:10 ratio). Risk of suicidal behavior was estimated using conditional logistic regressions. Predictors of suicidal behavior in the TD/CTD cohort were studied using Cox regression models. In unadjusted models, TD/CTD patients, compared with control subjects, had an increased risk of both dying by suicide (odds ratio: 4.39; 95% confidence interval [CI]: 2.89-6.67) and attempting suicide (odds ratio: 3.86; 95% CI: 3.50-4.26). After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial. Persistence of tics beyond young adulthood and a previous suicide attempt were the strongest predictors of death by suicide in TD/CTD patients (hazard ratio: 11.39; 95% CI: 3.71-35.02, and hazard ratio: 5.65; 95% CI: 2.21-14.42, respectively). TD/CTD are associated with substantial risk of suicide. Suicidal behavior should be monitored in these patients, particularly in those with persistent tics, history of suicide attempts, and psychiatric comorbidities. Preventive and intervention strategies aimed to reduce the suicidal risk in this group are warranted. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Lysines in the RNA Polymerase II C-Terminal Domain Contribute to TAF15 Fibril Recruitment.

PubMed

Janke, Abigail M; Seo, Da Hee; Rahmanian, Vahid; Conicella, Alexander E; Mathews, Kaylee L; Burke, Kathleen A; Mittal, Jeetain; Fawzi, Nicolas L

2018-05-01

Many cancer-causing chromosomal translocations result in transactivating protein products encoding FET family (FUS, EWSR1, TAF15) low-complexity (LC) domains fused to a DNA binding domain from one of several transcription factors. Recent work demonstrates that higher-order assemblies of FET LC domains bind the carboxy-terminal domain of the large subunit of RNA polymerase II (RNA pol II CTD), suggesting FET oncoproteins may mediate aberrant transcriptional activation by recruiting RNA polymerase II to promoters of target genes. Here we use nuclear magnetic resonance (NMR) spectroscopy and hydrogel fluorescence microscopy localization and fluorescence recovery after photobleaching to visualize atomic details of a model of this process, interactions of RNA pol II CTD with high-molecular weight TAF15 LC assemblies. We report NMR resonance assignments of the intact degenerate repeat half of human RNA pol II CTD alone and verify its predominant intrinsic disorder by molecular simulation. By measuring NMR spin relaxation and dark-state exchange saturation transfer, we characterize the interaction of RNA pol II CTD with amyloid-like hydrogel fibrils of TAF15 and hnRNP A2 LC domains and observe that heptads far from the acidic C-terminal tail of RNA pol II CTD bind TAF15 fibrils most avidly. Mutation of CTD lysines in heptad position 7 to consensus serines reduced the overall level of TAF15 fibril binding, suggesting that electrostatic interactions contribute to complex formation. Conversely, mutations of position 7 asparagine residues and truncation of the acidic tail had little effect. Thus, weak, multivalent interactions between TAF15 fibrils and heptads throughout RNA pol II CTD collectively mediate complex formation.

LONG-TERM EFFECTS OF CHLORTHALIDONE VS HYDROCHLOROTHIAZIDE ON ELECTROCARDIOGRAPHIC LEFT VENTRICULAR HYPERTROPHY IN THE MULTIPLE RISK FACTOR INTERVENTION TRIAL

PubMed Central

Ernst, Michael E.; Neaton, James D.; Grimm, Richard H.; Collins, Gary; Thomas, William; Soliman, Elsayed Z.; Prineas, Ronald J.

2011-01-01

Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy (LVH) is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial (MRFIT), which randomly assigned 8,012 hypertensive men to special intervention (SI) or usual care (UC). SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part, because higher mortality was observed for SI compared to UC participants in H-clinics, while the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic LVH using both an ecologic analysis by previously-reported C- or H-clinic groupings, and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and UC in LVH were larger for C-clinics compared to H-clinics (Sokolow-Lyon: −93.9 vs −54.9 μV, P=0.049; Cornell voltage: −68.1 vs −35.9 μV, P=0.019; Cornell voltage product: −4.6 vs −2.2 μV/ms, P=0.071; left ventricular mass: −4.4 vs −2.8 gm, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared to HCTZ through 48 months and 84 months of follow-up. Our findings on LVH support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in MRFIT. PMID:22025372

Comparison of cyclophosphamide-thalidomide-dexamethasone to bortezomib-cyclophosphamide-dexamethasone as induction therapy for multiple myeloma patients in Brazil.

PubMed

Vigolo, Suelen; Zuckermann, Joice; Bittencourt, Rosane Isabel; Silla, Lúcia; Pilger, Diogo André

2017-09-01

Chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) remains the standard treatment for multiple myeloma (MM). Thalidomide or bortezomib may be combined with cyclophosphamide and dexamethasone, in what are known as the CTD and VCD protocols, respectively. The objective of this study was to evaluate the clinical characteristics and response rates obtained with CTD and VCD, observing whether the inclusion of bortezomib to treat MM patients in Brazil increases therapeutic efficiency. Forty-three MM patients treated with induction protocols CTD and VCD between January 2010 and March 2015 were included. The parameters analyzed were staging, frequency of comorbidities prior to treatment, response rates obtained at each induction cycle, progression-free survival, and overall survival of patients. Very good partial response and complete response obtained with the VCD protocol were superior, compared with the CTD treatment. The presence of comorbidities was similar in the two groups, except kidney failure, which prevailed in the VCD group. Also, 78.3% and 48.3% of patients treated with the VCD and CTD protocols underwent autologous HSCT, respectively. In patients given the VCD protocol, 45.5% had complete response before autologous HSCT. Among those given CTD, this number was only 7.1% (p=0.023). Disease progression after autologous HSCT did not differ between the two groups. VCD afforded better responses than the CTD protocol, and improved patient condition before autologous HSCT. However, more studies are necessary including more patients and addressing various clinical conditions, besides the analysis of cost-effectiveness of these treatments. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Cdc15 Phosphorylates the C-terminal Domain of RNA Polymerase II for Transcription during Mitosis.

PubMed

Singh, Amit Kumar; Rastogi, Shivangi; Shukla, Harish; Asalam, Mohd; Rath, Srikanta Kumar; Akhtar, Md Sohail

2017-03-31

In eukaryotes, the basal transcription in interphase is orchestrated through the regulation by kinases (Kin28, Bur1, and Ctk1) and phosphatases (Ssu72, Rtr1, and Fcp1), which act through the post-translational modification of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II. The CTD comprises the repeated Tyr-Ser-Pro-Thr-Ser-Pro-Ser motif with potential epigenetic modification sites. Despite the observation of transcription and periodic expression of genes during mitosis with entailing CTD phosphorylation and dephosphorylation, the associated CTD specific kinase(s) and its role in transcription remains unknown. Here we have identified Cdc15 as a potential kinase phosphorylating Ser-2 and Ser-5 of CTD for transcription during mitosis in the budding yeast. The phosphorylation of CTD by Cdc15 is independent of any prior Ser phosphorylation(s). The inactivation of Cdc15 causes reduction of global CTD phosphorylation during mitosis and affects the expression of genes whose transcript levels peak during mitosis. Cdc15 also influences the complete transcription of clb2 gene and phosphorylates Ser-5 at the promoter and Ser-2 toward the 3' end of the gene. The observation that Cdc15 could phosphorylate Ser-5, as well as Ser-2, during transcription in mitosis is in contrast to the phosphorylation marks put by the kinases in interphase (G 1 , S, and G 2 ), where Cdck7/Kin28 phosphorylates Ser-5 at promoter and Bur1/Ctk1 phosphorylates Ser-2 at the 3' end of the genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Long-Term Monitoring of Waterborne Pathogens and Microbial Source Tracking Markers in Paired Agricultural Watersheds under Controlled and Conventional Tile Drainage Management

PubMed Central

Wilkes, Graham; Brassard, Julie; Edge, Thomas A.; Gannon, Victor; Gottschall, Natalie; Jokinen, Cassandra C.; Jones, Tineke H.; Khan, Izhar U. H.; Marti, Romain; Sunohara, Mark D.; Topp, Edward

2014-01-01

Surface waters from paired agricultural watersheds under controlled tile drainage (CTD) and uncontrolled tile drainage (UCTD) were monitored over 7 years in order to determine if there was an effect of CTD (imposed during the growing season) on occurrences and loadings of bacterial and viral pathogens, coliphages, and microbial source tracking markers. There were significantly lower occurrences of human, ruminant, and livestock (ruminant plus pig) Bacteroidales markers in the CTD watershed in relation to the UCTD watershed. As for pathogens, there were significantly lower occurrences of Salmonella spp. and Arcobacter spp. in the CTD watershed. There were no instances where there were significantly higher quantitative loadings of any microbial target in the CTD watershed, except for F-specific DNA (F-DNA) and F-RNA coliphages, perhaps as a result of fecal inputs from a hobby farm independent of the drainage practice treatments. There was lower loading of the ruminant marker in the CTD watershed in relation to the UCTD system, and results were significant at the level P = 0.06. The odds of Salmonella spp. occurring increased when a ruminant marker was present relative to when the ruminant marker was absent, yet for Arcobacter spp., the odds of this pathogen occurring significantly decreased when a ruminant marker was present relative to when the ruminant marker was absent (but increased when a wildlife marker was present relative to when the wildlife marker was absent). Interestingly, the odds of norovirus GII (associated with human and swine) occurring in water increased significantly when a ruminant marker was present relative to when a ruminant marker was absent. Overall, this study suggests that fecal pollution from tile-drained fields to stream could be reduced by CTD utilization. PMID:24727274

Specific threonine-4 phosphorylation and function of RNA polymerase II CTD during M phase progression

PubMed Central

Hintermair, Corinna; Voß, Kirsten; Forné, Ignasi; Heidemann, Martin; Flatley, Andrew; Kremmer, Elisabeth; Imhof, Axel; Eick, Dirk

2016-01-01

Dynamic phosphorylation of Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 heptad-repeats in the C-terminal domain (CTD) of the large subunit coordinates progression of RNA polymerase (Pol) II through the transcription cycle. Here, we describe an M phase-specific form of Pol II phosphorylated at Thr4, but not at Tyr1, Ser2, Ser5, and Ser7 residues. Thr4 phosphorylated Pol II binds to centrosomes and midbody and interacts with the Thr4-specific Polo-like kinase 1. Binding of Pol II to centrosomes does not require the CTD but may involve subunits of the non-canonical R2TP-Prefoldin-like complex, which bind to and co-localize with Pol II at centrosomes. CTD Thr4 mutants, but not Ser2 and Ser5 mutants, display severe mitosis and cytokinesis defects characterized by multipolar spindles and polyploid cells. We conclude that proper M phase progression of cells requires binding of Pol II to centrosomes to facilitate regulation of mitosis and cytokinesis in a CTD Thr4-P dependent manner. PMID:27264542

Specific threonine-4 phosphorylation and function of RNA polymerase II CTD during M phase progression.

PubMed

Hintermair, Corinna; Voß, Kirsten; Forné, Ignasi; Heidemann, Martin; Flatley, Andrew; Kremmer, Elisabeth; Imhof, Axel; Eick, Dirk

2016-06-06

Dynamic phosphorylation of Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 heptad-repeats in the C-terminal domain (CTD) of the large subunit coordinates progression of RNA polymerase (Pol) II through the transcription cycle. Here, we describe an M phase-specific form of Pol II phosphorylated at Thr4, but not at Tyr1, Ser2, Ser5, and Ser7 residues. Thr4 phosphorylated Pol II binds to centrosomes and midbody and interacts with the Thr4-specific Polo-like kinase 1. Binding of Pol II to centrosomes does not require the CTD but may involve subunits of the non-canonical R2TP-Prefoldin-like complex, which bind to and co-localize with Pol II at centrosomes. CTD Thr4 mutants, but not Ser2 and Ser5 mutants, display severe mitosis and cytokinesis defects characterized by multipolar spindles and polyploid cells. We conclude that proper M phase progression of cells requires binding of Pol II to centrosomes to facilitate regulation of mitosis and cytokinesis in a CTD Thr4-P dependent manner.

Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization.

PubMed

Gong, Xin; Qian, Hongwu; Shao, Wei; Li, Jingxian; Wu, Jianping; Liu, Jun-Jie; Li, Wenqi; Wang, Hong-Wei; Espenshade, Peter; Yan, Nieng

2016-11-01

Sterol regulatory element-binding protein (SREBP) transcription factors are master regulators of cellular lipid homeostasis in mammals and oxygen-responsive regulators of hypoxic adaptation in fungi. SREBP C-terminus binds to the WD40 domain of SREBP cleavage-activating protein (SCAP), which confers sterol regulation by controlling the ER-to-Golgi transport of the SREBP-SCAP complex and access to the activating proteases in the Golgi. Here, we biochemically and structurally show that the carboxyl terminal domains (CTD) of Sre1 and Scp1, the fission yeast SREBP and SCAP, form a functional 4:4 oligomer and Sre1-CTD forms a dimer of dimers. The crystal structure of Sre1-CTD at 3.5 Å and cryo-EM structure of the complex at 5.4 Å together with in vitro biochemical evidence elucidate three distinct regions in Sre1-CTD required for Scp1 binding, Sre1-CTD dimerization and tetrameric formation. Finally, these structurally identified domains are validated in a cellular context, demonstrating that the proper 4:4 oligomeric complex formation is required for Sre1 activation.

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

PubMed Central

Gago-Fuentes, Raquel; Bechberger, John F.; Varela-Eirin, Marta; Varela-Vazquez, Adrian; Acea, Benigno; Fonseca, Eduardo

2016-01-01

Chondrocytes in cartilage and bone cells population express connexin43 (Cx43) and gap junction intercellular communication (GJIC) is essential to synchronize cells for coordinated electrical, mechanical, metabolic and chemical communication in both tissues. Reduced Cx43 connectivity decreases chondrocyte differentiation and defective Cx43 causes skeletal defects. The carboxy terminal domain (CTD) of Cx43 is located in the cytoplasmic side and is key for protein functions. Here we demonstrated that chondrocytes from the CTD-deficient mice, K258stop/Cx43KO and K258stop/K258stop, have reduced GJIC, increased rates of proliferation and reduced expression of collagen type II and proteoglycans. We observed that CTD-truncated mice were significantly smaller in size. Together these results demonstrated that the deletion of the CTD negatively impacts cartilage structure and normal chondrocyte phenotype. These findings suggest that the proteolytic cleavage of the CTD under pathological conditions, such as under the activation of metalloproteinases during tissue injury or inflammation, may account for the deleterious effects of Cx43 in cartilage and bone disorders such as osteoarthritis. PMID:27682878

Interoceptive Accuracy in Youth with Tic Disorders: Exploring Links with Premonitory Urge, Anxiety and Quality of Life.

PubMed

Pile, Victoria; Lau, Jennifer Y F; Topor, Marta; Hedderly, Tammy; Robinson, Sally

2018-05-18

Aberrant interoceptive accuracy could contribute to the co-occurrence of anxiety and premonitory urge in chronic tic disorders (CTD). If it can be manipulated through intervention, it would offer a transdiagnostic treatment target for tics and anxiety. Interoceptive accuracy was first assessed consistent with previous protocols and then re-assessed following an instruction attempting to experimentally enhance awareness. The CTD group demonstrated lower interoceptive accuracy than controls but, importantly, this group difference was no longer significant following instruction. In the CTD group, better interoceptive accuracy was associated with higher anxiety and lower quality of life, but not with premonitory urge. Aberrant interoceptive accuracy may represent an underlying trait in CTD that can be manipulated, and relates to anxiety and quality of life.

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication.

PubMed

Thenin-Houssier, Suzie; de Vera, Ian Mitchelle S; Pedro-Rosa, Laura; Brady, Angela; Richard, Audrey; Konnick, Briana; Opp, Silvana; Buffone, Cindy; Fuhrmann, Jakob; Kota, Smitha; Billack, Blase; Pietka-Ottlik, Magdalena; Tellinghuisen, Timothy; Choe, Hyeryun; Spicer, Timothy; Scampavia, Louis; Diaz-Griffero, Felipe; Kojetin, Douglas J; Valente, Susana T

2016-04-01

The human immunodeficiency virus type 1 (HIV-1) capsid plays crucial roles in HIV-1 replication and thus represents an excellent drug target. We developed a high-throughput screening method based on a time-resolved fluorescence resonance energy transfer (HTS-TR-FRET) assay, using the C-terminal domain (CTD) of HIV-1 capsid to identify inhibitors of capsid dimerization. This assay was used to screen a library of pharmacologically active compounds, composed of 1,280in vivo-active drugs, and identified ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], an organoselenium compound, as an inhibitor of HIV-1 capsid CTD dimerization. Nuclear magnetic resonance (NMR) spectroscopic analysis confirmed the direct interaction of ebselen with the HIV-1 capsid CTD and dimer dissociation when ebselen is in 2-fold molar excess. Electrospray ionization mass spectrometry revealed that ebselen covalently binds the HIV-1 capsid CTD, likely via a selenylsulfide linkage with Cys198 and Cys218. This compound presents anti-HIV activity in single and multiple rounds of infection in permissive cell lines as well as in primary peripheral blood mononuclear cells. Ebselen inhibits early viral postentry events of the HIV-1 life cycle by impairing the incoming capsid uncoating process. This compound also blocks infection of other retroviruses, such as Moloney murine leukemia virus and simian immunodeficiency virus, but displays no inhibitory activity against hepatitis C and influenza viruses. This study reports the use of TR-FRET screening to successfully identify a novel capsid inhibitor, ebselen, validating HIV-1 capsid as a promising target for drug development. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Glaucophane chloritoid-bearing assemblages from NE Oman: petrologic significance and a petrogenetic grid for high P metapelites

NASA Astrophysics Data System (ADS)

El-Shazly, A. K.; Liou, J. G.

1991-04-01

Pelitic layers and lenses interbedded with blueschists and eclogites in Saih Hatat, NE Oman contain chloritoid- and sodic amphibole-bearing mineral assemblages that are useful for reconstructing the P-T history of the area. Textural and mineral chemical relations suggest that coexisting glaucophane (Gln) and chloritoid (Ctd) formed at the expense of chlorite (Chl)+paragonite (Pg) and later broke down to garnet (Gt)+Pg during prograde metamorphism according to the reaction: Gln+Ctd+Qz=Gt+Pg+H2O. During retrogression, Gln and Chl first formed at the expense of Gt and Pg, followed by the breakdown of Ctd and Gt to Chl. The final stages of retrogression are marked by the breakdown of Gln to an aggregate of Chl+albite (Ab). A projection from quartz (Qz), H2O and phengite (Ph) on the (Al2O3+Fe2O3)-(FeO+MgO)-Na2O plane in the system NFMASH is best suited for the representation of the phase relations in high P metapelites. Petrogenetic grids for the model systems NMASH and NFASH were calculated using program GEO-CALC (Berman et al. 1987) and its database (Berman 1988) after the retrieval of S{i/o}and ΔH{f/o}for Gln and Ctd by mathematical programming and calculating all possible reactions among Gln, Ctd, Chl, jadeite (Jd), Ab, Gt, Pg, talc (Tc), pyrophyllite (Prl) and kyanite (Ky). The calculated petrogenetic grid for the system NFASH shows that Fe-Ctd and ferroglaucophane coexist at P>6.5 kbar and T<525°C, whereas the assemblage: Ct-Gln-Pg is stable between 435 and 630°C and P>6 kbar. This grid is consistent with the P-T estimates for high P metapelites from Oman, New Caledonia, Seward Peninsula, Ile de Groix, Sifnos and Peloponnese, where Gln+Ctd bearing units are interbedded with cofacial mafic blueschists and eclogites. The grid also explains the observed textural relations in the metapelites of Oman, and is consistent with the “clockwise” P-T path proposed for this area, but differs from the grids of Guiraud et al. (1990) in showing a larger stability field for Gln+Ctd that overlaps with the stability fields of Jd+Qz as well as Ab. The petrogenetic grid calculated for the system NMASH shows that Mg-Ctd+Gln-bearing assemblages require unusually low geothermal gradients to form in metapelites. It also shows that Mg-rich Ctd+Tc coexist at high pressures over a wider P-T range than predicted by Guiraud et al. (1990). This grid can therefore be applied to high P metamorphic assemblages from the eastern and western Alps.

A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension.

PubMed

Cushman, William C; Bakris, George L; White, William B; Weber, Michael A; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2018-04-01

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.

A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension

PubMed Central

Cushman, William C.; Bakris, George L.; White, William B.; Weber, Michael A.; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2018-01-01

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). Objective/methods: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160–190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. Results: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (−37.6 and −38.2 mmHg) versus OLM/HCTZ (−31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (−26.4 and −27.9 versus −20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. Conclusion: This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ. PMID:29334491

COMPUTING THERAPY FOR PRECISION MEDICINE: COLLABORATIVE FILTERING INTEGRATES AND PREDICTS MULTI-ENTITY INTERACTIONS.

PubMed

Regenbogen, Sam; Wilkins, Angela D; Lichtarge, Olivier

2016-01-01

Biomedicine produces copious information it cannot fully exploit. Specifically, there is considerable need to integrate knowledge from disparate studies to discover connections across domains. Here, we used a Collaborative Filtering approach, inspired by online recommendation algorithms, in which non-negative matrix factorization (NMF) predicts interactions among chemicals, genes, and diseases only from pairwise information about their interactions. Our approach, applied to matrices derived from the Comparative Toxicogenomics Database, successfully recovered Chemical-Disease, Chemical-Gene, and Disease-Gene networks in 10-fold cross-validation experiments. Additionally, we could predict each of these interaction matrices from the other two. Integrating all three CTD interaction matrices with NMF led to good predictions of STRING, an independent, external network of protein-protein interactions. Finally, this approach could integrate the CTD and STRING interaction data to improve Chemical-Gene cross-validation performance significantly, and, in a time-stamped study, it predicted information added to CTD after a given date, using only data prior to that date. We conclude that collaborative filtering can integrate information across multiple types of biological entities, and that as a first step towards precision medicine it can compute drug repurposing hypotheses.

COMPUTING THERAPY FOR PRECISION MEDICINE: COLLABORATIVE FILTERING INTEGRATES AND PREDICTS MULTI-ENTITY INTERACTIONS

PubMed Central

REGENBOGEN, SAM; WILKINS, ANGELA D.; LICHTARGE, OLIVIER

2015-01-01

Biomedicine produces copious information it cannot fully exploit. Specifically, there is considerable need to integrate knowledge from disparate studies to discover connections across domains. Here, we used a Collaborative Filtering approach, inspired by online recommendation algorithms, in which non-negative matrix factorization (NMF) predicts interactions among chemicals, genes, and diseases only from pairwise information about their interactions. Our approach, applied to matrices derived from the Comparative Toxicogenomics Database, successfully recovered Chemical-Disease, Chemical-Gene, and Disease-Gene networks in 10-fold cross-validation experiments. Additionally, we could predict each of these interaction matrices from the other two. Integrating all three CTD interaction matrices with NMF led to good predictions of STRING, an independent, external network of protein-protein interactions. Finally, this approach could integrate the CTD and STRING interaction data to improve Chemical-Gene cross-validation performance significantly, and, in a time-stamped study, it predicted information added to CTD after a given date, using only data prior to that date. We conclude that collaborative filtering can integrate information across multiple types of biological entities, and that as a first step towards precision medicine it can compute drug repurposing hypotheses. PMID:26776170

Structure of Atg7 Alone and its Atg8-Bound Forms

NASA Astrophysics Data System (ADS)

Noda, Nobuo

Atg7 is a noncanonical E1 enzyme that activates Atg8 and transfers it to Atg3 (E2 enzyme), thus playing an essential role in conjugating Atg8 with phosphatidylethanolamine and thus in autophagy. Atg7 protomer is comprised of two globular domains, the N-terminal domain (NTD) and the C-terminal domain (CTD), and forms a homodimer through CTD. Atg7-Atg8 complex structures and biochemical analyses revealed that Atg8 is initially recognized by the C-terminal tail of CTD and is then transferred to the adenylation domain in CTD, where Atg8 Gly116 is adenylated and thioester-linked to the catalytic cysteine of Atg7. Atg8 is then transferred to Atg3 bound to the NTD of the opposite protomer within an Atg7 dimer via a trans mechanism.

The effects of gender discrimination on refugee torture survivors: a cross-cultural traumatology perspective.

PubMed

Kira, Ibrahim A; Smith, Iris; Lewandowski, Linda; Templin, Thomas

2010-09-01

Trauma developmental theory identifies gender discrimination (GD) as a type of persistent, ongoing trauma that has the potential for serious, negative effects on mental health. This study was conducted to examine the potential role of GD in the development of cumulative trauma disorders (CTD) and symptoms of posttraumatic stress disorder (PTSD) as well as the role of GD in mediating the effects of other traumas on these disorders. The sample included 160 female torture survivors from more than 30 countries. Measures of PTSD, CTD, and types of trauma exposure were acquired as part of a larger study on refugee torture survivors. Structural equation modeling was used to test several plausible models for the direct and indirect effects of GD on PTSD and CTD, within the context of other trauma exposure. Results suggest that GD mediates the effects of identity traumas on CTD and PTSD. GD also had direct effects on CTD, including relationships with dissociation, suicidality, and deficits in executive function. GD did not appear to directly influence the development of PTSD. The implications of these results for assessment and treatment of women's trauma-related disorders as well as strategies for their prevention are discussed.

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

PubMed Central

Chadha, Pooja; Sarfo, Akua; Zhang, Dan; Abraham, Thomas; Carmichael, Jillian

2016-01-01

ABSTRACT The UL16 tegument protein of herpes simplex virus 1 (HSV-1) is conserved among all herpesviruses and plays many roles during replication. This protein has an N-terminal domain (NTD) that has been shown to bind to several viral proteins, including UL11, VP22, and glycoprotein E, and these interactions are negatively regulated by a C-terminal domain (CTD). Thus, in pairwise transfections, UL16 binding is enabled only when the CTD is absent or altered. Based on these results, we hypothesized that direct interactions occur between the NTD and the CTD. Here we report that the separated and coexpressed functional domains of UL16 are mutually responsive to each other in transfected cells and form complexes that are stable enough to be captured in coimmunoprecipitation assays. Moreover, we found that the CTD can associate with itself. To our surprise, the CTD was also found to contain a novel and intrinsic ability to localize to specific spots on mitochondria in transfected cells. Subsequent analyses of HSV-infected cells by immunogold electron microscopy and live-cell confocal imaging revealed a population of UL16 that does not merely accumulate on mitochondria but in fact makes dynamic contacts with these organelles in a time-dependent manner. These findings suggest that the domain interactions of UL16 serve to regulate not just the interaction of this tegument protein with its viral binding partners but also its interactions with mitochondria. The purpose of this novel interaction remains to be determined. IMPORTANCE The HSV-1-encoded tegument protein UL16 is involved in multiple events of the virus replication cycle, ranging from virus assembly to cell-cell spread of the virus, and hence it can serve as an important drug target. Unfortunately, a lack of both structural and functional information limits our understanding of this protein. The discovery of domain interactions within UL16 and the novel ability of UL16 to interact with mitochondria in HSV-infected cells lays a foundational framework for future investigations aimed at deciphering the structure and function of not just UL16 of HSV-1 but also its homologs in other herpesviruses. PMID:27847362

Structure of the Z Ring-associated Protein, ZapD, Bound to the C-terminal Domain of the Tubulin-like Protein, FtsZ, Suggests Mechanism of Z Ring Stabilization through FtsZ Cross-linking.

PubMed

Schumacher, Maria A; Huang, Kuo-Hsiang; Zeng, Wenjie; Janakiraman, Anuradha

2017-03-03

Cell division in most bacteria is mediated by the tubulin-like FtsZ protein, which polymerizes in a GTP-dependent manner to form the cytokinetic Z ring. A diverse repertoire of FtsZ-binding proteins affects FtsZ localization and polymerization to ensure correct Z ring formation. Many of these proteins bind the C-terminal domain (CTD) of FtsZ, which serves as a hub for FtsZ regulation. FtsZ ring-associated proteins, ZapA-D (Zaps), are important FtsZ regulatory proteins that stabilize FtsZ assembly and enhance Z ring formation by increasing lateral assembly of FtsZ protofilaments, which then form the Z ring. There are no structures of a Zap protein bound to FtsZ; therefore, how these proteins affect FtsZ polymerization has been unclear. Recent data showed ZapD binds specifically to the FtsZ CTD. Thus, to obtain insight into the ZapD-CTD interaction and how it may mediate FtsZ protofilament assembly, we determined the Escherichia coli ZapD-FtsZ CTD structure to 2.67 Å resolution. The structure shows that the CTD docks within a hydrophobic cleft in the ZapD helical domain and adopts an unusual structure composed of two turns of helix separated by a proline kink. FtsZ CTD residue Phe-377 inserts into the ZapD pocket, anchoring the CTD in place and permitting hydrophobic contacts between FtsZ residues Ile-374, Pro-375, and Leu-378 with ZapD residues Leu-74, Trp-77, Leu-91, and Leu-174. The structural findings were supported by mutagenesis coupled with biochemical and in vivo studies. The combined data suggest that ZapD acts as a molecular cross-linking reagent between FtsZ protofilaments to enhance FtsZ assembly. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The HIP1 initiator element plays a role in determining the in vitro requirement of the dihydrofolate reductase gene promoter for the C-terminal domain of RNA polymerase II.

PubMed

Buermeyer, A B; Thompson, N E; Strasheim, L A; Burgess, R R; Farnham, P J

1992-05-01

We examined the ability of purified RNA polymerase (RNAP) II lacking the carboxy-terminal heptapeptide repeat domain (CTD), called RNAP IIB, to transcribe a variety of promoters in HeLa extracts in which endogenous RNAP II activity was inhibited with anti-CTD monoclonal antibodies. Not all promoters were efficiently transcribed by RNAP IIB, and transcription did not correlate with the in vitro strength of the promoter or with the presence of a consensus TATA box. This was best illustrated by the GC-rich, non-TATA box promoters of the bidirectional dihydrofolate reductase (DHFR)-REP-encoding locus. Whereas the REP promoter was transcribed by RNAP IIB, the DHFR promoter remained inactive after addition of RNAP IIB to the antibody-inhibited reactions. However, both promoters were efficiently transcribed when purified RNAP with an intact CTD was added. We analyzed a series of promoter deletions to identify which cis elements determine the requirement for the CTD of RNAP II. All of the promoter deletions of both DHFR and REP retained the characteristics of their respective full-length promoters, suggesting that the information necessary to specify the requirement for the CTD is contained within approximately 65 bp near the initiation site. Furthermore, a synthetic minimal promoter of DHFR, consisting of a single binding site for Sp1 and a binding site for the HIP1 initiator cloned into a bacterial vector sequence, required RNAP II with an intact CTD for activity in vitro. Since the synthetic minimal promoter of DHFR and the smallest REP promoter deletion are both activated by Sp1, the differential response in this assay does not result from upstream activators. However, the sequences around the start sites of DHFR and REP are not similar and our data suggest that they bind different proteins. Therefore, we propose that specific initiator elements are important for determination of the requirement of some promoters for the CTD.

Long-term monitoring of waterborne pathogens and microbial source tracking markers in paired agricultural watersheds under controlled and conventional tile drainage management.

PubMed

Wilkes, Graham; Brassard, Julie; Edge, Thomas A; Gannon, Victor; Gottschall, Natalie; Jokinen, Cassandra C; Jones, Tineke H; Khan, Izhar U H; Marti, Romain; Sunohara, Mark D; Topp, Edward; Lapen, David R

2014-06-01

Surface waters from paired agricultural watersheds under controlled tile drainage (CTD) and uncontrolled tile drainage (UCTD) were monitored over 7 years in order to determine if there was an effect of CTD (imposed during the growing season) on occurrences and loadings of bacterial and viral pathogens, coliphages, and microbial source tracking markers. There were significantly lower occurrences of human, ruminant, and livestock (ruminant plus pig) Bacteroidales markers in the CTD watershed in relation to the UCTD watershed. As for pathogens, there were significantly lower occurrences of Salmonella spp. and Arcobacter spp. in the CTD watershed. There were no instances where there were significantly higher quantitative loadings of any microbial target in the CTD watershed, except for F-specific DNA (F-DNA) and F-RNA coliphages, perhaps as a result of fecal inputs from a hobby farm independent of the drainage practice treatments. There was lower loading of the ruminant marker in the CTD watershed in relation to the UCTD system, and results were significant at the level P = 0.06. The odds of Salmonella spp. occurring increased when a ruminant marker was present relative to when the ruminant marker was absent, yet for Arcobacter spp., the odds of this pathogen occurring significantly decreased when a ruminant marker was present relative to when the ruminant marker was absent (but increased when a wildlife marker was present relative to when the wildlife marker was absent). Interestingly, the odds of norovirus GII (associated with human and swine) occurring in water increased significantly when a ruminant marker was present relative to when a ruminant marker was absent. Overall, this study suggests that fecal pollution from tile-drained fields to stream could be reduced by CTD utilization. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The CTD Teacher Opinion Poll.

ERIC Educational Resources Information Center

Arato, Agnes

1985-01-01

Within the framework of Hungary's Curriculum Theory Department (CTD-80) national assessment, 2,391 teachers from 70 general schools were surveyed. The questionnaire included teachers' characteristics, reaction to the new curriculum, and teaching practices. The results are described. (GDC)

Mediating role of critical thinking disposition in the relationship between perceived barriers to research use and evidence-based practice.

PubMed

Kim, Sun-Ae; Song, Youngshin; Sim, Hee-Sook; Ahn, Eun-Kyong; Kim, Jung-Hee

2015-01-01

Despite the importance of critical thinking in clinical and educational settings, little is known about its role in evidence-based practice (EBP). This study examined whether critical thinking disposition (CTD) mediates the relationship between perceived barriers to research use and EBP in clinical nurses (N=409). A path diagram using structural equation modeling was used to estimate the direct and indirect effects of perceived barriers to research use on EBP, controlling for CTD as a mediator. CTD partially mediated the relationship between perceived barriers to research use and EBP. Furthermore, the hypothesized mediation model demonstrated an appropriate fit to the data. Individual and organizational efforts are needed to help nurses further improve their critical thinking skills. CTD is important as research barriers to engage effectively in EBP. Without the skills to evaluate evidence carefully, research utilization may be compromised.

A conserved Mediator–CDK8 kinase module association regulates Mediator–RNA polymerase II interaction

PubMed Central

Tsai, Kuang-Lei; Sato, Shigeo; Tomomori-Sato, Chieri; Conaway, Ronald C.; Conaway, Joan W.; Asturias, Francisco J.

2013-01-01

The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a preeminent complex in eukaryotic transcription regulation. We used macromolecular electron microscopy and biochemistry to investigate the subunit organization, structure, and Mediator interaction of the Saccharomyces cerevisiae CKM. We found that interaction of the CKM with Mediator’s Middle module interferes with CTD-dependent RNAPII binding to a previously unknown Middle module CTD-binding site targeted early on in a multi-step holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD, and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the Mediator mechanism. PMID:23563140

Phosphorylation-regulated Binding of RNA Polymerase II to Fibrous Polymers of Low Complexity Domains

PubMed Central

Xiang, Siheng; Wu, Leeju; Theodoropoulos, Pano; Mirzaei, Hamid; Han, Tina; Xie, Shanhai; Corden, Jeffry L.; McKnight, Steven L.

2014-01-01

SUMMARY The low complexity (LC) domains of the products of the fused in sarcoma (FUS), Ewings sarcoma (EWS) and TAF15 genes are translocated onto a variety of different DNA-binding domains and thereby assist in driving the formation of cancerous cells. In the context of the translocated fusion proteins, these LC sequences function as transcriptional activation domains. Here we show that polymeric fibers formed from these LC domains directly bind the C-terminal domain (CTD) of RNA polymerase II in a manner reversible by phosphorylation of the iterated, heptad repeats of the CTD. Mutational analysis indicates that the degree of binding between the CTD and the LC domain polymers correlates with the strength of transcriptional activation. These studies offer a simple means of conceptualizing how RNA polymerase II is recruited to active genes in its unphosphorylated state, and released for elongation following phosphorylation of the CTD. PMID:24267890

Prenatal and early postnatal NOAEL-dose clothianidin exposure leads to a reduction of germ cells in juvenile male mice

PubMed Central

YANAI, Shogo; HIRANO, Tetsushi; OMOTEHARA, Takuya; TAKADA, Tadashi; YONEDA, Naoki; KUBOTA, Naoto; YAMAMOTO, Anzu; MANTANI, Youhei; YOKOYAMA, Toshifumi; KITAGAWA, Hiroshi; HOSHI, Nobuhiko

2017-01-01

Neonicotinoids are pesticides used worldwide. They bind to insect nicotinic acetylcholine receptors (nAChRs) with high affinity. We previously reported that clothianidin (CTD), one of the latest neonicotinoids, reduced antioxidant expression and induced germ cell death in the adult testis of vertebrates. Here, we investigated the male reproductive toxicity of prenatal and early postnatal exposure to CTD, because it is likely that developmental exposure more severely affects the testis compared to adults due to the absence of the blood-testis barrier. Pregnant C57BL/6 mice were given water gel blended with CTD (0, 10 or 50 mg/kg/day; no-observed-adverse-effect-level [NOAEL for mice]: 47.2 mg/kg/day) between gestational day 1 and 14 days post-partum. We then examined the testes of male offspring at postnatal day 14. The testis weights and the numbers of germ cells per seminiferous tubule were decreased in the CTD-50 group, and abnormal tubules containing no germ cells appeared. Nevertheless, the apoptotic cell number and proliferative activity were not significantly different between the control and CTD-exposed groups. There were no significant differences in the androgen-related parameters, such as the Leydig cell volume per testis, the Sertoli cell number and the tubule diameter. The present study is the first demonstration that in utero and lactational exposures to CTD at around the NOAEL for mice reduce the germ cell number, but our findings suggest that these exposures do not affect steroidogenesis in Leydig cells during prenatal or early postnatal life. PMID:28579575

A Thermodynamic Model for Genome Packaging in Hepatitis B Virus.

PubMed

Kim, Jehoon; Wu, Jianzhong

2015-10-20

Understanding the fundamentals of genome packaging in viral capsids is important for finding effective antiviral strategies and for utilizing benign viral particles for gene therapy. While the structure of encapsidated genomic materials has been routinely characterized with experimental techniques such as cryo-electron microscopy and x-ray diffraction, much less is known about the molecular driving forces underlying genome assembly in an intracellular environment and its in vivo interactions with the capsid proteins. Here we study the thermodynamic basis of the pregenomic RNA encapsidation in human Hepatitis B virus in vivo using a coarse-grained molecular model that captures the essential components of nonspecific intermolecular interactions. The thermodynamic model is used to examine how the electrostatic interaction between the packaged RNA and the highly charged C-terminal domains (CTD) of capsid proteins regulate the nucleocapsid formation. The theoretical model predicts optimal RNA content in Hepatitis B virus nucleocapsids with different CTD lengths in good agreement with mutagenesis measurements, confirming the predominant role of electrostatic interactions and molecular excluded-volume effects in genome packaging. We find that the amount of encapsidated RNA is not linearly correlated with the net charge of CTD tails as suggested by earlier theoretical studies. Our thermodynamic analysis of the nucleocapsid structure and stability indicates that ∼10% of the CTD residues are free from complexation with RNA, resulting in partially exposed CTD tails. The thermodynamic model also predicts the free energy of complex formation between macromolecules, which corroborates experimental results for the impact of CTD truncation on the nucleocapsid stability. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Comprehensive evaluations of cone-beam CT dose in image-guided radiation therapy via GPU-based Monte Carlo simulations

NASA Astrophysics Data System (ADS)

Montanari, Davide; Scolari, Enrica; Silvestri, Chiara; Jiang Graves, Yan; Yan, Hao; Cervino, Laura; Rice, Roger; Jiang, Steve B.; Jia, Xun

2014-03-01

Cone beam CT (CBCT) has been widely used for patient setup in image-guided radiation therapy (IGRT). Radiation dose from CBCT scans has become a clinical concern. The purposes of this study are (1) to commission a graphics processing unit (GPU)-based Monte Carlo (MC) dose calculation package gCTD for Varian On-Board Imaging (OBI) system and test the calculation accuracy, and (2) to quantitatively evaluate CBCT dose from the OBI system in typical IGRT scan protocols. We first conducted dose measurements in a water phantom. X-ray source model parameters used in gCTD are obtained through a commissioning process. gCTD accuracy is demonstrated by comparing calculations with measurements in water and in CTDI phantoms. Twenty-five brain cancer patients are used to study dose in a standard-dose head protocol, and 25 prostate cancer patients are used to study dose in pelvis protocol and pelvis spotlight protocol. Mean dose to each organ is calculated. Mean dose to 2% voxels that have the highest dose is also computed to quantify the maximum dose. It is found that the mean dose value to an organ varies largely among patients. Moreover, dose distribution is highly non-homogeneous inside an organ. The maximum dose is found to be 1-3 times higher than the mean dose depending on the organ, and is up to eight times higher for the entire body due to the very high dose region in bony structures. High computational efficiency has also been observed in our studies, such that MC dose calculation time is less than 5 min for a typical case.

77 FR 69634 - International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-20

... Document (CTD). The guidance is intended to harmonize the scientific and technical principles relating to... sections of the CTD. A summary of changes includes the following: (1) Revisions to the introduction and...

Creatine Transporter Deficiency in Two Brothers with Autism Spectrum Disorder.

PubMed

Aydin, Halil Ibrahim

2018-01-15

Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. Both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems. Serum creatinine levels, creatine peak at brain MR spectroscopy or creatine/creatinine ratio in urine should be evaluated to identify CTD in children with autistic behavior and language disorders.

Cor triatriatum dexter, atrial septal defects, and pulmonary stenosis-a rare association.

PubMed

Simsek, Ziya; Koza, Yavuzer; Tas, Hakan

2014-04-01

Cor triatriatum dexter (CTD) is an extremely rare congenital anomaly in which the right atrium is divided into 2 chambers by a membrane. The estimated incidence of cor triatriatum has been reported as 0.1% of congenital cardiac malformations. The septation of the right atrium in the setting of CTD is the result of failed resorption of the right valve of the sinus venosus. This results in anterolateral and posteromedial portions of the divided right atrium. CTD can be diagnosed at any age, especially if it is incidentally discovered. © 2014, Wiley Periodicals, Inc.

Phenol degradation by TiO2 photocatalysts combined with different pulsed discharge systems.

PubMed

Zhang, Yi; Lu, Jiani; Wang, Xiaoping; Xin, Qing; Cong, Yanqing; Wang, Qi; Li, Chunjuan

2013-11-01

Films of TiO2 nanotubes distributed over the inner surface of a discharge reactor cylinder (CTD) or adhered to a stainless steel electrode surface (PTD) in a discharge reactor were compared with a single-discharge (SD) system to investigate their efficiencies in phenol degradation. Morphology studies indicated that the TiO2 film was destroyed in the PTD system, but that there was no change in the CTD system after discharge. X-ray diffraction results revealed that the anatase phase of the original sample was preserved in the CTD system, but that an anatase-to-rutile phase transformation occurred in the PTD system after discharge. The highest efficiencies of phenol degradation and total organic carbon (TOC) mineralization were observed in the CTD system, and there was no decrease in phenol degradation efficiency upon reuse of a TiO2 film, indicating high catalysis activity and stability of the TiO2 photocatalysts in the combined treatment. TiO2 photocatalysts favored the formation of hydrogen peroxide and disfavored the formation of ozone. A greater degree of oxidation of intermediates and higher energy efficiency in phenol oxidation were observed with the TiO2-plasma systems, especially in the CTD system, compared to those with the SD system. Copyright © 2013 Elsevier Inc. All rights reserved.

The CTD-80 Survey Introduction.

ERIC Educational Resources Information Center

Kadar-Fulop, Judit; Bathory, Zoltan

1985-01-01

Hungary's national institute of education carried out the Curriculum Theory Department (CTD-80) national asessment in 1980. Reading, mathematics, and practical science achievement were measured, as well as teacher attitudes. Particular emphasis was placed on eighth-grade students; fourth graders were tested in reading. (GDC)

The CTD Science Practical Survey.

ERIC Educational Resources Information Center

Bathory, Zoltan

1985-01-01

As part of Hungary's Curriculum Theory Department (CTD-80) assessment, 1,543 14-year-olds were tested in the performance of science experiments in physics and chemistry. Skills included observing, measuring, hypothesizing, and drawing conclusions. Results are presented, and implications for curriculum are suggested. (GDC)

Lung cancer development in patients with connective tissue disease-related interstitial lung disease: A retrospective observational study.

PubMed

Enomoto, Yasunori; Inui, Naoki; Yoshimura, Katsuhiro; Nishimoto, Koji; Mori, Kazutaka; Kono, Masato; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Iwashita, Toshihide; Suda, Takafumi

2016-12-01

Previous studies have reported that patients with idiopathic pulmonary fibrosis occasionally develop lung cancer (LC). However, in connective tissue disease (CTD)-related interstitial lung disease (ILD), there are few data regarding the LC development. The aim of the present study was to evaluate the clinical significance of LC development in patients with CTD-ILD. A retrospective review of our database of 562 patients with ILD between 2000 and 2014 identified 127 patients diagnosed with CTD-ILD. The overall and cumulative incidences of LC were calculated. In addition, the risk factors and prognostic impact of LC development were evaluated. The median age at the ILD diagnosis was 63 years (range 37-84 years), and 73 patients (57.5%) were female. The median follow-up period from the ILD diagnosis was 67.4 months (range 10.4-322.1 months). During the period, 7 out of the 127 patients developed LC (overall incidence 5.5%). The cumulative incidences at 1, 3, and 5 years were 0.0%, 1.8%, and 2.9%, respectively. The risk of LC development was significantly higher in patients with higher smoking pack-year (odds ratio [OR] 1.028; 95% confidence interval [CI] 1.008-1.049; P = 0.007) and emphysema on chest high-resolution computed tomography (OR 14.667; 95% CI 2.871-74.926; P = 0.001). The median overall survival time after developing LC was 7.0 months (95% CI 4.9-9.1 months), and the most common cause of death was LC, not ILD. According to the Cox proportional hazard model analysis with time-dependent covariates, patients who developed LC showed significantly poorer prognosis than those who did not (hazard ratio 87.86; 95% CI 19.56-394.67; P < 0.001). In CTD-ILD, clinicians should be careful with the risk of LC development in patients with a heavy smoking history and subsequent emphysema. Although not so frequent, the complication could be a poor prognostic determinant.

Mechanisms Controlling Hypoxia Data Atlas: High-resolution hydrographic and chemical observations from 2003-2014

NASA Astrophysics Data System (ADS)

Zimmerle, H.; DiMarco, S. F.

2016-02-01

The Mechanisms Controlling Hypoxia (MCH) project consisted of 31 cruises from 2003-2014 with an objective to investigate the physical and biogeochemical processes that control the hypoxic zone on the Texas-Louisiana shelf in the northern Gulf of Mexico. The known seasonal low oxygen conditions in this region are the result of river-derived nutrients, freshwater input, and wind. The MCH Data Atlas showcases in situ data and subsequent products produced during the duration of the project, focusing on oceanographic observations from 2010-2014. The Atlas features 230 high-resolution vertical sections from nine cruises using the Acrobat undulating towed vehicle that contained a CTD along with sensors measuring oxygen, fluorescence, and turbidity. Vertical profiles along the 20-meter isobaths section feature temperature, salinity, chlorophyll, and dissolved oxygen from the Acrobat towfish and CTD rosette as well as separate selected profiles from the CTD. Surface planview maps show the horizontal distribution of temperature, salinity, chlorophyll, beam transmission, and CDOM observed by the shipboard flow-through system. Bottom planview maps present the horizontal distribution of dissolved oxygen as well as temperature and salinity from the CTD rosette and Acrobat towfish along the shelf's seafloor. Informational basemaps display the GPS cruise track as well as individual CTD stations for each cruise. The shelf concentrations of CTD rosette bottle nutrients, including nitrate, nitrite, phosphate, ammonia, and silicate are displayed in select plots. Shipboard ADCP current velocity fields are also represented. MCH datasets and additional products are featured as an electronic version to compliment the published atlas. The MCH Data Atlas provides a showcase for the spatial and temporal variability of the environmental parameters associated with the annual hypoxic event and will be a useful tool in the continued monitoring and assessment of Gulf coastal hypoxia.

Phosphatase Rtr1 Regulates Global Levels of Serine 5 RNA Polymerase II C-Terminal Domain Phosphorylation and Cotranscriptional Histone Methylation.

PubMed

Hunter, Gerald O; Fox, Melanie J; Smith-Kinnaman, Whitney R; Gogol, Madelaine; Fleharty, Brian; Mosley, Amber L

2016-09-01

In eukaryotes, the C-terminal domain (CTD) of Rpb1 contains a heptapeptide repeat sequence of (Y1S2P3T4S5P6S7)n that undergoes reversible phosphorylation through the opposing action of kinases and phosphatases. Rtr1 is a conserved protein that colocalizes with RNA polymerase II (RNAPII) and has been shown to be important for the transition from elongation to termination during transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes. In this study, we show that Rtr1 is a global regulator of the CTD code with deletion of RTR1 causing genome-wide changes in Ser5-P CTD phosphorylation and cotranscriptional histone H3 lysine 36 trimethylation (H3K36me3). Using chromatin immunoprecipitation and high-resolution microarrays, we show that RTR1 deletion results in global changes in RNAPII Ser5-P levels on genes with different lengths and transcription rates consistent with its role as a CTD phosphatase. Although Ser5-P levels increase, the overall occupancy of RNAPII either decreases or stays the same in the absence of RTR1 Additionally, the loss of Rtr1 in vivo leads to increases in H3K36me3 levels genome-wide, while total histone H3 levels remain relatively constant within coding regions. Overall, these findings suggest that Rtr1 regulates H3K36me3 levels through changes in the number of binding sites for the histone methyltransferase Set2, thereby influencing both the CTD and histone codes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Reduced specificity of autobiographical memories in young people with tic disorders.

PubMed

Pile, Victoria; Robinson, Sally; Roberts, Elystan; Topor, Marta; Hedderly, Tammy; Lau, Jennifer Y F

2018-05-01

Depression is common in Tourette syndrome and Chronic Tic Disorders (TS/CTD) and contributes to significant impairment. The specificity of autobiographical memories is implicated in an individual's sense of self and their daily functioning but also in the onset and development of depression in the general population. Here, we examined whether memory specificity is reduced in young people with TS/CTD, relative to control participants, and whether memory specificity is associated with depression. Thirty young people with TS/CTD (14 females; age: x̅ = 11.31; SD = 1.66; 87% White British) and twenty-six (12 females; age: x̅ = 11.23; SD = 2.43; 77% White British) control participants completed the study. Participants completed the Autobiographical Memory Task, which asks participants to respond with a specific memory to cue words, and a questionnaire measure of depressive symptoms. There was no significant difference between the two groups in terms of age, gender, ethnicity, IQ and depressive symptomatology. Young people with TS/CTD had less specific autobiographical memories than their peers (p < 0.001, r = 0.49). Across both groups, increased memory specificity for positive cue words was associated with reduced depressive symptomatology (p < 0.001, R 2  = 0.51). Our findings indicate that autobiographical memory in young people with TS is characterised by a lack of specificity and, as with neurotypical peers, reduced memory specificity for positive words is associated with depressive symptoms. Autobiographical memory specificity could be an important factor in understanding mood symptoms that characterise young people with TS/CTD and may be an important cognitive target to reduce the development of depression in young people with TS/CTD. Copyright © 2018 Elsevier Inc. All rights reserved.

The 13-kD FK506 Binding Protein, FKBP13, Interacts with a Novel Homologue of the Erythrocyte Membrane Cytoskeletal Protein 4.1

PubMed Central

Walensky, Loren D.; Gascard, Philippe; Field, Michael E.; Blackshaw, Seth; Conboy, John G.; Mohandas, Narla; Snyder, Solomon H.

1998-01-01

We have identified a novel generally expressed homologue of the erythrocyte membrane cytoskeletal protein 4.1, named 4.1G, based on the interaction of its COOH-terminal domain (CTD) with the immunophilin FKBP13. The 129-amino acid peptide, designated 4.1G–CTD, is the first known physiologic binding target of FKBP13. FKBP13 is a 13-kD protein originally identified by its high affinity binding to the immunosuppressant drugs FK506 and rapamycin (Jin, Y., M.W. Albers, W.S. Lane, B.E. Bierer, and S.J. Burakoff. 1991. Proc. Natl. Acad. Sci. USA. 88:6677– 6681); it is a membrane-associated protein thought to function as an ER chaperone (Bush, K.T., B.A. Henrickson, and S.K. Nigam. 1994. Biochem. J. [Tokyo]. 303:705–708). We report the specific association of FKBP13 with 4.1G–CTD based on yeast two-hybrid, in vitro binding and coimmunoprecipitation experiments. The histidyl-proline moiety of 4.1G–CTD is required for FKBP13 binding, as indicated by yeast experiments with truncated and mutated 4.1G–CTD constructs. In situ hybridization studies reveal cellular colocalizations for FKBP13 and 4.1G–CTD throughout the body during development, supporting a physiologic role for the interaction. Interestingly, FKBP13 cofractionates with the red blood cell homologue of 4.1 (4.1R) in ghosts, inside-out vesicles, and Triton shell preparations. The identification of FKBP13 in erythrocytes, which lack ER, suggests that FKBP13 may additionally function as a component of membrane cytoskeletal scaffolds. PMID:9531554

An Analysis of Effects of Background Variables on Student Achievement Based on the CTD Survey Data.

ERIC Educational Resources Information Center

Tolgyesi, Miklos

1985-01-01

Factors contributing to achievement were investigated as part of Hungary's Curriculum Theory Department (CTD-80) national assessment. Parent's education and occupation and student's sex predicted achievement results. School characteristics did not predict achievement or attitudes. (Author/GDC)

Idiopathic Interstitial Pneumonia Associated With Autoantibodies: A Large Case Series Followed Over 1 Year.

PubMed

Collins, Bridget F; Spiekerman, Charles F; Shaw, Megan A; Ho, Lawrence A; Hayes, Jennifer; Spada, Carolyn A; Stamato, Caroline M; Raghu, Ganesh

2017-07-01

Some patients with autoimmune characteristics and idiopathic interstitial pneumonia, particularly usual interstitial pneumonia (UIP), do not fit neatly into the category of connective tissue disease-associated interstitial lung disease (CTD-ILD), idiopathic pulmonary fibrosis (IPF), or recently proposed yet to be validated criteria for interstitial pneumonia with autoimmune features (IPAF). Outcomes of these patients are unknown. This was a retrospective single-center study. Analyses of variance compared differences in mean change in FVC and diffusion capacity (Dlco) over 1 year among 124 well-defined patients (20 patients with positive autoantibodies with or without symptoms of connective tissue disease [AI-ILD], 15 patients with IPAF, 36 patients with CTD-ILD, and 53 patients with IPF with negative CTD serologies [Lone-IPF]). Of the patients, 75% with AI-ILD, 33% with IPAF, and 33% with CTD-ILD had UIP. Initial FVC and Dlco were similarly moderately reduced across groups. Mean change in FVC over 12 months was as follows: -60 mL (IPAF), -110 mL (AI-ILD), -10 mL (CTD-ILD), and -90 mL (Lone-IPF) (P = .52). Mean change in Dlco was as follows: 2.39 mL/mm Hg/min (IPAF), -1.15 mL/mm Hg/min (AI-ILD), -0.27 mL/mm Hg/min (CTD-ILD), and -1.05 mL/mm Hg/min (Lone-IPF) (P < .001). By pattern of disease, the mean change in FVC was as follows: -140 mL (UIP), 10 mL (nonspecific interstitial pneumonia), and 12 mL (unclassifiable/other) (P = .001). No clinically significant differences in pulmonary function to distinguish between patients with AI-ILD, IPAF, CTD-ILD, and Lone-IPF were observed after 1 year. Longer periods of follow-up are needed to understand the outcomes of these patients. It is not yet clear whether AI-ILD is a distinct phenotype or a variant of the newly proposed entity IPAF. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship.

PubMed

Yoshimura, Natsue; Horiuchi, Daisuke; Shibata, Masao; Saitoe, Minoru; Qi, Mei-Ling; Okazawa, Hitoshi

2006-04-17

Frame shift mutations of the polyglutamine binding protein-1 (PQBP1) gene lead to total or partial truncation of the C-terminal domain (CTD) and cause mental retardation in human patients. Interestingly, normal Drosophila homologue of PQBP-1 lacks CTD. As a model to analyze the molecular network of PQBP-1 affecting intelligence, we generated transgenic flies expressing human PQBP-1 with CTD. Pavlovian olfactory conditioning revealed that the transgenic flies showed disturbance of long-term memory. In addition, they showed abnormal courtship that male flies follow male flies. Abnormal functions of PQBP-1 or its binding partner might be linked to these symptoms.

The CTD Reading Study.

ERIC Educational Resources Information Center

Kadar-Fulop, Judit

1985-01-01

Reading ability of fourth- and eighth-grade Hungarians was assessed as part of the national CTD-80 (Curriculum Theory Department) survey. The texts used in the reading tests are analyzed, as are the reading tasks involved. Resulting achievement test results are presented and described in terms of the text characteristics. (GDC)

Radioanalytical Chemistry for Automated Nuclear Waste Process Monitoring

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

Devol, Timothy A.

2005-06-01

Comparison of different pulse shape discrimination methods was performed under two different experimental conditions and the best method was identified. Beta/gamma discrimination of 90Sr/90Y and 137Cs was performed using a phoswich detector made of BC400 (2.5 cm OD x 1.2 cm) and BGO (2.5 cm O.D. x 2.5 cm ) scintillators. Alpha/gamma discrimination of 210Po and 137Cs was performed using a CsI:Tl (2.8 x 1.4 x 1.4 cm3) scintillation crystal. The pulse waveforms were digitized with a DGF-4c (X-Ray Instrumentation Associates) and analyzed offline with IGOR Pro software (Wavemetrics, Inc.). The four pulse shape discrimination methods that were compared include:more » rise time discrimination, digital constant fraction discrimination, charge ratio, and constant time discrimination (CTD) methods. The CTD method is the ratio of the pulse height at a particular time after the beginning of the pulse to the time at the maximum pulse height. The charge comparison method resulted in a Figure of Merit (FoM) of 3.3 (9.9 % spillover) and 3.7 (0.033 % spillover) for the phoswich and the CsI:Tl scintillator setups, respectively. The CTD method resulted in a FoM of 3.9 (9.2 % spillover) and 3.2 (0.25 % spillover), respectively. Inverting the pulse shape data typically resulted in a significantly higher FoM than conventional methods, but there was no reduction in % spillover values. This outcome illustrates that the FoM may not be a good scheme for the quantification of a system to perform pulse shape discrimination. Comparison of several pulse shape discrimination (PSD) methods was performed as a means to compare traditional analog and digital PSD methods on the same scintillation pulses. The X-ray Instrumentation Associates DGF-4C (40 Msps, 14-bit) was used to digitize waveforms from a CsI:Tl crystal and BC400/BGO phoswich detector.« less

The outer-membrane export signal of Porphyromonas gingivalis type IX secretion system (T9SS) is a conserved C-terminal β-sandwich domain

PubMed Central

de Diego, Iñaki; Ksiazek, Miroslaw; Mizgalska, Danuta; Koneru, Lahari; Golik, Przemyslaw; Szmigielski, Borys; Nowak, Magdalena; Nowakowska, Zuzanna; Potempa, Barbara; Houston, John A.; Enghild, Jan J.; Thøgersen, Ida B.; Gao, Jinlong; Kwan, Ann H.; Trewhella, Jill; Dubin, Grzegorz; Gomis-Rüth, F. Xavier; Nguyen, Ky-Anh; Potempa, Jan

2016-01-01

In the recently characterized Type IX Secretion System (T9SS), the conserved C-terminal domain (CTD) in secreted proteins functions as an outer membrane translocation signal for export of virulence factors to the cell surface in the Gram-negative Bacteroidetes phylum. In the periodontal pathogen Porphyromonas gingivalis, the CTD is cleaved off by PorU sortase in a sequence-independent manner, and anionic lipopolysaccharide (A-LPS) is attached to many translocated proteins, thus anchoring them to the bacterial surface. Here, we solved the atomic structure of the CTD of gingipain B (RgpB) from P. gingivalis, alone and together with a preceding immunoglobulin-superfamily domain (IgSF). The CTD was found to possess a typical Ig-like fold encompassing seven antiparallel β-strands organized in two β-sheets, packed into a β-sandwich structure that can spontaneously dimerise through C-terminal strand swapping. Small angle X-ray scattering (SAXS) revealed no fixed orientation of the CTD with respect to the IgSF. By introducing insertion or substitution of residues within the inter-domain linker in the native protein, we were able to show that despite the region being unstructured, it nevertheless is resistant to general proteolysis. These data suggest structural motifs located in the two adjacent Ig-like domains dictate the processing of CTDs by the T9SS secretion pathway. PMID:27005013

Clinical Features of Idiopathic Interstitial Pneumonia with Systemic Sclerosis-Related Autoantibody in Comparison with Interstitial Pneumonia with Systemic Sclerosis

PubMed Central

Yamakawa, Hideaki; Hagiwara, Eri; Kitamura, Hideya; Yamanaka, Yumie; Ikeda, Satoshi; Sekine, Akimasa; Baba, Tomohisa; Iso, Shinichiro; Okudela, Koji; Iwasawa, Tae; Takemura, Tamiko; Kuwano, Kazuyoshi; Ogura, Takashi

2016-01-01

Background Patients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD. Objective This study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies. Methods We retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody. Results Patients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD. Conclusion Data from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD. PMID:27564852

Protein-Protein Interaction Reagents | Office of Cancer Genomics

Cancer.gov

The CTD2 Center at Emory University has a library of genes used to study protein-protein interactions in mammalian cells. These genes are cloned in different mammalian expression vectors. A list of available cancer-associated genes can be accessed below. Emory_CTD^2_PPI_Reagents.xlsx Contact: Haian Fu

The Development of an Instrument to Measure Creative Teaching Abilities.

ERIC Educational Resources Information Center

Riley, John F.

The development of an instrument to measure creative teaching abilities, the Creative Teaching Dilemma (CTD), involved three phases. The instrument was constructed and refined, and scoring procedures were outlined. The activities comprising the CTD included defining the teaching dilemma, gathering additional facts, identifying and stating the…

The Comparative Toxicogenomics Database (CTD): A Resource for Comparative Toxicological Studies

PubMed Central

CJ, Mattingly; MC, Rosenstein; GT, Colby; JN, Forrest; JL, Boyer

2006-01-01

The etiology of most chronic diseases involves interactions between environmental factors and genes that modulate important biological processes (Olden and Wilson, 2000). We are developing the publicly available Comparative Toxicogenomics Database (CTD) to promote understanding about the effects of environmental chemicals on human health. CTD identifies interactions between chemicals and genes and facilitates cross-species comparative studies of these genes. The use of diverse animal models and cross-species comparative sequence studies has been critical for understanding basic physiological mechanisms and gene and protein functions. Similarly, these approaches will be valuable for exploring the molecular mechanisms of action of environmental chemicals and the genetic basis of differential susceptibility. PMID:16902965

Water masses in the Monterey Bay during the summer of 2000

NASA Astrophysics Data System (ADS)

Warn-Varnas, Alex; Gangopadhyay, Avijit; Hawkins, J. A.

2007-06-01

Water masses in Monterey Bay are determined from the CTD casts of the Monterey Ocean Observing System (MOOS) Upper-water-column Science Experiment (MUSE) August 2000 dataset. It is shown through cluster analysis that the MUSE 2000 CTD dataset contains 5 water masses. These five water masses are: bay surface water (BSW), bay warm water (BWW), bay intermediate water (BIW), sub arctic upper water (SUW) and North Pacific deep water (NPDW). The BWW is a new water mass that exists in one area and is attributed to the effects of solar heating. The volumes occupied by each of the water masses are obtained. The BIW water is the most dominant water mass and occupies 68.8% of the volume. The statistical means and standard deviations for each water parameter, including spiciness and oxygen concentration, are calculated during separate upwelling and relaxed periods. The water mass content and structure are analyzed and studied during upwelling and a relaxed period. During upwelling, along a CTD track off Pt. Ano Nuevo, the water mass T, S distribution tended to be organized along three branches. Off Pt. Ano Nuevo the innovative coastal observation network (ICON) model showed the formation of a cyclonic eddy during the analyzed upwelling period. In time the eddy moved southwest and became absorbed into the southerly flow during the initial phases of the following wind-relaxed period.

Construct Validity Examination of Critical Thinking Dispositions for Undergraduate Students in University Putra Malaysia

ERIC Educational Resources Information Center

Ghadi, Ibrahim; Alwi, Nor Hayati; Bakar, Kamariah Abu; Talib, Othman

2012-01-01

This research aims to evaluate the psychology properties of the construct validity for the Critical Thinking Disposition (CTD) instrument. The CTD instrument consists of 39 Likert-type items measuring seven dispositions, namely analyticity, open-mind, truth-seeking, systematicity, self-confidence inquisitiveness and maturity. The study involves…

Scholarships and School Improvement: Annual Report of Catching the Dream.

ERIC Educational Resources Information Center

Chavers, Dean, Ed.

2001-01-01

This issue of "The Native Scholar" is comprised entirely of the annual report of Catching the Dream (CTD), an organization that awards scholarships to Native American students and grants for improving Native American schools. CTD scholarship programs are described, as are scholarships in general and how to find them. Fourteen scholarship websites…

Using the Constructivist Tridimensional Design Model for Online Continuing Education for Health Care Clinical Faculty

ERIC Educational Resources Information Center

Seo, Kay Kyeong-Ju; Engelhard, Chalee

2014-01-01

This article presents a new paradigm for continuing education of Clinical Instructors (CIs): the Constructivist Tridimensional (CTD) model for the design of an online curriculum. Based on problem-based learning, self-regulated learning, and adult learning theory, the CTD model was designed to facilitate interactive, collaborative, and authentic…

[WMSDs in supermarket cashiers].

PubMed

Di Pede, Cinzia; Manuli, Gianluca; Dini, Fulvia; Pinelli, Marco; Turini, Lucia; Mariani, Maurizio; Taddeo, Domenico

2011-01-01

High prevalence of Cumulative Trauma Disorders (CTD) of shoulder and wristle among supermarket cashiers have been reported by several studies. To evaluate CTD prevalence in a group of supermarket cashiers in Pisa area is the aim of this study. Standardized Questionnaire and clinical examination have been performed in 128 female supermarket cashiers. In subjects having Symptoms and Signs, Elettroneurography and Echography have been performed. 54 subjects had Paresthesias and performed elettroneurography: 44 (34,4%) had Median nerve impairment at the wrist and among them 37 cases were bilateral; 15 had Ulnar nerve impairment (11,7%), among them 8 were bilateral. Moreover we have performed the echographies in all the 25 subjects with a positive medical examination of the shoulder and they all (19,5% del totale) showed a rotator cuff tendinosis. 25 subjects with CTD (44,6%) showed a comorbidity. An index called BiCo considering both bilaterality and comorbility has been calculated. The percentage of CTD is much more elevated than in general population and many workers present comorbility and bilaterality: a strategy for primary prevention improving ergonomy and information is needed.

Prioritizing PubMed articles for the Comparative Toxicogenomic Database utilizing semantic information

PubMed Central

Wilbur, W. John

2012-01-01

The Comparative Toxicogenomics Database (CTD) contains manually curated literature that describes chemical–gene interactions, chemical–disease relationships and gene–disease relationships. Finding articles containing this information is the first and an important step to assist manual curation efficiency. However, the complex nature of named entities and their relationships make it challenging to choose relevant articles. In this article, we introduce a machine learning framework for prioritizing CTD-relevant articles based on our prior system for the protein–protein interaction article classification task in BioCreative III. To address new challenges in the CTD task, we explore a new entity identification method for genes, chemicals and diseases. In addition, latent topics are analyzed and used as a feature type to overcome the small size of the training set. Applied to the BioCreative 2012 Triage dataset, our method achieved 0.8030 mean average precision (MAP) in the official runs, resulting in the top MAP system among participants. Integrated with PubTator, a Web interface for annotating biomedical literature, the proposed system also received a positive review from the CTD curation team. PMID:23160415

Prioritizing PubMed articles for the Comparative Toxicogenomic Database utilizing semantic information.

PubMed

Kim, Sun; Kim, Won; Wei, Chih-Hsuan; Lu, Zhiyong; Wilbur, W John

2012-01-01

The Comparative Toxicogenomics Database (CTD) contains manually curated literature that describes chemical-gene interactions, chemical-disease relationships and gene-disease relationships. Finding articles containing this information is the first and an important step to assist manual curation efficiency. However, the complex nature of named entities and their relationships make it challenging to choose relevant articles. In this article, we introduce a machine learning framework for prioritizing CTD-relevant articles based on our prior system for the protein-protein interaction article classification task in BioCreative III. To address new challenges in the CTD task, we explore a new entity identification method for genes, chemicals and diseases. In addition, latent topics are analyzed and used as a feature type to overcome the small size of the training set. Applied to the BioCreative 2012 Triage dataset, our method achieved 0.8030 mean average precision (MAP) in the official runs, resulting in the top MAP system among participants. Integrated with PubTator, a Web interface for annotating biomedical literature, the proposed system also received a positive review from the CTD curation team.

Structural and sequencing analysis of local target DNA recognition by MLV integrase.

PubMed

Aiyer, Sriram; Rossi, Paolo; Malani, Nirav; Schneider, William M; Chandar, Ashwin; Bushman, Frederic D; Montelione, Gaetano T; Roth, Monica J

2015-06-23

Target-site selection by retroviral integrase (IN) proteins profoundly affects viral pathogenesis. We describe the solution nuclear magnetic resonance structure of the Moloney murine leukemia virus IN (M-MLV) C-terminal domain (CTD) and a structural homology model of the catalytic core domain (CCD). In solution, the isolated MLV IN CTD adopts an SH3 domain fold flanked by a C-terminal unstructured tail. We generated a concordant MLV IN CCD structural model using SWISS-MODEL, MMM-tree and I-TASSER. Using the X-ray crystal structure of the prototype foamy virus IN target capture complex together with our MLV domain structures, residues within the CCD α2 helical region and the CTD β1-β2 loop were predicted to bind target DNA. The role of these residues was analyzed in vivo through point mutants and motif interchanges. Viable viruses with substitutions at the IN CCD α2 helical region and the CTD β1-β2 loop were tested for effects on integration target site selection. Next-generation sequencing and analysis of integration target sequences indicate that the CCD α2 helical region, in particular P187, interacts with the sequences distal to the scissile bonds whereas the CTD β1-β2 loop binds to residues proximal to it. These findings validate our structural model and disclose IN-DNA interactions relevant to target site selection. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Assessment of Cumulative Trauma Disorder (CTD) Risk for 3 Different Tasks Constructing and Repairing Multi-Layer Insulation (MLI) Blankets, Preparing the Dough for a Pizza, and Operating the Becton-Dickinson FACSAria Flow Cytometer

NASA Technical Reports Server (NTRS)

Gentzler, Marc; Kline, Martin; Palmer, Andrew; Terrone, Mark

2007-01-01

The Cumulative Trauma Disorder (CTD) risks for three different tasks using McCauley-Bell and Badiru's (1993) formula based on task, personal, and organizational factors were examined. For the Multi-Layer Insulation (MLI) blanket task, the results showed that the task, personal, and organizational risks were at about the same level. The personal risk factors for this task were evaluated using a hypothetical female employee age 52. For the pizza dough task, it was shown that the organizational risk was particularly high, with task related factors also at quite dangerous levels. On the other hand, there was a very low level of personal risk factors, based on a female age 17. The flow cytometer task was assessed with three different participants, a11 of whom had quite disparate levels of personal risk, which slightly affected the overall CTD risk. This reveals how individual difference variables certainly need to be considered. The task and organizational risks for this task were rated at about the same moderate level. The overall CTD risk averaged across the three participants was .335, indicating some risk. Compruing across the tasks revealed that the pizza dough task created the greatest overall CTD risk by far (.568), with the MLI (.325) and flow cytometer task (.335) having some risk associated with them. Future research should look into different tasks for more of a comparison

The design, status and performance of the ZEUS central tracking detector electronics

NASA Astrophysics Data System (ADS)

Cussans, D. G.; Fawcett, H. F.; Foster, B.; Gilmore, R. S.; Heath, G. P.; Llewellyn, T. J.; Malos, J.; Morgado, C. J. S.; Tapper, R. J.; Gingrich, D. M.; Harnew, N.; Hallam-Baker, P.; Nash, J.; Khatri, T.; Shield, P. D.; McArthur, I.; Topp-Jorgensen, S.; Wilson, F. F.; Allen, D.; Baird, S. A.; Carter, R.; Galagardera, S.; Gibson, M. D.; Hatley, R. S.; Jeffs, M.; Milborrow, R.; Morissey, M.; Quinton, S. P. H.; White, D. J.; Lane, J.; Nixon, G.; Postranecky, M.; Jamdagni, A. K.; Marcou, C.; Miller, D. B.; Toudup, L.

1992-05-01

The readout system developed for the ZEUS central trackign detector (CDT) is described. The CTD is required to provide an accurate measurement of the sagitta and energy loss of charged particles as well as provide fast trigger information. This must be carried out in the HERA environment in which beams cross every 96 ns. The first two aims are achieved by digitizing chamber pulses using a pipelined 104 MHz FADC system. The trigger uses a fast determination of the difference in the arrival times of a pulse at each end of the CTD. It processes this data and gives information to the ZEUS global first level trigger. The modules are housed in custom-built racks and crates and read out using a DAQ system based on Transputer readout controllers. These also monitor data quality and produce data for the ZEUS second level Trigger.

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; King, Benjamin L; Wiegers, Jolene; Grondin, Cynthia J; Sciaky, Daniela; Johnson, Robin J; Mattingly, Carolyn J

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

Evolution of RNA-Protein Interactions: Non-Specific Binding Led to RNA Splicing Activity of Fungal Mitochondrial Tyrosyl-tRNA Synthetases

PubMed Central

Lamech, Lilian T.; Mallam, Anna L.; Lambowitz, Alan M.

2014-01-01

The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (mtTyrRS; CYT-18 protein) evolved a new function as a group I intron splicing factor by acquiring the ability to bind group I intron RNAs and stabilize their catalytically active RNA structure. Previous studies showed: (i) CYT-18 binds group I introns by using both its N-terminal catalytic domain and flexibly attached C-terminal anticodon-binding domain (CTD); and (ii) the catalytic domain binds group I introns specifically via multiple structural adaptations that occurred during or after the divergence of Peziomycotina and Saccharomycotina. However, the function of the CTD and how it contributed to the evolution of splicing activity have been unclear. Here, small angle X-ray scattering analysis of CYT-18 shows that both CTDs of the homodimeric protein extend outward from the catalytic domain, but move inward to bind opposite ends of a group I intron RNA. Biochemical assays show that the isolated CTD of CYT-18 binds RNAs non-specifically, possibly contributing to its interaction with the structurally different ends of the intron RNA. Finally, we find that the yeast mtTyrRS, which diverged from Pezizomycotina fungal mtTyrRSs prior to the evolution of splicing activity, binds group I intron and other RNAs non-specifically via its CTD, but lacks further adaptations needed for group I intron splicing. Our results suggest a scenario of constructive neutral (i.e., pre-adaptive) evolution in which an initial non-specific interaction between the CTD of an ancestral fungal mtTyrRS and a self-splicing group I intron was “fixed” by an intron RNA mutation that resulted in protein-dependent splicing. Once fixed, this interaction could be elaborated by further adaptive mutations in both the catalytic domain and CTD that enabled specific binding of group I introns. Our results highlight a role for non-specific RNA binding in the evolution of RNA-binding proteins. PMID:25536042

Evolution of RNA-protein interactions: non-specific binding led to RNA splicing activity of fungal mitochondrial tyrosyl-tRNA synthetases.

PubMed

Lamech, Lilian T; Mallam, Anna L; Lambowitz, Alan M

2014-12-01

The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (mtTyrRS; CYT-18 protein) evolved a new function as a group I intron splicing factor by acquiring the ability to bind group I intron RNAs and stabilize their catalytically active RNA structure. Previous studies showed: (i) CYT-18 binds group I introns by using both its N-terminal catalytic domain and flexibly attached C-terminal anticodon-binding domain (CTD); and (ii) the catalytic domain binds group I introns specifically via multiple structural adaptations that occurred during or after the divergence of Peziomycotina and Saccharomycotina. However, the function of the CTD and how it contributed to the evolution of splicing activity have been unclear. Here, small angle X-ray scattering analysis of CYT-18 shows that both CTDs of the homodimeric protein extend outward from the catalytic domain, but move inward to bind opposite ends of a group I intron RNA. Biochemical assays show that the isolated CTD of CYT-18 binds RNAs non-specifically, possibly contributing to its interaction with the structurally different ends of the intron RNA. Finally, we find that the yeast mtTyrRS, which diverged from Pezizomycotina fungal mtTyrRSs prior to the evolution of splicing activity, binds group I intron and other RNAs non-specifically via its CTD, but lacks further adaptations needed for group I intron splicing. Our results suggest a scenario of constructive neutral (i.e., pre-adaptive) evolution in which an initial non-specific interaction between the CTD of an ancestral fungal mtTyrRS and a self-splicing group I intron was "fixed" by an intron RNA mutation that resulted in protein-dependent splicing. Once fixed, this interaction could be elaborated by further adaptive mutations in both the catalytic domain and CTD that enabled specific binding of group I introns. Our results highlight a role for non-specific RNA binding in the evolution of RNA-binding proteins.

Targeted journal curation as a method to improve data currency at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Johnson, Robin J.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Rosenstein, Michael C.; Wiegers, Thomas C.; Mattingly, Carolyn J.

2012-01-01

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and manually curate a triad of chemical–gene, chemical–disease and gene–disease interactions. Typically, articles for CTD are selected using a chemical-centric approach by querying PubMed to retrieve a corpus containing the chemical of interest. Although this technique ensures adequate coverage of knowledge about the chemical (i.e. data completeness), it does not necessarily reflect the most current state of all toxicological research in the community at large (i.e. data currency). Keeping databases current with the most recent scientific results, as well as providing a rich historical background from legacy articles, is a challenging process. To address this issue of data currency, CTD designed and tested a journal-centric approach of curation to complement our chemical-centric method. We first identified priority journals based on defined criteria. Next, over 7 weeks, three biocurators reviewed 2425 articles from three consecutive years (2009–2011) of three targeted journals. From this corpus, 1252 articles contained relevant data for CTD and 52 752 interactions were manually curated. Here, we describe our journal selection process, two methods of document delivery for the biocurators and the analysis of the resulting curation metrics, including data currency, and both intra-journal and inter-journal comparisons of research topics. Based on our results, we expect that curation by select journals can (i) be easily incorporated into the curation pipeline to complement our chemical-centric approach; (ii) build content more evenly for chemicals, genes and diseases in CTD (rather than biasing data by chemicals-of-interest); (iii) reflect developing areas in environmental health and (iv) improve overall data currency for chemicals, genes and diseases. Database URL: http://ctdbase.org/ PMID:23221299

Heat-shock-specific phosphorylation and transcriptional activity of RNA polymerase II.

PubMed

Egyházi, E; Ossoinak, A; Lee, J M; Greenleaf, A L; Mäkelä, T P; Pigon, A

1998-07-10

The carboxyl-terminal domain (CTD) of the largest RNA polymerase II (pol II) subunit is a target for extensive phosphorylation in vivo. Using in vitro kinase assays it was found that several different protein kinases can phosphorylate the CTD including the transcription factor IIH-associated CDK-activating CDK7 kinase (R. Roy, J. P. Adamczewski, T. Seroz, W. Vermeulen, J. P. Tassan, L. Schaeffer, E. A. Nigg, J. H. Hoeijmakers, and J. M. Egly, 1994, Cell 79, 1093-1101). Here we report the colocalization of CDK7 and the phosphorylated form of CTD (phosphoCTD) to actively transcribing genes in intact salivary gland cells of Chironomus tentans. Following a heat-shock treatment, both CDK7 and pol II staining disappear from non-heat-shock genes concomitantly with the abolishment of transcriptional activity of these genes. In contrast, the actively transcribing heat-shock genes, manifested as chromosomal puff 5C on chromosome IV (IV-5C), stain intensely for phosphoCTD, but are devoid of CDK7. Furthermore, the staining of puff IV-5C with anti-PCTD antibodies was not detectably influenced by the TFIIH kinase and transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). Following heat-shock treatment, the transcription of non-heat-shock genes was completely eliminated, while newly formed heat-shock gene transcripts emerged in a DRB-resistant manner. Thus, heat shock in these cells induces a rapid clearance of CDK7 from the non-heat-shock genes, indicating a lack of involvement of CDK7 in the induction and function of the heat-induced genes. The results taken together suggest the existence of heat-shock-specific CTD phosphorylation in living cells. This phosphorylation is resistant to DRB treatment, suggesting that not only phosphorylation but also transcription of heat-shock genes is DRB resistant and that CDK7 in heat shock cells is not associated with TFIIH.

Interactive effects of dietary adaptation period length and titration diet type on apparent ileal phosphorus digestibility and phosphorus retention in growing broilers.

PubMed

Perryman, K R; Cattley, R C; Masey O'Neill, H V; Bedford, M R; Dozier, W A

2016-10-01

Two experiments were conducted to examine the effects of different corn titration diets and dietary adaptation period length (DAPL) on intestinal histology, apparent ileal P digestibility (AIPD), and apparent P retention (APR) in Ross × Ross 708 male broilers from 20 to 24 d of age. It was hypothesized that purified ingredients in nutrient-deficient titration diets may affect P availability with varying DAPL. In experiment 1, 1,152 broilers were utilized in a 3 × 3 factorial treatment structure with 3 diets (control, 25% corn titration diet [25CTD], or 75% corn titration diet [75CTD]) and 3 DAPL (0, 24, or 72 h). Experiment 2 was conducted with 576 broilers as a 4 × 3 factorial arrangement with 4 diets (control, 25CTD, 75CTD, or nitrogen-free diet [NFD]) and 3 DAPL (24, 48, or 72 h). All diets contained purified ingredients except for the control diet, which had the same formulation as the common starter and served as a control for DAPL. The NFD diet was fed as a highly purified protein-free diet. Broilers were fed a common diet until 19 d of age and then transferred to experimental diets at 20 d of age. In experiment 1, diet type did not affect (P > 0.05) intestinal histology. However, diet type and DAPL each influenced (P.≤.0.001) diet AIPD. Higher (P.≤.0.001) AIPD was measured for the control diet compared with the 75CDT, and the 25CTD had the lowest AIPD. Following a 24 h DAPL, AIPD was higher (P.≤.0.001) than after a DAPL of 0 or 72 h. In experiment 2, diet type × DAPL interactions (P.≤.0.001) were observed for APR of the control diet, 75CTD, and NFD, but not the 25CTD. Because APR of the control diet was affected by varying DAPL, factors other than differences in diet type may have been responsible for inconsistencies in the measure of P availability. Furthermore, no clear evidence was observed that broilers were able to adapt to P-deficient diets by increasing APR or AIPD. In conclusion, a standard DAPL should be established as a means to reduce variability associated with measuring of feedstuff P availability. © 2016 Poultry Science Association Inc.

Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial.

PubMed

Saunders, Peter; Tsipouri, Vicky; Keir, Gregory J; Ashby, Deborah; Flather, Marcus D; Parfrey, Helen; Babalis, Daphne; Renzoni, Elisabetta A; Denton, Christopher P; Wells, Athol U; Maher, Toby M

2017-06-15

Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m 2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life-threatening complication affecting a rare group of CTDs. ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013.

77 FR 46763 - Documents to Support Submission of an Electronic Common Technical Document; Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0724... not prepared at present to accept submissions utilizing this new version because eCTD software vendors need time to update their software to accommodate this information and because its use will require...

Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo.

PubMed

Bergvall, Monika; Gagnon, David; Titolo, Steve; Lehoux, Michaël; D'Abramo, Claudia M; Melendy, Thomas; Archambault, Jacques

2016-01-06

The papillomavirus (PV) E1 helicase contains a conserved C-terminal domain (CTD), located next to its ATP-binding site, whose function in vivo is still poorly understood. The CTD is comprised of an alpha helix followed by an acidic region (AR) and a C-terminal extension termed the C-tail. Recent biochemical studies on bovine papillomavirus 1 (BPV1) E1 showed that the AR and C-tail regulate the oligomerization of the protein into a double hexamer at the origin. In this study, we assessed the importance of the CTD of human papillomavirus 11 (HPV11) E1 in vivo, using a cell-based DNA replication assay. Our results indicate that combined deletion of the AR and C-tail drastically reduces DNA replication, by 85%, and that further truncation into the alpha-helical region compromises the structural integrity of the E1 helicase domain and its interaction with E2. Surprisingly, removal of the C-tail alone or mutation of highly conserved residues within the domain still allows significant levels of DNA replication (55%). This is in contrast to the absolute requirement for the C-tail reported for BPV1 E1 in vitro and confirmed here in vivo. Characterization of chimeric proteins in which the AR and C-tail from HPV11 E1 were replaced by those of BPV1 indicated that while the function of the AR is transferable, that of the C-tail is not. Collectively, these findings define the contribution of the three CTD subdomains to the DNA replication activity of E1 in vivo and suggest that the function of the C-tail has evolved in a PV type-specific manner. While much is known about hexameric DNA helicases from superfamily 3, the papillomavirus E1 helicase contains a unique C-terminal domain (CTD) adjacent to its ATP-binding site. We show here that this CTD is important for the DNA replication activity of HPV11 E1 in vivo and that it can be divided into three functional subdomains that roughly correspond to the three conserved regions of the CTD: an alpha helix, needed for the structural integrity of the helicase domain, followed by an acidic region (AR) and a C-terminal tail (C-tail) that have been shown to regulate the oligomerization of BPV1 E1 in vitro. Characterization of E1 chimeras revealed that, while the function of the AR could be transferred from BPV1 E1 to HPV11 E1, that of the C-tail could not. These results suggest that the E1 CTD performs multiple functions in DNA replication, some of them in a virus type-specific manner. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo

PubMed Central

Bergvall, Monika; Gagnon, David; Titolo, Steve; Lehoux, Michaël; D'Abramo, Claudia M.

2016-01-01

ABSTRACT The papillomavirus (PV) E1 helicase contains a conserved C-terminal domain (CTD), located next to its ATP-binding site, whose function in vivo is still poorly understood. The CTD is comprised of an alpha helix followed by an acidic region (AR) and a C-terminal extension termed the C-tail. Recent biochemical studies on bovine papillomavirus 1 (BPV1) E1 showed that the AR and C-tail regulate the oligomerization of the protein into a double hexamer at the origin. In this study, we assessed the importance of the CTD of human papillomavirus 11 (HPV11) E1 in vivo, using a cell-based DNA replication assay. Our results indicate that combined deletion of the AR and C-tail drastically reduces DNA replication, by 85%, and that further truncation into the alpha-helical region compromises the structural integrity of the E1 helicase domain and its interaction with E2. Surprisingly, removal of the C-tail alone or mutation of highly conserved residues within the domain still allows significant levels of DNA replication (55%). This is in contrast to the absolute requirement for the C-tail reported for BPV1 E1 in vitro and confirmed here in vivo. Characterization of chimeric proteins in which the AR and C-tail from HPV11 E1 were replaced by those of BPV1 indicated that while the function of the AR is transferable, that of the C-tail is not. Collectively, these findings define the contribution of the three CTD subdomains to the DNA replication activity of E1 in vivo and suggest that the function of the C-tail has evolved in a PV type-specific manner. IMPORTANCE While much is known about hexameric DNA helicases from superfamily 3, the papillomavirus E1 helicase contains a unique C-terminal domain (CTD) adjacent to its ATP-binding site. We show here that this CTD is important for the DNA replication activity of HPV11 E1 in vivo and that it can be divided into three functional subdomains that roughly correspond to the three conserved regions of the CTD: an alpha helix, needed for the structural integrity of the helicase domain, followed by an acidic region (AR) and a C-terminal tail (C-tail) that have been shown to regulate the oligomerization of BPV1 E1 in vitro. Characterization of E1 chimeras revealed that, while the function of the AR could be transferred from BPV1 E1 to HPV11 E1, that of the C-tail could not. These results suggest that the E1 CTD performs multiple functions in DNA replication, some of them in a virus type-specific manner. PMID:26739052

Beyond Critical Thinking Skills: Investigating the Relationship between Critical Thinking Skills and Dispositions through Different Online Instructional Strategies

ERIC Educational Resources Information Center

Yang, Ya-Ting C.; Chou, Heng-An

2008-01-01

The purpose of this study was to investigate (1) the relationship between critical thinking skills (CTS) and critical thinking dispositions (CTD), and (2) the effectiveness of different levels of instructional strategy (asynchronous online discussions (AODs), CTS instruction via AODs, and CTS instruction with CTD cultivation via AODs) in improving…

A new non-pharmacological vacuum therapy for female sexual dysfunction.

PubMed

Billups, K L; Berman, L; Berman, J; Metz, M E; Glennon, M E; Goldstein, I

2001-01-01

Although Female Sexual Dysfunction (FSD) affects 40% of American women, there is no FDA-approved pharmaceutical therapy. The EROS-CTD (Clitoral Therapy Device, UroMetrics, Inc., St. Paul, MN) treatment is the first FDA cleared-to-market therapy for FSD. Clitoral engorgement is believed to play an important role in female sexual arousal and overall sexual satisfaction. The EROS-CTD is a small, battery-powered device designed to enhance clitoral engorgement, increase blood flow to the clitoris, and ultimately improve arousal in women with FSD. The objective of this study was to assess the effectiveness of the EROS-CTD on sexual arousal (genital sensation, vaginal lubrication, ability to reach orgasm, and sexual satisfaction) in normal volunteers and women with FSD.

Structural characterization of molecular complexes formed by trimethoprim and cimitidine with 2,3,5,6-tetrachloro-1,4-benzoquinone

NASA Astrophysics Data System (ADS)

Balraj, C.; Ganesh, K.; Elango, K. P.

2011-07-01

Spectroscopic and spectrofluorimetric techniques have been employed to investigate the structure of the charge transfer (CT) complexes of Trimethoprim (TMP) and Cimitidine (CTD) drugs with 2,3,5,6-tetrachloro-1,4-benzoquinone ( p-chloranil, p-CHL). The stoichiometry of the complexes was found to be 1:2 for TMP- p-CHL system and 1:1 for CTD- p-CHL system. The thermodynamic results indicated that the formation of molecular complex between the donors and the acceptor is spontaneous and endothermic. The results of electronic spectral studies indicated that the formation constant for CTD- p-CHL system is found to be higher than that for TMP- p-CHL system. The observation is well supported by the results of fluorescence quenching studies and the association constants calculated for CTD- p-CHL system is 36.2 × 10 3 mol L -1 and that for TMP- p-CHL system is 2.6 × 10 3 mol L -1. The kinetic results, in both the cases, indicated that the interaction is first order each with respect to the concentration of the donor and the acceptor. The physico-chemical parameters viz. oscillator strength, dipole moment, ionization potential and dissociation energy of the complexes were also determined and discussed. Structural characterization of the complexes were done using FT-IR and 1H NMR spectral techniques and the results indicated that, in TMP, the free NH 2 group while in CTD the pyrazole N sbnd H moiety involves in complexation with the acceptor, p-CHL.

LRET Determination of Molecular Distances during pH Gating of the Mammalian Inward Rectifier Kir1.1b.

PubMed

Nanazashvili, Mikheil; Sánchez-Rodríguez, Jorge E; Fosque, Ben; Bezanilla, Francisco; Sackin, Henry

2018-01-09

Gating of the mammalian inward rectifier Kir1.1 at the helix bundle crossing (HBC) by intracellular pH is believed to be mediated by conformational changes in the C-terminal domain (CTD). However, the exact motion of the CTD during Kir gating remains controversial. Crystal structures and single-molecule fluorescence resonance energy transfer of KirBac channels have implied a rigid body rotation and/or a contraction of the CTD as possible triggers for opening of the HBC gate. In our study, we used lanthanide-based resonance energy transfer on single-Cys dimeric constructs of the mammalian renal inward rectifier, Kir1.1b, incorporated into anionic liposomes plus PIP 2 , to determine unambiguous, state-dependent distances between paired Cys residues on diagonally opposite subunits. Functionality and pH dependence of our proteoliposome channels were verified in separate electrophysiological experiments. The lanthanide-based resonance energy transfer distances measured in closed (pH 6) and open (pH 8) conditions indicated neither expansion nor contraction of the CTD during gating, whereas the HBC gate widened by 8.8 ± 4 Å, from 6.3 ± 2 to 15.1 ± 6 Å, during opening. These results are consistent with a Kir gating model in which rigid body rotation of the large CTD around the permeation axis is correlated with opening of the HBC hydrophobic gate, allowing permeation of a 7 Å hydrated K ion. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Optical Constituents at the Mouth of the Columbia River: Variability and Signature in Remotely Sensed Reflectance

DTIC Science & Technology

2013-09-30

constructed at BIO, carried the new Machine Vision Floc Camera (MVFC), a Sequoia Scientific LISST 100x Type B, an RBR CTD, and two pressure-actuated...WetStar CDOM fluorometer, a Sequoia Scientific flow control switch, and a SeaBird 37 CTD. The flow-control switch allows the ac- 9 to collect 0.2-um

Using the Technology of Critical Thinking Development (CTD) as a Means of Forming Competencies of Students Majoring in "Life Safety"

ERIC Educational Resources Information Center

Kayumova, Leysan R.; Morozova, Marina A.

2016-01-01

The relevance of the research problem is caused by the need to use various teaching methods and techniques in training students majoring in pedagogical specialties while implementing the competency approach in education. Information about the technology of critical thinking development (CTD) in future teachers training is limited, and the…

A Review of the Accomplishments of the CTD² Network | Office of Cancer Genomics

Cancer.gov

The Office of Cancer Genomics (OCG) Cancer Target Discovery and Development or CTD2 initiative was established by the National Cancer Institute (NCI) to accelerate the “translation” of high-throughput, high-content genomic data to the bedside through functional genomics. The CTD2 initiative is a collaborative network of 13 different research teams, or Centers.

FT-IR Study Reveals Intrinsically Disordered Nature of Heat Shock Protein 90

NASA Astrophysics Data System (ADS)

Xie, Aihua; Neto, David; Balch, Maurie; Hendriks, Johnny; Causey, Oliver; Deng, Junpeng; Matts, Robert

Heat shock protein 90 (Hsp90) is a highly conserved chaperone protein that enables the proper folding of a large number of structurally diverse proteins (a.k.a., clients) in the crowded cytosolic environment and plays a key role in regulating the heat shock response. A long standing open question is how Hsp90 accommodates the structural diversity of a large cohort of client proteins? We report ATR FTIR study on structural properties of Hsp90 C-terminal domain (CTD) and their temperature dependences. Effects of temperature on Hsp90 structure are dissected into the C-terminal domain (CTD) and the N-terminal/middle domain (NTMD). One of our major findings reveals that within a narrow temperature window across the physiological temperatures (35 to 45 C), Hsp90CTD exhibits significant increases in protein aggregation and increases in unordered structures. Despite the intrinsically disordered nature of Hsp90CTD, it retains a protected hydrophobic core at 40 C. Implications of these results will be discussed in the light of the structural dynamics and client diversity of Hsp90. AX is grateful for Grant supports from OCAST HR10-078 and NSF MRI DBI1338097.

Activation and modulation of human α4β2 nicotinic acetylcholine receptors by the neonicotinoids clothianidin and imidacloprid

PubMed Central

Li, Ping; Ann, Jason; Akk, Gustav

2013-01-01

Neonicotinoids are synthetic, nicotine-derived insecticides used for agricultural and household pest control. While highly effective at activating insect nicotinic receptors, many neonicotinoids are also capable of directly activating and/or modulating the activation of vertebrate nicotinic receptors. In this study, we have investigated the actions of the neonicotinoids clothianidin (CTD) and imidacloprid (IMI) on human neuronal α4β2 nicotinic acetylcholine receptors. The data demonstrate that the compounds are weak agonists of the human receptors with relative peak currents of 1–4 % of the response to 1 mM acetylcholine (ACh). Coapplication of IMI strongly inhibited currents elicited by ACh. From Schild plot analysis, we estimate that the affinity of IMI to the human α4β2 receptor is 18 µM. The application of low concentrations of CTD potentiated responses to low concentrations of ACh, suggesting that receptors occupied by one ACh and one CTD molecule have a higher gating efficacy than receptors with one ACh bound. Interestingly, subunit stoichiometry affected inhibition by CTD, with (α4)2(β2)3 receptors significantly more strongly inhibited than the (α4)3(β2)2 receptors. PMID:21538459

Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review.

PubMed

Atzeni, Fabiola; Gerardi, Maria Chiara; Barilaro, Giuseppe; Masala, Ignazio Francesco; Benucci, Maurizio; Sarzi-Puttini, Piercarlo

2018-01-01

Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD-ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.

Analysis of costs to dispense prescriptions in independently owned, closed-door long-term care pharmacies.

PubMed

Carroll, Norman V; Rupp, Michael T; Holdford, David A

2014-03-01

The need for accurate calculation of long-term care (LTC) pharmacies' costs to dispense (CTD) has become more important as payers have moved toward reimbursement models based on pharmacies' actual acquisition cost for drug products and the Centers for Medicare Medicaid Services (CMS) has implemented requirements that LTC pharmacies must dispense prescriptions for certain branded drugs in 14-day-or-less quantities. To (a) calculate the average cost that the typical independently owned, closed-door LTC pharmacy currently incurs to dispense and deliver a prescription to the resident of a client LTC facility and (b) estimate how CMS-mandated changes to a 14-day-or-less dispensing cycle would affect the typical LTC pharmacy's average CTD. The data requirements and measurement model were developed by academic researchers in consultation with an industry advisory committee of independent LTC pharmacy owners. A survey instrument was constructed to collect financial and operating data required to calculate the CTD. Surveys were distributed via 3 dissemination channels to approximately 1,000 independently owned, closed-door LTC pharmacies. The National Community Pharmacists Association mailed surveys to their LTC members; 3 major national wholesalers distributed surveys to their LTC customers through their newsletters; and 3 LTC group purchasing organizations distributed the surveys to their members through emails, newsletters, mailings, and/or regional meetings. Each pharmacy's CTD was calculated by dividing total LTC dispensing-related 
costs by the total number of prescriptions dispensed. Dispensing-related costs included costs incurred to physically dispense and deliver prescriptions (e.g., dispensing pharmacists' and technicians' salaries and costs of medication containers) and costs incurred to support the dispensing function (e.g., salaries of delivery and medical records personnel). A model based on dispensing-related fixed, variable, and semivariable costs was developed to examine the impact of shorter dispensing cycles on LTC pharmacies' CTD. A prescription volume increase of 19% was assumed based on converting only solid oral branded drugs to short-cycle dispensing. A diverse sample of 64 closed-door LTC pharmacies returned usable surveys. Sales from dispensing to LTC facilities accounted for more than 98% of total sales. Respondents indicated that they currently dispensed 23% of total doses in 14-day-or-less cycles and 76% in 28-31 day cycles. Most pharmacies used automated medication packaging technology, heat and cold package sealers, bar code systems, sterile compounding hoods, LTC printers or labelers, and electronic prescribing. The median CTD was $13.54 with an interquartile range (25th to 75th percentiles) of $10.51 to $17.66. More than half of dispensing-related costs were from personnel expense, of which pharmacists and managers accounted for more than 40%. The results of the fixed and variable cost modeling suggested that converting solid oral brand-name drugs from 30-day to 14-day dispensing cycles would lower the median per prescription CTD to between $11.63 and $12.54, depending on the assumptions made about the effects of semivariable costs. However, this decrease in per prescription dispensing cost is dwarfed by an increase in total dispensing cost incurred by pharmacies that results from doubling the monthly volume of short-cycle prescriptions that must be dispensed. The result is that the typical LTC pharmacy in our sample incurred a CTD of $13.54 if the medication is dispensed in a 30-day cycle or $23.26 if the medication is dispensed in two 14-day cycles (at a cost of $11.63 for each cycle dispensed). Our results indicated a median CTD of $13.54 for the typical independently owned, closed-door LTC pharmacy. Moving to a shorter cycle would reduce pharmacies' average per-prescription CTD but would increase the number of prescriptions dispensed per month. Our results indicated that transitioning solid oral branded products to 14-day cycles would reduce the median CTD to a minimum of $11.63 but would increase total dispensing costs because each sold oral branded prescription would require twice the number of monthly dispensing events.

VAX-11 Programs for Computing Available Potential Energy from CTD Data.

DTIC Science & Technology

1981-08-01

the plots can be plotted as many times as desired. The use of the translators is described at the end of section 3. The multiple branch structure of...are listed later in this section, and short * versions of them may be obtained on the terminal any time the program prompts the user for branch number...input, by typing 0/. Within each branch there may be options which are accessible by varying parameters input by the user at the time the branch

Towed Thermistor Chain Observations in Fronts-80,

DTIC Science & Technology

1980-10-01

thermistors were manu- factured by Thermometrics (Model P-85) and had a time constant of about 0.1 s (D. Caldwell, personal communication). The thermistors were...salinometer and occasionally by titration . A time series of salinity determined by the three aforementioned methods appears in Figure 8. Some of the...obviously erroneous values have been removed. The difference between salinity from the CTD and from the salinometer and titration is shown in Figure 9

Documentation of Software for the Neil Brown Instrument Systems/NORDA Velocity/CTD Profiler.

DTIC Science & Technology

1982-07-01

maximum pressure of sensor M - cast start time (dec. days) * (12- 13 - cast end time (141 - magnetic variation shp’s speed (kt) 19 -ship’s heading...100 C I 265 10? C CHECK THAT THE TIPOE FIELDS APE EACH IN RA4 6E 1084 C 0T .. -- 105 49. VAR (153 .CE,24*.00 Ilo -___-TO_999- 106 IF 4VARfib6).G(E.6r

Long non-coding RNA-CTD-2108O9.1 represses breast cancer metastasis by influencing leukemia inhibitory factor receptor.

PubMed

Wang, Mozhi; Wang, Mengshen; Wang, Zhenning; Yu, Xueting; Song, Yongxi; Wang, Chong; Xu, Yujie; Wei, Fengheng; Zhao, Yi; Xu, Yingying

2018-06-01

Breast cancer (BC) is an aggressive malignant disease in women worldwide with a high tendency to metastasize. However, important biomarkers for BC metastasis remain largely undefined. In the present study, we identified that long non-coding RNA-CTD-2108O9.1 is downregulated in BC tissues and cells and acts as a metastatic inhibitor of BC. Mechanistic investigation determined that lncRNA-CTD-2108O9.1 represses metastasis by targeting leukemia inhibitory factor receptor (LIFR), which is designated as a metastasis suppressor in BC. Our study characterizes a significant tumor suppressor active in BC metastasis repression through the known metastasis inhibitor LIFR. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Biomechanical considerations in slipped capital femoral epiphysis and insights into prophylactic fixation.

PubMed

Leblanc, E; Bellemore, J M; Cheng, T; Little, D G; Birke, O

2017-04-01

Slipped capital femoral epiphysis (SCFE) is a deformity of the proximal femur secondary to widened and unstable physis. In stabilising the slip, gold standard treatments stop growth and involve premature physeal closure, which prevents the remodelling of the acquired deformity and creates a leg length discrepancy that may be significant in younger patients. We measured the impact of placing threaded screws across the proximal femoral physis by measuring the centre-trochanteric distance (CTD) and articulo-trochanteric distance (ATD) in participants with or without prophylactic fixation. We then compared the mechanical performance of static (stainless and titanium cannulated Synthes screws) and potentially growing implants (Synthes SCFE screw and Pega Medical Free Gliding screw) in a validated synthetic bone model. In the review of 30 non-fixed and 60 fixated hips over a mean follow-up of 1.9 years, we have noted a significant difference in pre/post CTD and ATD, as well as the change in CTD and ATD over time. In the biomechanical study, the newer implants allowing growth (Synthes SCFE screw and Pega Medical Free Gliding screw) were both shown to be at least non-inferior. The primary deformity of a SCFE in itself alters hip mechanics. Also, as confirmed in this study, there is a secondary deformity that is created by static fixation and relative trochanteric overgrowth. To help remodel mild deformities and prevent secondary trochanteric overgrowth, growing implants seem to be non-inferior to the more standard means of fixation in static testing.

The C-terminal domain of Nrf1 negatively regulates the full-length CNC-bZIP factor and its shorter isoform LCR-F1/Nrf1β; both are also inhibited by the small dominant-negative Nrf1γ/δ isoforms that down-regulate ARE-battery gene expression.

PubMed

Zhang, Yiguo; Qiu, Lu; Li, Shaojun; Xiang, Yuancai; Chen, Jiayu; Ren, Yonggang

2014-01-01

The C-terminal domain (CTD, aa 686-741) of nuclear factor-erythroid 2 p45-related factor 1 (Nrf1) shares 53% amino acid sequence identity with the equivalent Neh3 domain of Nrf2, a homologous transcription factor. The Neh3 positively regulates Nrf2, but whether the Neh3-like (Neh3L) CTD of Nrf1 has a similar role in regulating Nrf1-target gene expression is unknown. Herein, we report that CTD negatively regulates the full-length Nrf1 (i.e. 120-kDa glycoprotein and 95-kDa deglycoprotein) and its shorter isoform LCR-F1/Nrf1β (55-kDa). Attachment of its CTD-adjoining 112-aa to the C-terminus of Nrf2 yields the chimaeric Nrf2-C112Nrf1 factor with a markedly decreased activity. Live-cell imaging of GFP-CTD reveals that the extra-nuclear portion of the fusion protein is allowed to associate with the endoplasmic reticulum (ER) membrane through the amphipathic Neh3L region of Nrf1 and its basic c-tail. Thus removal of either the entire CTD or the essential Neh3L portion within CTD from Nrf1, LCR-F1/Nrf1β and Nrf2-C112Nrf1, results in an increase in their transcriptional ability to regulate antioxidant response element (ARE)-driven reporter genes. Further examinations unravel that two smaller isoforms, 36-kDa Nrf1γ and 25-kDa Nrf1δ, act as dominant-negative inhibitors to compete against Nrf1, LCR-F1/Nrf1β and Nrf2. Relative to Nrf1, LCR-F1/Nrf1β is a weak activator, that is positively regulated by its Asn/Ser/Thr-rich (NST) domain and acidic domain 2 (AD2). Like AD1 of Nrf1, both AD2 and NST domain of LCR-F1/Nrf1β fused within two different chimaeric contexts to yield Gal4D:Nrf1β607 and Nrf1β:C270Nrf2, positively regulate their transactivation activity of cognate Gal4- and Nrf2-target reporter genes. More importantly, differential expression of endogenous ARE-battery genes is attributable to up-regulation by Nrf1 and LCR-F1/Nrf1β and down-regulation by Nrf1γ and Nrf1δ.

Initial Psychometric Properties of a Brief Parent-Report Instrument for Assessing Tic Severity in Children with Chronic Tic Disorders

ERIC Educational Resources Information Center

Chang, Susanna; Himle, Michael B.; Tucker, Benjamin T. P.; Woods, Douglas W.; Piacentini, John

2009-01-01

This article describes the development and initial psychometric properties of the Parent Tic Questionnaire (PTQ)--a new measure assessing the number, frequency, and intensity of motor and vocal tics in children and adolescents with Chronic Tic Disorder (CTD). Parents of 40 children with a CTD completed the PTQ as part of a larger assessment…

A CTD-Pfizer collaboration: manual curation of 88,000 scientific articles text mined for drug-disease and drug-phenotype interactions.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; Roberts, Phoebe M; King, Benjamin L; Lay, Jean M; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J; Enayetallah, Ahmed E; Mattingly, Carolyn J

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88,629 articles relating over 1,200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 254,173 toxicogenomic interactions (152,173 chemical-disease, 58,572 chemical-gene, 5,345 gene-disease and 38,083 phenotype interactions). All chemical-gene-disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer's text-mining process to collate the articles, and CTD's curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug-disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades' worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/

Text Mining Effectively Scores and Ranks the Literature for Improving Chemical-Gene-Disease Curation at the Comparative Toxicogenomics Database

PubMed Central

Johnson, Robin J.; Lay, Jean M.; Lennon-Hopkins, Kelley; Saraceni-Richards, Cynthia; Sciaky, Daniela; Murphy, Cynthia Grondin; Mattingly, Carolyn J.

2013-01-01

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS), wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel). Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency. PMID:23613709

Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding.

PubMed

Gui, Miao; Song, Wenfei; Zhou, Haixia; Xu, Jingwei; Chen, Silian; Xiang, Ye; Wang, Xinquan

2017-01-01

The global outbreak of SARS in 2002-2003 was caused by the infection of a new human coronavirus SARS-CoV. The infection of SARS-CoV is mediated mainly through the viral surface glycoproteins, which consist of S1 and S2 subunits and form trimer spikes on the envelope of the virions. Here we report the ectodomain structures of the SARS-CoV surface spike trimer in different conformational states determined by single-particle cryo-electron microscopy. The conformation 1 determined at 4.3 Å resolution is three-fold symmetric and has all the three receptor-binding C-terminal domain 1 (CTD1s) of the S1 subunits in "down" positions. The binding of the "down" CTD1s to the SARS-CoV receptor ACE2 is not possible due to steric clashes, suggesting that the conformation 1 represents a receptor-binding inactive state. Conformations 2-4 determined at 7.3, 5.7 and 6.8 Å resolutions are all asymmetric, in which one RBD rotates away from the "down" position by different angles to an "up" position. The "up" CTD1 exposes the receptor-binding site for ACE2 engagement, suggesting that the conformations 2-4 represent a receptor-binding active state. This conformational change is also required for the binding of SARS-CoV neutralizing antibodies targeting the CTD1. This phenomenon could be extended to other betacoronaviruses utilizing CTD1 of the S1 subunit for receptor binding, which provides new insights into the intermediate states of coronavirus pre-fusion spike trimer during infection.

Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization*

PubMed Central

Joseph, John; Wang, Sen; Lee, Jongseok; Ro, Jin Y.; Chung, Man-Kyo

2013-01-01

Multiple Ca2+-dependent processes are involved in capsaicin-induced desensitization of transient receptor potential vanilloid 1 (TRPV1), but desensitization of TRPV1 by heat occurs even in the absence of extracellular Ca2+, although the mechanisms are unknown. In this study, we tested the hypothesis that capsaicin and heat desensitize TRPV1 through distinct mechanisms involving distinct structural segments of TRPV1. In HEK293 cells that heterologously express TRPV1, we found that heat-induced desensitization was not affected by the inclusion of intracellular ATP or alanine mutation of Lys155, both of which attenuate capsaicin-induced desensitization, suggesting that heat-induced desensitization occurs through mechanisms distinct from capsaicin-induced desensitization. To determine protein domains involved in heat-induced desensitization, we generated chimeric proteins between TRPV1 and TRPV3, a heat-gated channel lacking heat-induced desensitization. We found that TRPV1 with the carboxyl-terminal domain (CTD) of TRPV3 retained heat activation but was impaired in heat-induced desensitization. Further experiments using chimeric or deletion mutants within TRPV1 CTD indicated that the distal half of CTD regulates the activation and desensitization of TRPV1 in modality-specific manners. Within the distal CTD, we identified two segments that distinctly regulated capsaicin- and heat-induced desensitization. The results suggest that the activation and desensitization of TRPV1 by capsaicin and heat can be modulated differentially and disproportionally through different regions of TRPV1 CTD. Identifying the domains involved in thermal regulation of TRPV1 may facilitate the development of novel anti-hyperalgesic approaches aimed at attenuating activation and enhancing desensitization of TRPV1 by thermal stimuli. PMID:24174527

Forecast of drifter trajectories using a Rapid Environmental Assessment based on CTD observations

NASA Astrophysics Data System (ADS)

Sorgente, R.; Tedesco, C.; Pessini, F.; De Dominicis, M.; Gerin, R.; Olita, A.; Fazioli, L.; Di Maio, A.; Ribotti, A.

2016-11-01

A high resolution submesoscale resolving ocean model was implemented in a limited area north of Island of Elba where a maritime exercise, named Serious Game 1 (SG1), took place on May 2014 in the framework of the project MEDESS-4MS (Mediterranean Decision Support System for Marine Safety). During the exercise, CTD data have been collected responding to the necessity of a Rapid Environmental Assessment, i.e. to a rapid evaluation of the marine conditions able to provide sensible information for initialisation of modelling tools, in the scenario of possible maritime accidents. The aim of this paper is to evaluate the impact of such mesoscale-resolving CTD observations on short-term forecasts of the surface currents, within the framework of possible oil-spill related emergencies. For this reason, modelling outputs were compared with Lagrangian observations at sea: the high resolution modelled currents, together with the ones of the coarser sub-regional model WMED, are used to force the MEDSLIK-II oil-spill model to simulate drifter trajectories. Both ocean models have been assessed by comparing the prognostic scalar and vector fields as an independent CTD data set and with real drifter trajectories acquired during SG1. The diagnosed and prognosed circulation reveals that the area was characterised by water masses of Atlantic origin influenced by small mesoscale cyclonic and anti-cyclonic eddies, which govern the spatial and temporal evolution of the drifter trajectories and of the water masses distribution. The assimilation of CTD data into the initial conditions of the high resolution model highly improves the accuracy of the short-term forecast in terms of location and structure of the thermocline and positively influence the ability of the model in reproducing the observed paths of the surface drifters.

Euclidean commute time distance embedding and its application to spectral anomaly detection

NASA Astrophysics Data System (ADS)

Albano, James A.; Messinger, David W.

2012-06-01

Spectral image analysis problems often begin by performing a preprocessing step composed of applying a transformation that generates an alternative representation of the spectral data. In this paper, a transformation based on a Markov-chain model of a random walk on a graph is introduced. More precisely, we quantify the random walk using a quantity known as the average commute time distance and find a nonlinear transformation that embeds the nodes of a graph in a Euclidean space where the separation between them is equal to the square root of this quantity. This has been referred to as the Commute Time Distance (CTD) transformation and it has the important characteristic of increasing when the number of paths between two nodes decreases and/or the lengths of those paths increase. Remarkably, a closed form solution exists for computing the average commute time distance that avoids running an iterative process and is found by simply performing an eigendecomposition on the graph Laplacian matrix. Contained in this paper is a discussion of the particular graph constructed on the spectral data for which the commute time distance is then calculated from, an introduction of some important properties of the graph Laplacian matrix, and a subspace projection that approximately preserves the maximal variance of the square root commute time distance. Finally, RX anomaly detection and Topological Anomaly Detection (TAD) algorithms will be applied to the CTD subspace followed by a discussion of their results.

A Multi-Pumping Flow System for In Situ Measurements of Dissolved Manganese in Aquatic Systems

PubMed Central

Meyer, David; Prien, Ralf D.; Dellwig, Olaf; Waniek, Joanna J.; Schuffenhauer, Ingo; Donath, Jan; Krüger, Siegfried; Pallentin, Malte; Schulz-Bull, Detlef E.

2016-01-01

A METals In Situ analyzer (METIS) has been used to determine dissolved manganese (II) concentrations in the subhalocline waters of the Gotland Deep (central Baltic Sea). High-resolution in situ measurements of total dissolved Mn were obtained in near real-time by spectrophotometry using 1-(2-pyridylazo)-2-naphthol (PAN). PAN is a complexing agent of dissolved Mn and forms a wine-red complex with a maximum absorbance at a wavelength of 562 nm. Results are presented together with ancillary temperature, salinity, and dissolved O2 data. Lab calibration of the analyzer was performed in a pressure testing tank. A detection limit of 77 nM was obtained. For validation purposes, discrete water samples were taken by using a pump-CTD system. Dissolved Mn in these samples was determined by an independent laboratory based method (inductively coupled plasma–optical emission spectrometry, ICP-OES). Mn measurements from both METIS and ICP-OES analysis were in good agreement. The results showed that the in situ analysis of dissolved Mn is a powerful technique reducing dependencies on heavy and expensive equipment (pump-CTD system, ICP-OES) and is also cost and time effective. PMID:27916898

Evaluation of the Sparton tight-tolerance AXBT

NASA Technical Reports Server (NTRS)

Boyd, Janice D.; Linzell, Robert S.

1993-01-01

Forty-six near-simultaneous pairs of conductivity - temperature - depth (CTD) and Sparton 'tight tolerance' air expendable bathythermograph (AXBT) temperature profiles were obtained in summer 1991 from a location in the Sargasso Sea. The data were analyzed to assess the temperature and depth accuracies of the Sparton AXBTs. The tight-tolerance criterion was not achieved using the manufacturer's equations but may have been achieved using customized equations computed from the CTD data. The temperature data from the customized equations had a one standard deviation error of 0.13 C. A customized elapsed fall time-to-depth conversion equation was found to be z = 1.620t - 2.2384 x 10(exp -4) t(exp 2) + 1.291 x 10(exp -7) t(exp 3), with z the depth in meters and t the elapsed fall time after probe release in seconds. The standard deviation of the depth error was about 5 m; a rule of thumb for estimating maximum bounds on the depth error below 100 m could be expressed as +/-2% of depth or +/- 10 m, whichever is greater. This equation gave greater depth accuracy than either the manufacturer's supplied equation or the navy standard equation.

Transport of the Norwegian Atlantic current as determined from satellite altimetry

NASA Technical Reports Server (NTRS)

Pistek, Pavel; Johnson, Donald R.

1992-01-01

Relatively warm and salty North Atlantic surface waters flow through the Faeroe-Shetland Channel into the higher latitudes of the Nordic Seas, preserving an ice-free winter environment for much of the exterior coast of northern Europe. This flow was monitored along the Norwegian coast using Geosat altimetry on two ascending arcs during the Exact Repeat Mission in 1987-1989. Concurrent undertrack CTD surveys were used to fix a reference surface for the altimeter-derived SSH anomalies, in effect creating time series of alongtrack surface dynamic height topographies. Climatologic CTD casts were then used, with empirical orthogonal function (EOF) analysis, to derive relationships between historical surface dynamic heights and vertical temperature and salinity profiles. Applying these EOF relationships to the altimeter signals, mean transports of volume, heat, and salt were calculated at approximately 2.9 Sverdrups, 8.1 x 10 exp 11 KCal/s and 1.0 x 10 exp 8 Kg/s, respectively. Maximum transports occurred in February/March and minimum in July/August.

Acquisition of an Underway CTD System for the Flow Encountering Abrupt Topography DRI

DTIC Science & Technology

2015-09-30

Acquisition of an Underway CTD System for the Flow Encountering Abrupt Topography DRI T. M. Shaun Johnston Scripps Institution of Oceanography...westward flow in the North Equatorial Current (NEC) encounters tall, steep, submarine topography and islands. During the Flow Encountering Abrupt... Topography (FLEAT) DRI, investigators will determine: • Whether appreciable energy/momentum is lost from the large-scale NEC flow to smaller scales and

The Acquisition, Calibration, and Analysis of CTD Data. Unesco Technical Papers in Marine Science No. 54. (A Report of SCOR Working Group 51).

ERIC Educational Resources Information Center

United Nations Educational, Scientific, and Cultural Organization, Paris (France). Div. of Marine Sciences.

In this report the members of the Scientific Committee on Ocean Research Working Group 51 have attempted to describe the total process involved in obtaining salinity and temperature profiles with modern conductivity-temperature-depth (CTD) instruments. Their objective has been to provide a guide to procedures which will, if allowed, lead to the…

Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist.

PubMed

Li, Xuefei; Azlina, Ahmad; Karabasil, Mileva Ratko; Purwanti, Nunuk; Hasegawa, Takahiro; Yao, Chenjuan; Akamatsu, Tetsuya; Hosoi, Kazuo

2008-07-01

By chorda tympani denervation (CTD, parasympathectomy), the aquaporin 5 (AQP5), but not AQP1, protein level in the rat submandibular gland (SMG) was significantly decreased, dropping to 37% of that of the contralateral gland at 4 wk. The protein levels of AQP5 and AQP1 were not significantly affected by denervation of the cervical sympathetic trunk (sympathectomy). Administration of cevimeline hydrochloride, an M3 muscarinic receptor agonist (10 mg/kg for 7 days po), but not pilocarpine (0.3 mg/kg for 7 days po), recovered the AQP5 protein level reduced by CTD and increased the AQP1 protein level above the control one. The mRNA level of AQP5 was scarcely affected by CTD and cevimeline hydrochloride administration. Administration of chloroquine (50 mg/kg for 7 days po), a denaturant of lysosomes, increased the AQP5 protein level reduced by CTD. An extract obtained from the submandibular lysosomal fraction degraded the AQP5 protein in the total membrane fraction in vitro. These results suggest the possible regulation of the AQP5 protein level in the SMG by the parasympathetic nerves/M3 muscarinic receptor agonist and imply the involvement of lysosomal enzymes, but not a transcriptional mechanism, in this regulation.

Gene-Environment Interplay in Twin Models

PubMed Central

Hatemi, Peter K.

2013-01-01

In this article, we respond to Shultziner’s critique that argues that identical twins are more alike not because of genetic similarity, but because they select into more similar environments and respond to stimuli in comparable ways, and that these effects bias twin model estimates to such an extent that they are invalid. The essay further argues that the theory and methods that undergird twin models, as well as the empirical studies which rely upon them, are unaware of these potential biases. We correct this and other misunderstandings in the essay and find that gene-environment (GE) interplay is a well-articulated concept in behavior genetics and political science, operationalized as gene-environment correlation and gene-environment interaction. Both are incorporated into interpretations of the classical twin design (CTD) and estimated in numerous empirical studies through extensions of the CTD. We then conduct simulations to quantify the influence of GE interplay on estimates from the CTD. Due to the criticism’s mischaracterization of the CTD and GE interplay, combined with the absence of any empirical evidence to counter what is presented in the extant literature and this article, we conclude that the critique does not enhance our understanding of the processes that drive political traits, genetic or otherwise. PMID:24808718

Tubular Crystals and Helical Arrays: Structural Determination of HIV-1 Capsid Assemblies Using Iterative Helical Real-Space Reconstruction

PubMed Central

Zhang, Peijun; Meng, Xin; Zhao, Gongpu

2013-01-01

Helical structures are important in many different life forms and are well-suited for structural studies by cryo-EM. A unique feature of helical objects is that a single projection image contains all the views needed to perform a three-dimensional (3D) crystallographic reconstruction. Here, we use HIV-1 capsid assemblies to illustrate the detailed approaches to obtain 3D density maps from helical objects. Mature HIV-1 particles contain a conical- or tubular-shaped capsid that encloses the viral RNA genome and performs essential functions in the virus life cycle. The capsid is composed of capsid protein (CA) oligomers which are helically arranged on the surface. The N-terminal domain (NTD) of CA is connected to its C-terminal domain (CTD) through a flexible hinge. Structural analysis of two- and three-dimensional crystals provided molecular models of the capsid protein (CA) and its oligomer forms. We determined the 3D density map of helically assembled HIV-1 CA hexamers at 16 Å resolution using an iterative helical real-space reconstruction method. Docking of atomic models of CA-NTD and CA-CTD dimer into the electron density map indicated that the CTD dimer interface is retained in the assembled CA. Furthermore, molecular docking revealed an additional, novel CTD trimer interface. PMID:23132072

Randomized interpolative decomposition of separated representations

NASA Astrophysics Data System (ADS)

Biagioni, David J.; Beylkin, Daniel; Beylkin, Gregory

2015-01-01

We introduce an algorithm to compute tensor interpolative decomposition (dubbed CTD-ID) for the reduction of the separation rank of Canonical Tensor Decompositions (CTDs). Tensor ID selects, for a user-defined accuracy ɛ, a near optimal subset of terms of a CTD to represent the remaining terms via a linear combination of the selected terms. CTD-ID can be used as an alternative to or in combination with the Alternating Least Squares (ALS) algorithm. We present examples of its use within a convergent iteration to compute inverse operators in high dimensions. We also briefly discuss the spectral norm as a computational alternative to the Frobenius norm in estimating approximation errors of tensor ID. We reduce the problem of finding tensor IDs to that of constructing interpolative decompositions of certain matrices. These matrices are generated via randomized projection of the terms of the given tensor. We provide cost estimates and several examples of the new approach to the reduction of separation rank.

Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation.

PubMed

Tang, Xiaoling; Jang, Sung-Wuk; Wang, Xuerong; Liu, Zhixue; Bahr, Scott M; Sun, Shi-Yong; Brat, Daniel; Gutmann, David H; Ye, Keqiang

2007-10-01

The neurofibromatosis-2 (NF2) tumour-suppressor gene encodes an intracellular membrane-associated protein, called merlin, whose growth-suppressive function is dependent on its ability to form interactions through its intramolecular amino-terminal domain (NTD) and carboxy-terminal domain (CTD). Merlin phosphorylation plays a critical part in dictating merlin NTD/CTD interactions as well as in controlling binding to its effector proteins. Merlin is partially regulated by phosphorylation of Ser 518, such that hyperphosphorylated merlin is inactive and fails to form productive intramolecular and intermolecular interactions. Here, we show that the protein kinase Akt directly binds to and phosphorylates merlin on residues Thr 230 and Ser 315, which abolishes merlin NTD/CTD interactions and binding to merlin's effector protein PIKE-L and other binding partners. Furthermore, Akt-mediated phosphorylation leads to merlin degradation by ubiquitination. These studies demonstrate that Akt-mediated merlin phosphorylation regulates the function of merlin in the absence of an inactivating mutation.

The C-Terminal Domain of Nrf1 Negatively Regulates the Full-Length CNC-bZIP Factor and Its Shorter Isoform LCR-F1/Nrf1β; Both Are Also Inhibited by the Small Dominant-Negative Nrf1γ/δ Isoforms that Down-Regulate ARE-Battery Gene Expression

PubMed Central

Zhang, Yiguo; Qiu, Lu; Li, Shaojun; Xiang, Yuancai; Chen, Jiayu; Ren, Yonggang

2014-01-01

The C-terminal domain (CTD, aa 686–741) of nuclear factor-erythroid 2 p45-related factor 1 (Nrf1) shares 53% amino acid sequence identity with the equivalent Neh3 domain of Nrf2, a homologous transcription factor. The Neh3 positively regulates Nrf2, but whether the Neh3-like (Neh3L) CTD of Nrf1 has a similar role in regulating Nrf1-target gene expression is unknown. Herein, we report that CTD negatively regulates the full-length Nrf1 (i.e. 120-kDa glycoprotein and 95-kDa deglycoprotein) and its shorter isoform LCR-F1/Nrf1β (55-kDa). Attachment of its CTD-adjoining 112-aa to the C-terminus of Nrf2 yields the chimaeric Nrf2-C112Nrf1 factor with a markedly decreased activity. Live-cell imaging of GFP-CTD reveals that the extra-nuclear portion of the fusion protein is allowed to associate with the endoplasmic reticulum (ER) membrane through the amphipathic Neh3L region of Nrf1 and its basic c-tail. Thus removal of either the entire CTD or the essential Neh3L portion within CTD from Nrf1, LCR-F1/Nrf1β and Nrf2-C112Nrf1, results in an increase in their transcriptional ability to regulate antioxidant response element (ARE)-driven reporter genes. Further examinations unravel that two smaller isoforms, 36-kDa Nrf1γ and 25-kDa Nrf1δ, act as dominant-negative inhibitors to compete against Nrf1, LCR-F1/Nrf1β and Nrf2. Relative to Nrf1, LCR-F1/Nrf1β is a weak activator, that is positively regulated by its Asn/Ser/Thr-rich (NST) domain and acidic domain 2 (AD2). Like AD1 of Nrf1, both AD2 and NST domain of LCR-F1/Nrf1β fused within two different chimaeric contexts to yield Gal4D:Nrf1β607 and Nrf1β:C270Nrf2, positively regulate their transactivation activity of cognate Gal4- and Nrf2-target reporter genes. More importantly, differential expression of endogenous ARE-battery genes is attributable to up-regulation by Nrf1 and LCR-F1/Nrf1β and down-regulation by Nrf1γ and Nrf1δ. PMID:25290918

Elephant Seals and Temperature Data: Calibrations and Limitations.

NASA Astrophysics Data System (ADS)

Simmons, S. E.; Tremblay, Y.; Costa, D. P.

2006-12-01

In recent years with technological advances, instruments deployed on diving marine animals have been used to sample the environment in addition to their behavior. Of all oceanographic variables one of the most valuable and easiest to record is temperature. Here we report on a series of lab calibration and field validation experiments that consider the accuracy of temperature measurements from animal borne ocean samplers. Additionally we consider whether sampling frequency or animal behavior affects the quality of the temperature data collected by marine animals. Rapid response, external temperature sensors on eight Wildlife Computers MK9 time-depth recorders (TDRs) were calibrated using water baths at the Naval Postgraduate School (Monterey, CA). These water baths are calibrated using a platinum thermistor to 0.001° C. Instruments from different production batches were calibrated before and after deployments on adult female northern elephant seals, to examine tag performance over time and under `normal' usage. Tag performance in the field was validated by comparisons with temperature data from a Seabird CTD. In April/May of 2004, casts to 200m were performed over the Monterey Canyon using a CTD array carrying MK9s. These casts were performed before and after the release of a juvenile elephant seal from the boat. The seal was also carrying an MK9 TDR, allowing the assessment of any animal effect on temperature profiles. Sampling frequency during these field validations was set at one second intervals and the data from TDRs on both the CTD and the seals was sub-sampled at four, eight, 30 and 300 (5 min) seconds. The sub-sampled data was used to determine thermocline depth, a thermocline depth zone and temperature gradients and assess whether sampling frequency or animal behavior affects the quality of temperature data. Preliminary analyses indicate that temperature sensors deployed on elephant seals can provide water column temperature data of high quality and precision.

Molecular determinants of tetramerization in the KcsA cytoplasmic domain.

PubMed

Kamnesky, Guy; Hirschhorn, Orel; Shaked, Hadassa; Chen, Jingfei; Yao, Lishan; Chill, Jordan H

2014-10-01

The cytoplasmic C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is an amphiphilic domain that forms a helical bundle with four-fold symmetry mediated by hydrophobic and electrostatic interactions. Previously we have established that a CTD-derived 34-residue peptide associates into a tetramer in a pH-dependent manner (Kamnesky et al., JMB 2012;418:237-247). Here we further investigate the molecular determinants of tetramer formation in the CTD by characterizing the kinetics of monomer-tetramer equilibrium for 10 alanine mutants using NMR, sedimentation equilibrium (SE) and molecular dynamics simulation. NMR and SE concur in finding single-residue contributions to tetramer stability to be in the 0.5 to 3.5 kcal/mol range. Hydrophobic interactions between residues lining the tetramer core generally contributed more to formation of tetramer than electrostatic interactions between residues R147, D149 and E152. In particular, alanine replacement of residue R147, a key contributor to inter-subunit salt bridges, resulted in only a minor effect on tetramer dissociation. Mutations outside of the inter-subunit interface also influenced tetramer stability by affecting the tetramerization on-rate, possibly by changing the inherent helical propensity of the peptide. These findings are interpreted in the context of established paradigms of protein-protein interactions and protein folding, and lay the groundwork for further studies of the CTD in full-length KcsA channels. © 2014 The Protein Society.

Molecular determinants of tetramerization in the KcsA cytoplasmic domain

PubMed Central

Kamnesky, Guy; Hirschhorn, Orel; Shaked, Hadassa; Chen, Jingfei; Yao, Lishan; Chill, Jordan H

2014-01-01

The cytoplasmic C-terminal domain (CTD) of KcsA, a bacterial homotetrameric potassium channel, is an amphiphilic domain that forms a helical bundle with four-fold symmetry mediated by hydrophobic and electrostatic interactions. Previously we have established that a CTD-derived 34-residue peptide associates into a tetramer in a pH-dependent manner (Kamnesky et al., JMB 2012;418:237-247). Here we further investigate the molecular determinants of tetramer formation in the CTD by characterizing the kinetics of monomer-tetramer equilibrium for 10 alanine mutants using NMR, sedimentation equilibrium (SE) and molecular dynamics simulation. NMR and SE concur in finding single-residue contributions to tetramer stability to be in the 0.5 to 3.5 kcal/mol range. Hydrophobic interactions between residues lining the tetramer core generally contributed more to formation of tetramer than electrostatic interactions between residues R147, D149 and E152. In particular, alanine replacement of residue R147, a key contributor to inter-subunit salt bridges, resulted in only a minor effect on tetramer dissociation. Mutations outside of the inter-subunit interface also influenced tetramer stability by affecting the tetramerization on-rate, possibly by changing the inherent helical propensity of the peptide. These findings are interpreted in the context of established paradigms of protein-protein interactions and protein folding, and lay the groundwork for further studies of the CTD in full-length KcsA channels. PMID:25042120

The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes.

PubMed

Fletcher, Katherine; Ulferts, Rachel; Jacquin, Elise; Veith, Talitha; Gammoh, Noor; Arasteh, Julia M; Mayer, Ulrike; Carding, Simon R; Wileman, Thomas; Beale, Rupert; Florey, Oliver

2018-02-15

A hallmark of macroautophagy is the covalent lipidation of LC3 and insertion into the double-membrane phagophore, which is driven by the ATG16L1/ATG5-ATG12 complex. In contrast, non-canonical autophagy is a pathway through which LC3 is lipidated and inserted into single membranes, particularly endolysosomal vacuoles during cell engulfment events such as LC3-associated phagocytosis. Factors controlling the targeting of ATG16L1 to phagophores are dispensable for non-canonical autophagy, for which the mechanism of ATG16L1 recruitment is unknown. Here we show that the WD repeat-containing C-terminal domain (WD40 CTD) of ATG16L1 is essential for LC3 recruitment to endolysosomal membranes during non-canonical autophagy, but dispensable for canonical autophagy. Using this strategy to inhibit non-canonical autophagy specifically, we show a reduction of MHC class II antigen presentation in dendritic cells from mice lacking the WD40 CTD Further, we demonstrate activation of non-canonical autophagy dependent on the WD40 CTD during influenza A virus infection. This suggests dependence on WD40 CTD distinguishes between macroautophagy and non-canonical use of autophagy machinery. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

From pole to pole: 33 years of physical oceanography onboard R/V Polarstern

NASA Astrophysics Data System (ADS)

Driemel, Amelie; Fahrbach, Eberhard; Rohardt, Gerd; Beszczynska-Möller, Agnieszka; Boetius, Antje; Budéus, Gereon; Cisewski, Boris; Engbrodt, Ralph; Gauger, Steffen; Geibert, Walter; Geprägs, Patrizia; Gerdes, Dieter; Gersonde, Rainer; Gordon, Arnold L.; Grobe, Hannes; Hellmer, Hartmut H.; Isla, Enrique; Jacobs, Stanley S.; Janout, Markus; Jokat, Wilfried; Klages, Michael; Kuhn, Gerhard; Meincke, Jens; Ober, Sven; Østerhus, Svein; Peterson, Ray G.; Rabe, Benjamin; Rudels, Bert; Schauer, Ursula; Schröder, Michael; Schumacher, Stefanie; Sieger, Rainer; Sildam, Jüri; Soltwedel, Thomas; Stangeew, Elena; Stein, Manfred; Strass, Volker H.; Thiede, Jörn; Tippenhauer, Sandra; Veth, Cornelis; von Appen, Wilken-Jon; Weirig, Marie-France; Wisotzki, Andreas; Wolf-Gladrow, Dieter A.; Kanzow, Torsten

2017-03-01

Measuring temperature and salinity profiles in the world's oceans is crucial to understanding ocean dynamics and its influence on the heat budget, the water cycle, the marine environment and on our climate. Since 1983 the German research vessel and icebreaker Polarstern has been the platform of numerous CTD (conductivity, temperature, depth instrument) deployments in the Arctic and the Antarctic. We report on a unique data collection spanning 33 years of polar CTD data. In total 131 data sets (1 data set per cruise leg) containing data from 10 063 CTD casts are now freely available at doi:10.1594/PANGAEA.860066. During this long period five CTD types with different characteristics and accuracies have been used. Therefore the instruments and processing procedures (sensor calibration, data validation, etc.) are described in detail. This compilation is special not only with regard to the quantity but also the quality of the data - the latter indicated for each data set using defined quality codes. The complete data collection includes a number of repeated sections for which the quality code can be used to investigate and evaluate long-term changes. Beginning with 2010, the salinity measurements presented here are of the highest quality possible in this field owing to the introduction of the OPTIMARE Precision Salinometer.

NOAEL-dose of a neonicotinoid pesticide, clothianidin, acutely induce anxiety-related behavior with human-audible vocalizations in male mice in a novel environment.

PubMed

Hirano, Tetsushi; Yanai, Shogo; Takada, Tadashi; Yoneda, Naoki; Omotehara, Takuya; Kubota, Naoto; Minami, Kiichi; Yamamoto, Anzu; Mantani, Youhei; Yokoyama, Toshifumi; Kitagawa, Hiroshi; Hoshi, Nobuhiko

2018-01-05

Neonicotinoids are novel systemic pesticides acting as agonists on the nicotinic acetylcholine receptors (nAChRs) of insects. Experimental studies have revealed that neonicotinoids pose potential risks for the nervous systems of non-target species, but the brain regions responsible for their behavioral effects remain incompletely understood. This study aimed to assess the neurobehavioral effects of clothianidin (CTD), a later neonicotinoid developed in 2001 and widely used worldwide, and to explore the target regions of neonicotinoids in the mammalian brain. A single-administration of 5 or 50mg/kg CTD to male C57BL/6N mice at or below the no-observed-adverse-effect level (NOAEL) induced an acute increase in anxiety during the elevated plus-maze test. In addition, mice in the CTD-administered group spontaneously emitted human-audible vocalizations (4-16kHz), which are behavioral signs of aversive emotions, and showed increased numbers of c-fos immunoreactive cells in the paraventricular thalamic nucleus and dentate gyrus of the hippocampus. In conclusion, mice exposed to NOAEL-dose CTD would be rendered vulnerable to a novel environment via the activation of thalamic and hippocampal regions related to stress responses. These findings should provide critical insight into the neurobehavioral effects of neonicotinoids on mammals. Copyright © 2017 Elsevier B.V. All rights reserved.

Spacing requirements for interactions between the C-terminal domain of the alpha subunit of Escherichia coli RNA polymerase and the cAMP receptor protein.

PubMed Central

Lloyd, G S; Busby, S J; Savery, N J

1998-01-01

During transcription initiation at bacterial promoters, the C-terminal domain of the RNA polymerase alpha subunit (alphaCTD) can interact with DNA-sequence elements (known as UP elements) and with activator proteins. We have constructed a series of semi-synthetic promoters carrying both an UP element and a consensus DNA-binding site for the Escherichia coli cAMP receptor protein (CRP; a factor that activates transcription by making direct contacts with alphaCTD). At these promoters, the UP element was located at a variety of distances upstream of the CRP-binding site, which was fixed at position -41.5 bp upstream of the transcript start. At some positions, the UP element caused enhanced promoter activity whereas, at other positions, it had very little effect. In no case was the CRP-dependence of the promoter relieved. DNase I and hydroxyl-radical footprinting were used to study ternary RNA polymerase-CRP-promoter complexes formed at two of the most active of these promoters, and co-operativity between the binding of CRP and purified alpha subunits was studied. The footprints show that alphaCTD binds to the UP element as it is displaced upstream but that this displacement does not prevent alphaCTD from being contacted by CRP. Models to account for this are discussed. PMID:9461538

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; King, Benjamin L.; Wiegers, Jolene; Grondin, Cynthia J.; Sciaky, Daniela; Johnson, Robin J.; Mattingly, Carolyn J.

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD’s gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects. PMID:27171405

The Binding of Plasmodium falciparum Adhesins and Erythrocyte Invasion Proteins to Aldolase Is Enhanced by Phosphorylation.

PubMed

Diaz, Suraya A; Martin, Stephen R; Howell, Steven A; Grainger, Munira; Moon, Robert W; Green, Judith L; Holder, Anthony A

2016-01-01

Aldolase has been implicated as a protein coupling the actomyosin motor and cell surface adhesins involved in motility and host cell invasion in the human malaria parasite Plasmodium falciparum. It binds to the cytoplasmic domain (CTD) of type 1 membrane proteins of the thrombospondin-related anonymous protein (TRAP) family. Other type 1 membrane proteins located in the apical organelles of merozoites, the form of the parasite that invades red blood cells, including apical membrane antigen 1 (AMA1) and members of the erythrocyte binding ligand (EBL) and reticulocyte binding homologue (RH) protein families have been implicated in host cell binding and invasion. Using a direct binding method we confirm that TRAP and merozoite TRAP (MTRAP) bind aldolase and show that the interaction is mediated by more than just the C-terminal six amino acid residues identified previously. Single amino acid substitutions in the MTRAP CTD abolished binding to aldolase. The CTDs of AMA1 and members of the EBL and RH protein families also bound to aldolase. MTRAP competed with AMA1 and RH4 for binding to aldolase, indicating overlapping binding sites. MTRAP CTD was phosphorylated in vitro by both calcium dependent kinase 1 (CDPK1) and protein kinase A, and this modification increased the affinity of binding to aldolase by ten-fold. Phosphorylation of the CTD of members of the EBL and RH protein families also increased their affinity for aldolase in some cases. To examine whether or not MTRAP expressed in asexual blood stage parasites is phosphorylated, it was tagged with GFP, purified and analysed, however no phosphorylation was detected. We propose that CTD binding to aldolase may be dynamically modulated by phosphorylation, and there may be competition for aldolase binding between different CTDs. The use and efficiency of alternate invasion pathways may be determined by the affinity of adhesins and cell invasion proteins for aldolase, in addition to their host ligand specificity.

Cruise Summary of WHP P6, A10, I3 and I4 Revisits in 2003

NASA Astrophysics Data System (ADS)

Kawano, T.; Uchida, H.; Schneider, W.; Kumamoto, Y.; Nishina, A.; Aoyama, M.; Murata, A.; Sasaki, K.; Yoshikawa, Y.; Watanabe, S.; Fukasawa, M.

2004-12-01

Japan Agency for Marin-Earth Science and Technology (JAMSTEC) conducted a research cruise to round in the southern hemisphere by R/V Mirai. In this presentation, we introduce an outline of the cruise and data quality obtained during the cruise. The cruise started on Aug. 3, 2003 in Brisbane, Australia and sailed eastward until it reached Fremantle, Australia on Feb. 19, 2004. It contained six legs and legs 1, 2, 4 and 5 were revisits of WOCE Hydrographic Program (WHP) sections P6W, P6E, A10 and I3/I4, respectively. The sections consisted of about 500 hydrographic stations in total. On each station, CTD profiles and up to 36 water samples by 12L Niskin-X bottles were taken from the surface to within 10 m of the bottom. Water samples were analyzed at every station for salinity, dissolved oxygen (DO), and nutrients and at alternate stations for concentration of freons, dissolved inorganic carbon (CT), total alkalinity (AT), pH, and so on. Approximately 17,000 samples were obtained for salinity. The standard seawater was measured repeatedly to estimate the uncertainty caused by the setting and stability of the salinometer. The standard deviation of 699 repeated runs of standard seawater was 0.0002 in salinity. Replicate samples, which are a pair of samples drawn from the same Niskin bottle to different sample bottles, were taken to evaluate the overall uncertainty. The standard deviation of absolute differences of 2,769 replicates was also 0.0002 in salinity. For DO, about 13,400 samples were obtained. The analysis was made by a photometric titration technique. The reproducibility estimated from the absolute standard deviation of 1,625 replicates was about 0.09 umol/kg. CTD temperature was calibrated against a deep ocean standards thermometer (SBE35) which was attached to the CTD using a polynomial expression Tcal = T - (a +b*P + c*t), where Tcal is calibrated temperature, T is CTD temperature, P is CTD pressure and t is time. Calibration coefficients, a, b and c, were determined for each station by minimizing the sum of absolute deviation from SBE35 temperature below 2,000dbar. CTD salinity and DO were fitted to values obtained by sampled water analysis using similar polynomials. These corrections yielded deviations of about 0.0002 K in temperature, 0.0003 in salinity and 0.6 umol/kg in DO. Nutrients analyses were accomplished on 16,000 samples using the reference material of nutrients in seawater (RMNS). To establish the traceability and to get higher quality data, 500 bottles of RMNS from the same lot and 150 sets of RMNSs were used. The precisions of phosphate, nitrate and silicate measurements were 0.18 %, 0.17 % and 0.16 % in terms of median of those at 493 stations, respectively. The nutrients concentrations could be expressed with uncertainties explicitly because of the repeated runs of RMNSs. All the analyses for the CO{2}-system parameters in water columns were finished onboard. Analytical precisions of CT, AT and pH were estimated to be \\sim1.0 umol/kg, \\sim2.0 umol/kg, and \\sim7*10-4 pH unit, respectively. Approximately 6,300 samples were obtained for CFC-11 and CFC-12. The concentrations were determined with an electron capture detector - gas chromatograph (ECD-GC) attached the purge and trapping system. The reproducibility estimated from the absolute standard deviation of 365 replicates was less than 1% with respect to the surface concentrations.

Recommendations for Improving FBI Joint Counterterrorism Operations

DTIC Science & Technology

2012-03-13

Division (CTD), via an electronic database. Within the database, vacant positions post for a period of two weeks, which limits the time for a...in Comparative Politics at New York University. 30 Mueller, p.1 31 Cigar , Norman. Al-Qaida, The Tribes, and The Government: Lessons and Prospects...Reflections on US Intelligence. Washington, DC: Center for the Study of Intelligence. 1996. Cigar , Norman. Al-Qaida, The Tribes, and The Government

Accelerating Adverse Outcome Pathway (AOP) development ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. However, the conventional process for assembly of these AOPs is time and resource intensive, and has been a rate limiting step for AOP use and development. Therefore computational approaches to accelerate the process need to be developed. We previously developed a method for generating computationally predicted AOPs (cpAOPs) by association mining and integration of data from publicly available databases. In this work, a cpAOP network of ~21,000 associations was established between 105 phenotypes from TG-GATEs rat liver data from different time points (including microarray, pathological effects and clinical chemistry data), 994 REACTOME pathways, 688 High-throughput assays from ToxCast and 194 chemicals. A second network of 128,536 associations was generated by connecting 255 biological target genes from ToxCast to 4,980 diseases from CTD using either HT screening activity from ToxCast for 286 chemicals or CTD gene expression changes in response to 2,330 chemicals. Both networks were separately evaluated through manual extraction of disease-specific cpAOPs and comparison with expert curation of the relevant literature. By employing data integration strategies that involve the weighting of n

Baseline Characteristics of the Korean Registry of Pulmonary Arterial Hypertension.

PubMed

Chung, Wook-Jin; Park, Yong Bum; Jeon, Chan Hong; Jung, Jo Won; Ko, Kwang-Phil; Choi, Sung Jae; Seo, Hye Sun; Lee, Jae Seung; Jung, Hae Ok

2015-10-01

Despite recent advances in understanding of the pathobiology and targeted treatments of pulmonary arterial hypertension (PAH), epidemiologic data from large populations have been limited to western countries. The aim of the Korean Registry of Pulmonary Arterial Hypertension (KORPAH) was to examine the epidemiology and prognosis of Korean patients with PAH. KORPAH was designed as a nationwide, multicenter, prospective data collection using an internet webserver from September 2008 to December 2011. A total of 625 patients were enrolled. The patients' mean age was 47.6 ± 15.7 yr, and 503 (80.5%) were women. The diagnostic methods included right heart catheterization (n = 249, 39.8%) and Doppler echocardiography (n = 376, 60.2%). The etiologies, in order of frequency, were connective tissue disease (CTD), congenital heart disease, and idiopathic PAH (IPAH) (49.8%, 25.4%, and 23.2%, respectively). Patients with WHO functional class III or IV at diagnosis were 43.4%. In total, 380 (60.8%) patients received a single PAH-specific treatment at the time of enrollment, but only 72 (18.9%) patients received combination therapy. Incident cases during the registry represented 297 patients; therefore, the incidence rate of PAH was 1.9 patients/yr/million people. The 1st-, 2nd-, and 3rd-yr estimated survival rates were 90.8%, 87.8%, and 84.4%, respectively. Although Korean PAH patients exhibited similar age, gender, and survival rate compared with western registries, they showed relatively more CTD-PAH in the etiology and also systemic lupus erythematosus among CTD-PAH. The data suggest that earlier diagnosis and more specialized therapies should be needed to improve the survival of PAH patients.

Architecture of the bacteriophage T4 activator MotA/promoter DNA interaction during sigma appropriation.

PubMed

Hsieh, Meng-Lun; James, Tamara D; Knipling, Leslie; Waddell, M Brett; White, Stephen; Hinton, Deborah M

2013-09-20

Gene expression can be regulated through factors that direct RNA polymerase to the correct promoter sequence at the correct time. Bacteriophage T4 controls its development in this way using phage proteins that interact with host RNA polymerase. Using a process called σ appropriation, the T4 co-activator AsiA structurally remodels the σ(70) subunit of host RNA polymerase, while a T4 activator, MotA, engages the C terminus of σ(70) and binds to a DNA promoter element, the MotA box. Structures for the N-terminal (NTD) and C-terminal (CTD) domains of MotA are available, but no structure exists for MotA with or without DNA. We report the first molecular map of the MotA/DNA interaction within the σ-appropriated complex, which we obtained by using the cleaving reagent, iron bromoacetamidobenzyl-EDTA (FeBABE). We conjugated surface-exposed, single cysteines in MotA with FeBABE and performed cleavage reactions in the context of stable transcription complexes. The DNA cleavage sites were analyzed using ICM Molsoft software and three-dimensional physical models of MotA(NTD), MotA(CTD), and the DNA to investigate shape complementarity between the protein and the DNA and to position MotA on the DNA. We found that the unusual "double wing" motif present within MotA(CTD) resides in the major groove of the MotA box. In addition, we have used surface plasmon resonance to show that MotA alone is in a very dynamic equilibrium with the MotA element. Our results demonstrate the utility of fine resolution FeBABE mapping to determine the architecture of protein-DNA complexes that have been recalcitrant to traditional structure analyses.

Alterations in receptor expression or agonist concentration change the pathways gastrin-releasing peptide receptor uses to regulate extracellular signal-regulated kinase.

PubMed

Chen, Pei-Wen; Kroog, Glenn S

2004-12-01

G protein-coupled receptors activate extracellular signal-regulated kinases (ERKs) via different pathways in different cell types. In this study, we demonstrate that gastrin-releasing peptide receptor (GRPr) regulates ERK through multiple pathways in a single cell type depending upon receptor expression and agonist concentration. We examined stably transfected BALB/c 3T3 fibroblasts expressing GRPr constructs at different levels and treated the cells with several concentrations of bombesin (BN, a GRPr agonist) to activate a variable number of GRPr per cell. GRPr induced two waves of ERK activation and one wave of ERK inhibition. One wave of activation required an intact GRPr carboxyl-terminal domain (CTD). It peaked 6 min after addition of high BN concentration ([BN]) in cells with high GRPr expression. Another wave of activation was CTD-independent. It peaked 2 to 4 min after BN addition in cells when [BN] and/or GRPr expression were lower. The early wave of ERK activation was more sensitive than the later one to pretreatment with Bisindolylmaleimide I (GF 109203X) (a protein kinase C inhibitor) or hypertonic sucrose. Because these two waves of activation differ in time course, dose-response curve, requirement for GRPr CTD, and sensitivity to inhibitors, they result from different signaling pathways. A third pathway in these cells inhibited ERK phosphorylation 2 min after addition of high [BN] in cells with high GRPr expression. Furthermore, a GRPr-expressing human duodenal cancer cell line showed differential sensitivity to GF 109203X throughout BN-induced ERK activation, indicating that GRPr may activate ERK via multiple pathways in cells expressing endogenous GRPr.

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation.

PubMed

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A; Nurva, Shailika Reddy; Mishra, Smriti; Mchaourab, Hassane S; Minor, Daniel L

2016-02-25

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNa(V)) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNa(V) CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNa(V) CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNa(V) voltage dependencies, and demonstrate that a discrete domain can encode the temperature-dependent response of a channel. Copyright © 2016 Elsevier Inc. All rights reserved.

Unfolding of a temperature-sensitive domain controls voltage-gated channel activation

PubMed Central

Arrigoni, Cristina; Rohaim, Ahmed; Shaya, David; Findeisen, Felix; Stein, Richard A.; Nurva, Shailika Reddy; Mishra, Smriti; Mchaourab, Hassane S.; Minor, Daniel L.

2016-01-01

Voltage-gated ion channels (VGICs) are outfitted with diverse cytoplasmic domains that impact function. To examine how such elements may affect VGIC behavior, we addressed how the bacterial voltage-gated sodium channel (BacNaV) C-terminal cytoplasmic domain (CTD) affects function. Our studies show that the BacNaV CTD exerts a profound influence on gating through a temperature-dependent unfolding transition in a discrete cytoplasmic domain, the neck domain, proximal to the pore. Structural and functional studies establish that the BacNaV CTD comprises a bi-partite four-helix bundle that bears an unusual hydrophilic core whose integrity is central to the unfolding mechanism and that couples directly to the channel activation gate. Together, our findings define a general principle for how the widespread four-helix bundle cytoplasmic domain architecture can control VGIC responses, uncover a mechanism underlying the diverse BacNaV voltage dependencies, and demonstrate that a discrete domain can encode the temperature dependent response of a channel. PMID:26919429

Solution structure and DNA-binding properties of the C-terminal domain of UvrC from E.coli

PubMed Central

Singh, S.; Folkers, G.E.; Bonvin, A.M.J.J.; Boelens, R.; Wechselberger, R.; Niztayev, A.; Kaptein, R.

2002-01-01

The C-terminal domain of the UvrC protein (UvrC CTD) is essential for 5′ incision in the prokaryotic nucleotide excision repair process. We have determined the three-dimensional structure of the UvrC CTD using heteronuclear NMR techniques. The structure shows two helix–hairpin–helix (HhH) motifs connected by a small connector helix. The UvrC CTD is shown to mediate structure-specific DNA binding. The domain binds to a single-stranded–double-stranded junction DNA, with a strong specificity towards looped duplex DNA that contains at least six unpaired bases per loop (‘bubble DNA’). Using chemical shift perturbation experiments, the DNA-binding surface is mapped to the first hairpin region encompassing the conserved glycine–valine–glycine residues followed by lysine–arginine–arginine, a positively charged surface patch and the second hairpin region consisting of glycine–isoleucine–serine. A model for the protein– DNA complex is proposed that accounts for this specificity. PMID:12426397

Salinity and temperature structure of a freezing Arctic fjord-monitored by white whales (Delphinapterus leucas)

NASA Astrophysics Data System (ADS)

Lydersen, Christian; Nøst, Ole Anders; Lovell, Phil; McConnell, Bernie J.; Gammelsrød, Tor; Hunter, Colin; Fedak, Michael A.; Kovacs, Kit M.

2002-12-01

In this study we report results from satellite-linked conductivity-temperature-depth (CTD) loggers that were deployed on wild, free-ranging white whales to study the oceanographic structure of an Arctic fjord, Storfjorden, Svalbard. The whales dove to the bottom of the fjord routinely during the study and occupied areas with up to 90% ice-cover, where performance of conventional ship-based CTD-casts would have been difficult. During the initial period of freezing in the fjord, over a period of approximately 2 weeks, 540 CTD profiles were successfully transmitted. The data indicate that Storfjorden has a substantial inflow of warm North Atlantic Water; this is contrary to conventional wisdom that has suggested that it contains only cold Arctic water. This study confirms that marine-mammal-based CTDs have enormous potential for cost-effective, future oceanographic studies; many different marine mammal species target oceanographic discontinuities for foraging and thus may be good `adaptive samplers' that naturally seek areas of high oceanographic interest.

Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation

PubMed Central

Wang, Chaojian; Chung, Ben C.; Yan, Haidun; Wang, Hong-Gang; Lee, Seok-Yong; Pitt, Geoffrey S.

2014-01-01

Ca2+ regulates voltage-gated Na+ (NaV) channels and perturbed Ca2+ regulation of NaV function is associated with epilepsy syndromes, autism, and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of structural information and competing models for how Ca2+ affects NaV channel function. Here, we report the crystal structures of two ternary complexes of a human NaV cytosolic C-terminal domain (CTD), a fibroblast growth factor homologous factor, and Ca2+/calmodulin (Ca2+/CaM). These structures rule out direct binding of Ca2+ to the NaV CTD, and uncover new contacts between CaM and the NaV CTD. Probing these new contacts with biochemical and functional experiments allows us to propose a mechanism by which Ca2+ could regulate NaV channels. Further, our model provides hints towards understanding the molecular basis of the neurologic disorders and cardiac arrhythmias caused by NaV channel mutations. PMID:25232683

Charge Transfer Dissociation of Complex Oligosaccharides: Comparison with Collision-Induced Dissociation and Extreme Ultraviolet Dissociative Photoionization

NASA Astrophysics Data System (ADS)

Ropartz, David; Li, Pengfei; Fanuel, Mathieu; Giuliani, Alexandre; Rogniaux, Hélène; Jackson, Glen P.

2016-10-01

The structural characterization of oligosaccharides still challenges the field of analytical chemistry. Tandem mass spectrometry offers many advantages toward this aim, although the generic fragmentation method (low-energy collision-induced dissociation) shows clear limitations and is often insufficient to retrieve some essential structural information on these molecules. In this work, we present the first application of helium charge transfer dissociation (He-CTD) to characterize the structure of complex oligosaccharides. We compare this method with low-energy collision-induced dissociation and extreme-ultraviolet dissociative photoionization (XUV-DPI), which was shown previously to ensure the successful characterization of complex glycans. Similarly to what could be obtained by XUV-DPI, He-CTD provides a complete description of the investigated structures by producing many informative cross-ring fragments and no ambiguous fragmentation. Unlike XUV-DPI, which is performed at a synchrotron source, He-CTD has the undeniable advantage of being implementable in a conventional benchtop ion trap in a conventional laboratory setting.

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

PubMed Central

Kang, Hyeog; Oka, Shinichi; Lee, Duck-Yeon; Park, Junhong; Aponte, Angel M.; Jung, Young-Sang; Bitterman, Jacob; Zhai, Peiyong; He, Yi; Kooshapur, Hamed; Ghirlando, Rodolfo; Tjandra, Nico; Lee, Sean B.; Kim, Myung K.; Sadoshima, Junichi; Chung, Jay H.

2017-01-01

Sirt1 is an NAD+-dependent protein deacetylase that regulates many physiological functions, including stress resistance, adipogenesis, cell senescence and energy production. Sirt1 can be activated by energy deprivation, but the mechanism is poorly understood. Here, we report that Sirt1 is negatively regulated by ATP, which binds to the C-terminal domain (CTD) of Sirt1. ATP suppresses Sirt1 activity by impairing the CTD's ability to bind to the deacetylase domain as well as its ability to function as the substrate recruitment site. ATP, but not NAD+, causes a conformational shift to a less compact structure. Mutations that prevent ATP binding increase Sirt1's ability to promote stress resistance and inhibit adipogenesis under high-ATP conditions. Interestingly, the CTD can be attached to other proteins, thereby converting them into energy-regulated proteins. These discoveries provide insight into how extreme energy deprivation can impact Sirt1 activity and underscore the complex nature of Sirt1 structure and regulation. PMID:28504272

MDCT quantification is the dominant parameter in decision–making regarding chest tube drainage for stable patients with traumatic pneumothorax

PubMed Central

Cai, Wenli; Lee, June-Goo; Fikry, Karim; Yoshida, Hiroyuki; Novelline, Robert; de Moya, Marc

2013-01-01

It is commonly believed that the size of a pneumothorax is an important determinant of treatment decision, in particular regarding whether chest tube drainage (CTD) is required. However, the volumetric quantification of pneumothoraces has not routinely been performed in clinics. In this paper, we introduced an automated computer-aided volumetry (CAV) scheme for quantification of volume of pneumothoraces in chest multi-detect CT (MDCT) images. Moreover, we investigated the impact of accurate volume of pneumothoraces in the improvement of the performance in decision-making regarding CTD in the management of traumatic pneumothoraces. For this purpose, an occurrence frequency map was calculated for quantitative analysis of the importance of each clinical parameter in the decision-making regarding CTD by a computer simulation of decision-making using a genetic algorithm (GA) and a support vector machine (SVM). A total of 14 clinical parameters, including volume of pneumothorax calculated by our CAV scheme, was collected as parameters available for decision-making. The results showed that volume was the dominant parameter in decision-making regarding CTD, with an occurrence frequency value of 1.00. The results also indicated that the inclusion of volume provided the best performance that was statistically significant compared to the other tests in which volume was excluded from the clinical parameters. This study provides the scientific evidence for the application of CAV scheme in MDCT volumetric quantification of pneumothoraces in the management of clinically stable chest trauma patients with traumatic pneumothorax. PMID:22560899

Mindfulness-based stress reduction for Tourette Syndrome and Chronic Tic Disorder: a pilot study.

PubMed

Reese, Hannah E; Vallejo, Zayda; Rasmussen, Jessica; Crowe, Katherine; Rosenfield, Elizabeth; Wilhelm, Sabine

2015-03-01

In this pilot study we sought to develop and test a modified form of mindfulness-based stress reduction (MBSR-tics) for the treatment of Tourette Syndrome (TS) and Chronic Tic Disorder (CTD). Our specific aims were: 1) To determine the feasibility and acceptability of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD and 2) To determine the efficacy of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD. Eighteen individuals age 16-67 completed an uncontrolled open trial of MBSR-tics. The intervention consisted of 8 weekly 2-hour classes and one 4hour retreat in the fifth or sixth week of the program. Symptomatic assessments were performed at baseline, post-treatment, and one-month follow-up. MBSR-tics proved to be a feasible and acceptable intervention. It resulted in significant improvement in tic severity and tic-related impairment. 58.8% of subjects were deemed treatment responders. Therapeutic gains were maintained at 1-month follow-up. Improvements in tic severity were correlated with increases in self-reported levels of mindfulness. This small open pilot study provides preliminary support for the feasibility, acceptability, and efficacy of MBSR-tics for individuals 16 or older with TS or CTD. A larger randomized controlled trial with blind assessment is necessary to confirm these initial, promising findings. Trial Registration Partners Clinical Trials Registry Number 2011P000606 (clinicaltrials.partners.org). Copyright © 2014 Elsevier Inc. All rights reserved.

Caenorhabditis elegans fibroblast growth factor receptor signaling can occur independently of the multi-substrate adaptor FRS2.

PubMed

Lo, Te-Wen; Bennett, Daniel C; Goodman, S Jay; Stern, Michael J

2010-06-01

The components of receptor tyrosine kinase signaling complexes help to define the specificity of the effects of their activation. The Caenorhabditis elegans fibroblast growth factor receptor (FGFR), EGL-15, regulates a number of processes, including sex myoblast (SM) migration guidance and fluid homeostasis, both of which require a Grb2/Sos/Ras cassette of signaling components. Here we show that SEM-5/Grb2 can bind directly to EGL-15 to mediate SM chemoattraction. A yeast two-hybrid screen identified SEM-5 as able to interact with the carboxy-terminal domain (CTD) of EGL-15, a domain that is specifically required for SM chemoattraction. This interaction requires the SEM-5 SH2-binding motifs present in the CTD (Y(1009) and Y(1087)), and these sites are required for the CTD role of EGL-15 in SM chemoattraction. SEM-5, but not the SEM-5 binding sites located in the CTD, is required for the fluid homeostasis function of EGL-15, indicating that SEM-5 can link to EGL-15 through an alternative mechanism. The multi-substrate adaptor protein FRS2 serves to link vertebrate FGFRs to Grb2. In C. elegans, an FRS2-like gene, rog-1, functions upstream of a Ras/MAPK pathway for oocyte maturation but is not required for EGL-15 function. Thus, unlike the vertebrate FGFRs, which require the multi-substrate adaptor FRS2 to recruit Grb2, EGL-15 can recruit SEM-5/Grb2 directly.

The combined effect of clothianidin and environmental stress on the behavioral and reproductive function in male mice

PubMed Central

HIRANO, Tetsushi; YANAI, Shogo; OMOTEHARA, Takuya; HASHIMOTO, Rie; UMEMURA, Yuria; KUBOTA, Naoto; MINAMI, Kiichi; NAGAHARA, Daichi; MATSUO, Eiko; AIHARA, Yoshiko; SHINOHARA, Ryota; FURUYASHIKI, Tomoyuki; MANTANI, Youhei; YOKOYAMA, Toshifumi; KITAGAWA, Hiroshi; HOSHI, Nobuhiko

2015-01-01

Neonicotinoids, some of the most widely used pesticides in the world, act as agonists to the nicotinic acetylcholine receptors (nAChRs) of insects, resulting in death from abnormal excitability. Neonicotinoids unexpectedly became a major topic as a compelling cause of honeybee colony collapse disorder, which is damaging crop production that requires pollination worldwide. Mammal nAChRs appear to have a certain affinity for neonicotinoids with lower levels than those of insects; there is thus rising concern about unpredictable adverse effects of neonicotinoids on vertebrates. We hypothesized that the effects of neonicotinoids would be enhanced under a chronic stressed condition, which is known to alter the expression of targets of neonicotinoids, i.e., neuronal nAChRs. We performed immunohistochemical and behavioral analyses in male mice actively administered a neonicotinoid, clothianidin (CTD; 0, 10, 50 and 250 mg/kg/day), for 4 weeks under an unpredictable chronic stress procedure. Vacuolated seminiferous epithelia and a decrease in the immunoreactivity of the antioxidant enzyme glutathione peroxidase 4 were observed in the testes of the CTD+stress mice. In an open field test, although the locomotor activities were not affected, the anxiety-like behaviors of the mice were elevated by both CTD and stress. The present study demonstrates that the behavioral and reproductive effects of CTD become more serious in combination with environmental stress, which may reflect our actual situation of multiple exposure. PMID:25960033

Structural and functional probing of PorZ, an essential bacterial surface component of the type-IX secretion system of human oral-microbiomic Porphyromonas gingivalis.

PubMed Central

Lasica, Anna M.; Goulas, Theodoros; Mizgalska, Danuta; Zhou, Xiaoyan; de Diego, Iñaki; Ksiazek, Mirosław; Madej, Mariusz; Guo, Yonghua; Guevara, Tibisay; Nowak, Magdalena; Potempa, Barbara; Goel, Apoorv; Sztukowska, Maryta; Prabhakar, Apurva T.; Bzowska, Monika; Widziolek, Magdalena; Thøgersen, Ida B.; Enghild, Jan J.; Simonian, Mary; Kulczyk, Arkadiusz W.; Nguyen, Ky-Anh; Potempa, Jan; Gomis-Rüth, F. Xavier

2016-01-01

Porphyromonas gingivalis is a member of the human oral microbiome abundant in dysbiosis and implicated in the pathogenesis of periodontal (gum) disease. It employs a newly described type-IX secretion system (T9SS) for secretion of virulence factors. Cargo proteins destined for secretion through T9SS carry a recognition signal in the conserved C-terminal domain (CTD), which is removed by sortase PorU during translocation. Here, we identified a novel component of T9SS, PorZ, which is essential for surface exposure of PorU and posttranslational modification of T9SS cargo proteins. These include maturation of enzyme precursors, CTD removal and attachment of anionic lipopolysaccharide for anchorage in the outer membrane. The crystal structure of PorZ revealed two β-propeller domains and a C-terminal β-sandwich domain, which conforms to the canonical CTD architecture. We further documented that PorZ is itself transported to the cell surface via T9SS as a full-length protein with its CTD intact, independently of the presence or activity of PorU. Taken together, our results shed light on the architecture and possible function of a novel component of the T9SS. Knowledge of how T9SS operates will contribute to our understanding of protein secretion as part of host-microbiome interactions by dysbiotic members of the human oral cavity. PMID:27883039

USGS Field Activities 11CEV01 and 11CEV02 on the West Florida Shelf, Gulf of Mexico, in January and February 2011

USGS Publications Warehouse

Robbins, Lisa L.; Knorr, Paul O.; Daly, Kendra L.; Taylor, Carl A.

2014-01-01

During January and February 2011 the U.S. Geological Survey (USGS), in cooperation with the University of South Florida (USF), conducted geochemical surveys on the west Florida Shelf. Data collected will allow USGS and USF scientists to investigate the effects of climate change on ocean acidification within the northern Gulf of Mexico, specifically, the effect of ocean acidification on marine organisms and habitats. This work is part of a larger USGS study on Climate and Environmental Variability (CEV). The first cruise was conducted from January 3 – 7 (11CEV01) and the second from February 17 - 27 (11CEV02). To view each cruise's survey lines, please see the Trackline page. Both cruises took place aboard the R/V Weatherbird II, a ship of opportunity led by Dr. Kendra Daly (USF), which departed and returned from Saint Petersburg, Florida. Data collection included sampling of the surface and water column (referred to as station samples) with lab analysis of pH, dissolved inorganic carbon (DIC), and total alkalinity. Augmenting the lab analysis was a continuous flow-through system with a Conductivity-Temperature-Depth (CTD) sensor, which also recorded salinity, and pH. Corroborating the USGS data are the vertical CTD profiles collected by USF. The CTD casts measured continuous vertical profiles of oxygen, chlorophyll fluorescence, optical backscatter, and transmissometer. Discrete samples for nutrients, chlorophyll, and particulate organic carbon/nitrogen were also collected during the CTD casts.

Rediscovery and Exploration of Magic Mountain, Explorer Ridge, NE Pacific

NASA Astrophysics Data System (ADS)

Embley, R. W.

2002-12-01

A two-part exploration program at Explorer Ridge, the northernmost spreading segment of the NE Pacific spreading centers, was conducted in two phases during June to August of 2002. A robust hydrothermal system (Magic Mountain) was found in this area in the early 1980s by the Canadian PISCES IV submersible, but its dimensions and geologic relationships were not well determined due to limited dives and poor navigation. The first part of the 2002 exploration program utilized an EM300 multibeam sonar on T. G. Thompson, the autonomous vehicle ABE, and a CTD/rosette system to map the seafloor and conduct hydrothermal plume surveys. While ABE conducted detailed surveys in the area where the most intense hydrothermal plume was found on the initial CTD survey, the T. G. Thompson conducted additional multibeam surveys, CTD casts and CTD tow-yos on the other second order segments up to 60 km away. This increased the efficiency of the expedition by at least 30%. After 12 days on site, a multibeam map was completed of the entire segment, the spatial distribution and character of the hydrothermal plumes were mapped out and a section of seafloor measuring 2 x 5.5 km was mapped in detail with ABE. The ABE used two sonar systems, a previously proven Imagenex pencil beam sonar, and, for the first time, a multibeam sonar (SM2000). In addition to the high-resolution bathymetry (1 m grid-cell size resolution for the SM2000), ABE collected temperature, optical backscatter, eH redox potential, and magnetic field data. Using the CTD and ABE data, a major hydrothermal system was easily located on the seafloor during the second part of the exploration program using the ROPOS remotely operated vehicle. The Magic Mountain hydrothermal system is located almost entirely on the eastern constructional shoulder of the ridge eastward of the rim of the eastern boundary fault of the axial valley. This is in contrast to most other hydrothermal systems on intermediate rate spreading ridges, which are either centered within the neovolcanic zone or associated with a boundary fault. The active venting occurs over at least 400 m along axis and is mostly concentrated in clusters of high temperature chimneys, each about 50 m in diameter. Two of these clusters have a basal sulfide mound. There is obvious structural control of many of the vents - many lie along or in line with distinct fissures or small faults and the entire field appears to have developed within a shallow graben formed on the ridge flank. Most of the chimneys consist of relatively friable sulfates (barite/anhydrite) that vent clear fluid at up to about 290°C. Several larger active chimneys consist primarily of sulfide minerals that emit gray smoke with temperatures as high as 312§ C. Biologic communities were primarily associated with the more stable sulfide structures. The mixture of proven technology used from a capable surface vessel during the 2002 Explorer Ridge program, including a cutting edge deep AUV and a large ROV, provided the tools to explore a little-known site at a full range of scales in a short amount of time and collect invaluable samples for research. These initial data sets from the 2002 exploration program set the stage for more detailed studies of this unique hydrothermal system in the future.

Comparison of seasonal variability of Aquarius sea surface salinity time series with in situ observations in the Karimata Strait, Indonesia

NASA Astrophysics Data System (ADS)

Susanto, R. D.; Setiawan, A.; Zheng, Q.; Sulistyo, B.; Adi, T. R.; Agustiadi, T.; Trenggono, M.; Triyono, T.; Kuswardani, A.

2016-12-01

The seasonal variability of a full lifetime of Aquarius sea surface salinity time series from August 25, 2011 to June 7, 2015 is compared to salinity time series obtained from in situ observations in the Karimata Strait. The Karimata Strait plays dual roles in water exchange between the Pacific and the Indian Ocean. The salinity in the Karimata Strait is strongly affected by seasonal monsoon winds. During the boreal winter monsoon, northwesterly winds draws low salinity water from the South China Sea into the Java Sea and at the same time, the Java Sea receives an influx of the Indian Ocean water via the Sunda Strait. The Java Sea water will reduce the main Indonesian throughflow in the Makassar Strait. Conditions are reversed during the summer monsoon. Low salinity water from the South China Sea also controls the vertical structure of water properties in the upper layer of the Makassar Strait and the Lombok Strait. As a part of the South China Sea and Indonesian Seas Transport/Exchange (SITE) program, trawl resistance bottom mounted CTD was deployed in the Karimata Strait in mid-2010 to mid-2016 at water depth of 40 m. CTD casts during the mooring recoveries and deployments are used to compare the bottom salinity data. This in situ salinity time series is compared with various Aquarius NASA salinity products (the level 2, level 3 ascending and descending tracks and the seven-days rolling averaged) to check the consistency, correlation and statistical analysis. The preliminary results show that the seasonal variability of Aquarius salinity time series has larger amplitude variability compared to that of in situ data.

Unique sail-like structure of cor triatriatum dexter in three-dimensional echocardiogram.

PubMed

Low, Ting Ting; Uy, Celia Catherine C; Wong, Raymond Ching Chiew

2014-08-01

Cor triatriatum dexter (CTD) is an extremely rare congenital condition arising from the persistence of the right valve of the sinus venosus. It divides the right atrium (RA) into 2 separate chambers. We report a case of a 50-year-old man who had an incidental finding of CTD on transesophageal echocardiogram. An incomplete membrane of the RA was seen, and three-dimensional echocardiogram delineated the structure clearly as a triangular sail-like structure with multiple orifices and a fenestration. © 2013, Wiley Periodicals, Inc.

Collaborative Research to Advance Precision Medicine in the Post-Genomic World | Office of Cancer Genomics

Cancer.gov

My name is Subhashini Jagu, and I am the Scientific Program Manager for the Cancer Target Discovery and Development (CTD2) Network at the Office of Cancer Genomics (OCG). In my new role, I help CTD2 work toward its mission, which is to develop new scientific approaches to accelerate the translation of genomic discoveries into new treatments. Collaborative efforts that bring together a variety of expertise and infrastructure are needed to understand and successfully treat cancer, a highly complex disease.

Entitymetrics: Measuring the Impact of Entities

PubMed Central

Ding, Ying; Song, Min; Han, Jia; Yu, Qi; Yan, Erjia; Lin, Lili; Chambers, Tamy

2013-01-01

This paper proposes entitymetrics to measure the impact of knowledge units. Entitymetrics highlight the importance of entities embedded in scientific literature for further knowledge discovery. In this paper, we use Metformin, a drug for diabetes, as an example to form an entity-entity citation network based on literature related to Metformin. We then calculate the network features and compare the centrality ranks of biological entities with results from Comparative Toxicogenomics Database (CTD). The comparison demonstrates the usefulness of entitymetrics to detect most of the outstanding interactions manually curated in CTD. PMID:24009660

Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study.

PubMed

Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Brun, Anne Laure; Egashira, Ryoko; Karwoski, Ronald; Kokosi, Maria; Wells, Athol U; Hansell, David M

2016-11-23

To evaluate computer-based computer tomography (CT) analysis (CALIPER) against visual CT scoring and pulmonary function tests (PFTs) when predicting mortality in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). To identify outcome differences between distinct CTD-ILD groups derived following automated stratification of CALIPER variables. A total of 203 consecutive patients with assorted CTD-ILDs had CT parenchymal patterns evaluated by CALIPER and visual CT scoring: honeycombing, reticular pattern, ground glass opacities, pulmonary vessel volume, emphysema, and traction bronchiectasis. CT scores were evaluated against pulmonary function tests: forced vital capacity, diffusing capacity for carbon monoxide, carbon monoxide transfer coefficient, and composite physiologic index for mortality analysis. Automated stratification of CALIPER-CT variables was evaluated in place of and alongside forced vital capacity and diffusing capacity for carbon monoxide in the ILD gender, age physiology (ILD-GAP) model using receiver operating characteristic curve analysis. Cox regression analyses identified four independent predictors of mortality: patient age (P < 0.0001), smoking history (P = 0.0003), carbon monoxide transfer coefficient (P = 0.003), and pulmonary vessel volume (P < 0.0001). Automated stratification of CALIPER variables identified three morphologically distinct groups which were stronger predictors of mortality than all CT and functional indices. The Stratified-CT model substituted automated stratified groups for functional indices in the ILD-GAP model and maintained model strength (area under curve (AUC) = 0.74, P < 0.0001), ILD-GAP (AUC = 0.72, P < 0.0001). Combining automated stratified groups with the ILD-GAP model (stratified CT-GAP model) strengthened predictions of 1- and 2-year mortality: ILD-GAP (AUC = 0.87 and 0.86, respectively); stratified CT-GAP (AUC = 0.89 and 0.88, respectively). CALIPER-derived pulmonary vessel volume is an independent predictor of mortality across all CTD-ILD patients. Furthermore, automated stratification of CALIPER CT variables represents a novel method of prognostication at least as robust as PFTs in CTD-ILD patients.

USGS field activities 11BHM03 and 11BHM04 on the west Florida shelf, Gulf of Mexico, September and November 2011

USGS Publications Warehouse

Robbins, Lisa L.; Knorr, Paul O.; Daly, Kendra L.; Barrera, Kira E.

2014-01-01

During September and November 2011 the (USGS), in cooperation with (USF), conducted geochemical surveys on the west Florida Shelf to investigate the effects of climate change on ocean acidification within the northern Gulf of Mexico, specifically, the effect of ocean acidification on marine organisms and habitats. The first cruise was conducted from September 20 to 28 (11BHM03) and the second was from November 2 to 4 (11BHM04). To view each cruise's survey lines, please see the Trackline page. Each cruise took place aboard the Research Vessel (R/V) Weatherbird II, a ship of opportunity led by Dr. Kendra Daly (USF), which departed from and returned to Saint Petersburg, Florida. Data collection included sampling of the surface and water column with lab analysis of pH, dissolved inorganic carbon (DIC) or total carbon dioxide (TCO2), and total alkalinity (TA). lLb analysis was augmented with a continuous flow-through system (referred to as sonde data) with a conductivity-temperature-depth (CTD) sensor, which also recorded salinity and pH. Corroborating the USGS data are the vertical CTD profiles (referred to as station samples) collected by USF. The CTD casts measured continuous vertical profiles of oxygen, chlorophyll fluorescence and optical backscatter. Discrete samples for nutrients, chlorophyll, and particulate organic carbon/nitrogen were also collected during the CTD casts. Two autonomous flow-through (AFT) instruments recorded pH and CO2 every 3-5 minutes on each cruise (referred to as AFT data).

MDCT quantification is the dominant parameter in decision-making regarding chest tube drainage for stable patients with traumatic pneumothorax.

PubMed

Cai, Wenli; Lee, June-Goo; Fikry, Karim; Yoshida, Hiroyuki; Novelline, Robert; de Moya, Marc

2012-07-01

It is commonly believed that the size of a pneumothorax is an important determinant of treatment decision, in particular regarding whether chest tube drainage (CTD) is required. However, the volumetric quantification of pneumothoraces has not routinely been performed in clinics. In this paper, we introduced an automated computer-aided volumetry (CAV) scheme for quantification of volume of pneumothoraces in chest multi-detect CT (MDCT) images. Moreover, we investigated the impact of accurate volume of pneumothoraces in the improvement of the performance in decision-making regarding CTD in the management of traumatic pneumothoraces. For this purpose, an occurrence frequency map was calculated for quantitative analysis of the importance of each clinical parameter in the decision-making regarding CTD by a computer simulation of decision-making using a genetic algorithm (GA) and a support vector machine (SVM). A total of 14 clinical parameters, including volume of pneumothorax calculated by our CAV scheme, was collected as parameters available for decision-making. The results showed that volume was the dominant parameter in decision-making regarding CTD, with an occurrence frequency value of 1.00. The results also indicated that the inclusion of volume provided the best performance that was statistically significant compared to the other tests in which volume was excluded from the clinical parameters. This study provides the scientific evidence for the application of CAV scheme in MDCT volumetric quantification of pneumothoraces in the management of clinically stable chest trauma patients with traumatic pneumothorax. Copyright © 2012 Elsevier Ltd. All rights reserved.

The disordered C-terminal domain of human DNA glycosylase NEIL1 contributes to its stability via intramolecular interactions.

PubMed

Hegde, Muralidhar L; Tsutakawa, Susan E; Hegde, Pavana M; Holthauzen, Luis Marcelo F; Li, Jing; Oezguen, Numan; Hilser, Vincent J; Tainer, John A; Mitra, Sankar

2013-07-10

NEIL1 [Nei (endonuclease VIII)-like protein 1], one of the five mammalian DNA glycosylases that excise oxidized DNA base lesions in the human genome to initiate base excision repair, contains an intrinsically disordered C-terminal domain (CTD; ~100 residues), not conserved in its Escherichia coli prototype Nei. Although dispensable for NEIL1's lesion excision and AP lyase activities, this segment is required for efficient in vivo enzymatic activity and may provide an interaction interface for many of NEIL1's interactions with other base excision repair proteins. Here, we show that the CTD interacts with the folded domain in native NEIL1 containing 389 residues. The CTD is poised for local folding in an ordered structure that is induced in the purified fragment by osmolytes. Furthermore, deletion of the disordered tail lacking both Tyr and Trp residues causes a red shift in NEIL1's intrinsic Trp-specific fluorescence, indicating a more solvent-exposed environment for the Trp residues in the truncated protein, which also exhibits reduced stability compared to the native enzyme. These observations are consistent with stabilization of the native NEIL1 structure via intramolecular, mostly electrostatic, interactions that were disrupted by mutating a positively charged (Lys-rich) cluster of residues (amino acids 355-360) near the C-terminus. Small-angle X-ray scattering (SAXS) analysis confirms the flexibility and dynamic nature of NEIL1's CTD, a feature that may be critical to providing specificity for NEIL1's multiple, functional interactions. Copyright © 2013 Elsevier Ltd. All rights reserved.

USGS field activities 11BHM01 and 11BHM02 on the west Florida shelf, Gulf of Mexico, May and June 2011

USGS Publications Warehouse

Robbins, Lisa L.; Knorr, Paul O.; Daly, Kendra L.; Taylor, Carl A.; Barrera, Kira E.

2014-01-01

During May and June 2011 the (USGS), in cooperation with (USF), conducted geochemical surveys on the west Florida Shelf to investigate the effects of climate change on ocean acidification within the northern Gulf of Mexico, specifically, the effect of ocean acidification on marine organisms and habitats. The first cruise was conducted from May 3 to 9 (11BHM01) and the second was from June 25 to 30 (11BHM02). To view each cruise's survey lines, please see the Trackline page. Each cruise took place aboard the Research Vessel (R/V) Weatherbird II, a ship of opportunity led by Dr. Kendra Daly (USF), which departed from and returned to Saint Petersburg, Florida. Data collection included sampling of the surface and water column with lab analysis of pH, dissolved inorganic carbon (DIC) or total carbon dioxide (TCO2), and total alkalinity (TA). lLb analysis was augmented with a continuous flow-through system (referred to as sonde data) with a conductivity-temperature-depth (CTD) sensor, which also recorded salinity and pH. Corroborating the USGS data are the vertical CTD profiles (referred to as station samples) collected by USF. The CTD casts measured continuous vertical profiles of oxygen, chlorophyll fluorescence and optical backscatter. Discrete samples for nutrients, chlorophyll, and particulate organic carbon/nitrogen were also collected during the CTD casts. Two autonomous flow-through (AFT) instruments recorded pH and CO2 every 3-5 minutes on each cruise (referred to as AFT data).

Occlusion pressure analysis role in partitioning of pulmonary vascular resistance in CTEPH.

PubMed

Toshner, Mark; Suntharalingam, Jay; Fesler, Pierre; Soon, Elaine; Sheares, Karen K; Jenkins, David; White, Paul; Morrell, Nicholas W; Naeije, Robert; Pepke-Zaba, Joanna

2012-09-01

Flow-directed pulmonary artery occlusion is posited to enable partitioning of vascular resistance into small and large vessels. As such it may have a role in assessment for pulmonary endarterectomy. To test if the occlusion technique distinguished small from large vessel disease we studied 59 subjects with chronic thromboembolic pulmonary hypertension (CTEPH), idiopathic pulmonary arterial hypertension (IPAH), and connective tissue disease (CTD)-associated PAH. At right heart catheterisation, occlusion pressures were recorded. With fitting of the pressure decay curve, pulmonary vascular resistance was partitioned into downstream (small vessels) and upstream (large vessels, Rup). 47 patients completed the study; 14 operable CTEPH, 15 inoperable CTEPH, 13 idiopathic or CTD-PAH and five post-operative CTEPH. There was a significant difference in mean Rup in the proximal operable CTEPH group 87.3 (95% CI 84.1-90.5); inoperable CTEPH mean 75.8 (95% CI 66.76-84.73), p=0.048; and IPAH/CTD, mean 77.1 (95% CI 71.86-82.33), p=0.003. Receiver operating characteristic curves to distinguish operable from inoperable CTEPH demonstrated an area under the curve of 0.75, p=0.0001. A cut-off of 79.3 gave 100% sensitivity (95% CI 73.5-100%) but 57.1% specificity (95% CI 28.9-82.3%). In a subgroup analysis of multiple lobar sampling there was demonstrable heterogeneity. Rup is significantly increased in operable proximal CTEPH compared with non-operable distal CTEPH and IPAH/CTD-PAH. Rup variability in patients with CTEPH and PAH is suggestive of pathophysiological heterogeneity.

Interdomain Contacts Control Native State Switching of RfaH on a Dual-Funneled Landscape

PubMed Central

Ramírez-Sarmiento, César A.; Noel, Jeffrey K.; Valenzuela, Sandro L.; Artsimovitch, Irina

2015-01-01

RfaH is a virulence factor from Escherichia coli whose C-terminal domain (CTD) undergoes a dramatic α-to-β conformational transformation. The CTD in its α-helical fold is stabilized by interactions with the N-terminal domain (NTD), masking an RNA polymerase binding site until a specific recruitment site is encountered. Domain dissociation is triggered upon binding to DNA, allowing the NTD to interact with RNA polymerase to facilitate transcription while the CTD refolds into the β-barrel conformation that interacts with the ribosome to activate translation. However, structural details of this transformation process in the context of the full protein remain to be elucidated. Here, we explore the mechanism of the α-to-β conformational transition of RfaH in the full-length protein using a dual-basin structure-based model. Our simulations capture several features described experimentally, such as the requirement of disruption of interdomain contacts to trigger the α-to-β transformation, confirms the roles of previously indicated residues E48 and R138, and suggests a new important role for F130, in the stability of the interdomain interaction. These native basins are connected through an intermediate state that builds up upon binding to the NTD and shares features from both folds, in agreement with previous in silico studies of the isolated CTD. We also examine the effect of RNA polymerase binding on the stabilization of the β fold. Our study shows that native-biased models are appropriate for interrogating the detailed mechanisms of structural rearrangements during the dramatic transformation process of RfaH. PMID:26230837

TFIIH and P-TEFb Coordinate Transcription with Capping Enzyme Recruitment at Specific Genes in Fission Yeast

PubMed Central

Viladevall, Laia; St. Amour, Courtney V.; Rosebrock, Adam; Schneider, Susanne; Zhang, Chao; Allen, Jasmina J.; Shokat, Kevan M.; Schwer, Beate; Leatherwood, Janet K.; Fisher, Robert P.

2009-01-01

Summary Cyclin-dependent kinases (CDKs) are subunits of transcription factor (TF) IIH and positive transcription elongation factor b (P-TEFb). To define their functions, we mutated the TFIIH-associated kinase Mcs6 and P-TEFb homologs Cdk9 and Lsk1 of fission yeast, making them sensitive to bulky purine analogs. Selective inhibition of Mcs6 or Cdk9 blocks cell division, alters RNA polymerase (Pol) II carboxyl-terminal domain (CTD) phosphorylation and represses specific, overlapping subsets of transcripts. At a common target gene, both CDKs must be active for normal Pol II occupancy, and Spt5—a CDK substrate and regulator of elongation—accumulates disproportionately to Pol II when either kinase is inhibited. In contrast, Mcs6 activity is sufficient, and necessary, to recruit the Cdk9/Pcm1 (mRNA cap methyltransferase) complex. In vitro, phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. We propose that TFIIH primes the CTD and promotes recruitment of P-TEFb/Pcm1, serving to couple elongation and capping of select pre-mRNAs. PMID:19328067

Allosteric control of transcription in GntR family of transcription regulators: A structural overview.

PubMed

Jain, Deepti

2015-07-01

The GntR family of transcription regulators constitutes one of the most abundant family of transcription factors. These modulators are involved in a variety of mechanisms controlling various metabolic processes. GntR family members are typically two domain proteins with a smaller N-terminus domain (NTD) with conserved architecture of winged-helix-turn-helix (wHTH) for DNA binding and a larger C-terminus domain (CTD) or the effector binding domain which is also involved in oligomerization. Interestingly, the CTD shows structural heterogeneity depending upon the type of effector molecule that it binds and displays structural homology to various classes of proteins. Binding of the effector molecule to the CTD brings about a conformational change in the transcription factor such that its affinity for its cognate DNA sequence is altered. This review summarizes the structural information available on the members of GntR family and discusses the common features of the DNA binding and operator recognition within the family. The variation in the allosteric mechanism employed by the members of this family is also discussed. © 2015 International Union of Biochemistry and Molecular Biology.

The Comparative Toxicogenomics Database: update 2017.

PubMed

Davis, Allan Peter; Grondin, Cynthia J; Johnson, Robin J; Sciaky, Daniela; King, Benjamin L; McMorran, Roy; Wiegers, Jolene; Wiegers, Thomas C; Mattingly, Carolyn J

2017-01-04

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) provides information about interactions between chemicals and gene products, and their relationships to diseases. Core CTD content (chemical-gene, chemical-disease and gene-disease interactions manually curated from the literature) are integrated with each other as well as with select external datasets to generate expanded networks and predict novel associations. Today, core CTD includes more than 30.5 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, Gene Ontology (GO) annotations, pathways, and gene interaction modules. In this update, we report a 33% increase in our core data content since 2015, describe our new exposure module (that harmonizes exposure science information with core toxicogenomic data) and introduce a novel dataset of GO-disease inferences (that identify common molecular underpinnings for seemingly unrelated pathologies). These advancements centralize and contextualize real-world chemical exposures with molecular pathways to help scientists generate testable hypotheses in an effort to understand the etiology and mechanisms underlying environmentally influenced diseases. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Structural and functional insights into 5'-ppp RNA pattern recognition by the innate immune receptor RIG-I.

PubMed

Wang, Yanli; Ludwig, Janos; Schuberth, Christine; Goldeck, Marion; Schlee, Martin; Li, Haitao; Juranek, Stefan; Sheng, Gang; Micura, Ronald; Tuschl, Thomas; Hartmann, Gunther; Patel, Dinshaw J

2010-07-01

RIG-I is a cytosolic helicase that senses 5'-ppp RNA contained in negative-strand RNA viruses and triggers innate antiviral immune responses. Calorimetric binding studies established that the RIG-I C-terminal regulatory domain (CTD) binds to blunt-end double-stranded 5'-ppp RNA a factor of 17 more tightly than to its single-stranded counterpart. Here we report on the crystal structure of RIG-I CTD bound to both blunt ends of a self-complementary 5'-ppp dsRNA 12-mer, with interactions involving 5'-pp clearly visible in the complex. The structure, supported by mutation studies, defines how a lysine-rich basic cleft within the RIG-I CTD sequesters the observable 5'-pp of the bound RNA, with a stacked phenylalanine capping the terminal base pair. Key intermolecular interactions observed in the crystalline state are retained in the complex of 5'-ppp dsRNA 24-mer and full-length RIG-I under in vivo conditions, as evaluated from the impact of binding pocket RIG-I mutations and 2'-OCH(3) RNA modifications on the interferon response.

Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin

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

Wang, Chaojian; Chung, Ben C.; Yan, Haidun

2012-11-13

Voltage-gated Na{sup +} (Na{sub V}) channels initiate neuronal action potentials. Na{sub V} channels are composed of a transmembrane domain responsible for voltage-dependent Na{sup +} conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human NaV CTD, an FHF, and Ca{sup 2+}-free CaM at 2.2 {angstrom}.more » Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in NaV channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual NaV CTD isoforms for distinctive FHFs.« less

Complete A-V block: incidental or a part of cor triatriatum dexter.

PubMed

Guler, Y; Akgun, T; Toprak, C; Guler, A; Esen, A M

2014-05-01

Cor triatriatum dexter (CTD) is an extremely rare cardiac anomaly in which the right atrium is divided into two distinct chambers by a membrane. The persistence of the right valve of sinus venosus results in a complete septation of the right atrium. This anomaly is frequently associated with other right-sided cardiac abnormalities. Its clinical manifestation and the need for intervention are determined by the number and the size of the fenestrations on the membrane, associated cardiac anomalies and arrhythmias. We describe a case of CTD in a patient with complete atrioventricular (A-V) block.

Domain activities of PapC usher reveal the mechanism of action of an Escherichia coli molecular machine.

PubMed

Volkan, Ender; Ford, Bradley A; Pinkner, Jerome S; Dodson, Karen W; Henderson, Nadine S; Thanassi, David G; Waksman, Gabriel; Hultgren, Scott J

2012-06-12

P pili are prototypical chaperone-usher pathway-assembled pili used by Gram-negative bacteria to adhere to host tissues. The PapC usher contains five functional domains: a transmembrane β-barrel, a β-sandwich Plug, an N-terminal (periplasmic) domain (NTD), and two C-terminal (periplasmic) domains, CTD1 and CTD2. Here, we delineated usher domain interactions between themselves and with chaperone-subunit complexes and showed that overexpression of individual usher domains inhibits pilus assembly. Prior work revealed that the Plug domain occludes the pore of the transmembrane domain of a solitary usher, but the chaperone-adhesin-bound usher has its Plug displaced from the pore, adjacent to the NTD. We demonstrate an interaction between the NTD and Plug domains that suggests a biophysical basis for usher gating. Furthermore, we found that the NTD exhibits high-affinity binding to the chaperone-adhesin (PapDG) complex and low-affinity binding to the major tip subunit PapE (PapDE). We also demonstrate that CTD2 binds with lower affinity to all tested chaperone-subunit complexes except for the chaperone-terminator subunit (PapDH) and has a catalytic role in dissociating the NTD-PapDG complex, suggesting an interplay between recruitment to the NTD and transfer to CTD2 during pilus initiation. The Plug domain and the NTD-Plug complex bound all of the chaperone-subunit complexes tested including PapDH, suggesting that the Plug actively recruits chaperone-subunit complexes to the usher and is the sole recruiter of PapDH. Overall, our studies reveal the cooperative, active roles played by periplasmic domains of the usher to initiate, grow, and terminate a prototypical chaperone-usher pathway pilus.

A Study of Future Communications Concepts and Technologies for the National Airspace System-Part III

NASA Technical Reports Server (NTRS)

Ponchak, Denise S.; Apaza, Rafael D.; Wichgersm Joel M.; Haynes, Brian; Roy, Aloke

2014-01-01

The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) is investigating current and anticipated wireless communications concepts and technologies that the National Airspace System (NAS) may need in the next 50 years. NASA has awarded three NASA Research Announcements (NAR) studies with the objective to determine the most promising candidate technologies for air-to-air and air-to-ground data exchange and analyze their suitability in a post-NextGen NAS environment. This paper will present progress made in the studies and describe the communications challenges and opportunities that have been identified as part of the study. NASA's NextGen Concepts and Technology Development (CTD) Project integrates solutions for a safe, efficient and high-capacity airspace system through joint research efforts and partnerships with other government agencies. The CTD Project is one of two within NASA's Airspace Systems Program and is managed by the NASA Ames Research Center. Research within the CTD Project is in support the 2011 NASA Strategic Plan Sub-Goal 4.1: Develop innovative solutions and advanced technologies, through a balanced research portfolio, to improve current and future air transportation. The focus of CTD is on developing capabilities in traffic flow management, dynamic airspace configuration, separation assurance, super density operations and airport surface operations. Important to its research is the development of human/automation information requirements and decisionmaking guidelines for human-human and human-machine airportal decision-making. Airborne separation, oceanic intrail climb/descent and interval management applications depend on location and intent information of surrounding aircraft. ADS-B has been proposed to provide the information exchange, but other candidates such as satellite-based receivers, broadband or airborne internet, and cellular communications are possible candidate's.

Molecular Dissection of the Homotrimeric Sliding Clamp of T4 Phage: Two Domains of a Subunit Display Asymmetric Characteristics.

PubMed

Singh, Manika Indrajit; Jain, Vikas

2016-01-26

Sliding clamp proteins are circular dimers or trimers that encircle DNA and serve as processivity factors during DNA replication. Their presence in all the three domains of life and in bacteriophages clearly indicates their high level of significance. T4 gp45, besides functioning as the DNA polymerase processivity factor, also moonlights as the late promoter transcription determinant. Here we report a detailed biophysical analysis of gp45. The chemical denaturation of gp45 probed by circular dichroism spectroscopy, tryptophan fluorescence anisotropy, and blue-native polyacrylamide gel electrophoresis suggests that the protein follows a three-state denaturation profile and displays an intermediate molten globule-like state. The three-state transition was found to be the result of the sequential unfolding of the two domains, the N-terminal domain (NTD) and the C-terminal domain (CTD), of gp45. The experiments involving Trp fluorescence quenching by acrylamide demonstrate that the CTD undergoes substantial changes in conformation during formation of the intermediate state. Further biophysical dissection of the individual domain reveals contrasting properties of the two domains. The NTD unfolds at low urea concentrations and is also susceptible to protease cleavage, whereas the CTD resists urea-mediated denaturation and is not amenable to protease digestion even at higher urea concentrations. These experiments allow us to conclude that the two domains of gp45 differ in their dynamics. While the CTD shows stability and rigidity, we find that the NTD is unstable and flexible. We believe that the asymmetric characteristics of the two domains and the interface they form hold significance in gp45 structure and function.

Undifferentiated connective tissue disease and interstitial lung disease: Trying to define patterns.

PubMed

Alberti, María Laura; Paulin, Francisco; Toledo, Heidegger Mateos; Fernández, Martín Eduardo; Caro, Fabián Matías; Rojas-Serrano, Jorge; Mejía, Mayra Edith

To identify clinical or immunological features in patients with undifferentiated connective tissue disease (UCTD) associated interstitial lung disease (ILD), in order to group them and recognize different functional and high resolution computed tomography (HRCT) behavior. Retrospective cohort study. Patients meeting Kinder criteria for UCTD were included. We defined the following predictive variables: 'highly specific' connective tissue disease (CTD) manifestations (Raynaud's phenomenon, dry eyes or arthritis), high antinuclear antibody (ANA) titer (above 1: 320), and 'specific' ANA staining patterns (centromere, cytoplasmic and nucleolar patterns). We evaluated the following outcomes: change in the percentage of the predicted forced vital capacity (FVC%) during the follow-up period, and HRCT pattern. Sixty-six patients were included. Twenty-nine (43.94%) showed at least one 'highly specific' CTD manifestation, 16 (28.57%) had a 'specific' ANA staining pattern and 29 (43.94%) high ANA titer. Patients with 'highly specific' CTD manifestations were younger (mean [SD] 52 years [14.58] vs 62.08 years [9.46], P<.001), were more likely men (10.34% vs 48.65%, P<.001) and showed a smaller decline of the FVC% (median [interquartile range] 1% [-1 to 10] vs -6% [-16 to -4], P<.006). In the multivariate analysis, the presence of highly specific manifestations was associated with improvement in the FVC% (B coefficient of 13.25 [95% confidence interval, 2.41 to 24.09]). No association was observed in relation to the HRCT pattern. The presence of 'highly specific' CTD manifestations was associated with female sex, younger age and better functional behavior. These findings highlight the impact of the clinical features in the outcome of patients with UCTD ILD. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Structural basis of HIV-1 capsid recognition by PF74 and CPSF6

DOE PAGES

Bhattacharya, Akash; Alam, Steven L.; Fricke, Thomas; ...

2014-12-17

Upon infection of susceptible cells by HIV-1, the conical capsid formed by ~250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. In this study, the capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host–virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD–CTD interface is criticalmore » for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD–CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD–CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.« less

Glider Observations of Internal Tide Packets on the Australian Northwest Shelf

NASA Astrophysics Data System (ADS)

Book, J. W.; Steinberg, C. R.; Brinkman, R. M.; Jones, N. L.; Lowe, R.; Ivey, G. N.; Pattiaratchi, C. B.; Rice, A. E.

2016-02-01

The rapid profiling capabilities (less than 10 minutes per profile in 100 m of water excluding surfacing times) of autonomous gliders were utilized to study the structure of non-linear internal tide packets on the Australian Northwest Shelf. A total of five gliders were deployed on the shelf from 11 February - 21 April 2012 with more than 2900 glider CTD profiles collected during the final three weeks of this time period when the internal tide activity was intense. In general the internal tide packets showed high degrees of non-linearity, for example in one case a glider observed a 62 m rise of the 28° isotherm over 2.25 hours in a shelf location of 90 meters water depth. In addition to the glider measurements, moored strings of CTD sensors were used to measure the internal tide packets at fixed positions and the results show that the wave packets vary significantly with respect to their structure and arrival times from one tidal period to the next. This fact complicates interpretation of the glider data as wave packet spatial evolution is non-stationary and cannot be simply recovered from repeat glider visits to the same location. Furthermore, the packets were found to move at speeds near or greater (e.g., 0.55 m/s) than the speed that the gliders were moving. Despite these challenges, the gliders offer the only resource that can measure the spatial structure of the wave packets beyond the scope of our limited mooring positions. Therefore, we have implemented methods such as time-augmented empirical orthogonal functions to combine these glider measurements with the fixed mooring measurements in order to better understand the spatial and temporal patterns of the wave packet evolution over the slope and shelf of this region.

Quality DOTS management and empowering tuberculosis patients.

PubMed

Chugh, Satish

2009-03-01

Central Tuberculosis Division (CTD) has covered whole of India under DOTS. IMA is a proud partner of RNTCP which is managed by CTD. International Standards for Tuberculosis Care is expected from all healthcare providers. The basic principles of care is same worldwide. IMA GFATM RNTCP PPM is completing 2 years of its inception. Sensitisation programme and district training programmes has yielded DOTS/DMC centres in the target states. IMA is having 100% commitment for containing tuberculosis in India. There are International Standards for quality management in tuberculosis control, some of the Standards are elaborated in this write-up. In the Indian context, DOTS needs some innovations that is discussed in this article.

Threonine-4 of mammalian RNA polymerase II CTD is targeted by Polo-like kinase 3 and required for transcriptional elongation

PubMed Central

Hintermair, Corinna; Heidemann, Martin; Koch, Frederic; Descostes, Nicolas; Gut, Marta; Gut, Ivo; Fenouil, Romain; Ferrier, Pierre; Flatley, Andrew; Kremmer, Elisabeth; Chapman, Rob D; Andrau, Jean-Christophe; Eick, Dirk

2012-01-01

Eukaryotic RNA polymerase II (Pol II) has evolved an array of heptad repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 at the carboxy-terminal domain (CTD) of the large subunit (Rpb1). Differential phosphorylation of Ser2, Ser5, and Ser7 in the 5′ and 3′ regions of genes coordinates the binding of transcription and RNA processing factors to the initiating and elongating polymerase complexes. Here, we report phosphorylation of Thr4 by Polo-like kinase 3 in mammalian cells. ChIPseq analyses indicate an increase of Thr4-P levels in the 3′ region of genes occurring subsequently to an increase of Ser2-P levels. A Thr4/Ala mutant of Pol II displays a lethal phenotype. This mutant reveals a global defect in RNA elongation, while initiation is largely unaffected. Since Thr4 replacement mutants are viable in yeast we conclude that this amino acid has evolved an essential function(s) in the CTD of Pol II for gene transcription in mammalian cells. PMID:22549466

Disease-Homologous Mutation in the Cation Diffusion Facilitator Protein MamM Causes Single-Domain Structural Loss and Signifies Its Importance

PubMed Central

Barber-Zucker, Shiran; Uebe, René; Davidov, Geula; Navon, Yotam; Sherf, Dror; Chill, Jordan H.; Kass, Itamar; Bitton, Ronit; Schüler, Dirk; Zarivach, Raz

2016-01-01

Cation diffusion facilitators (CDF) are highly conserved, metal ion efflux transporters that maintain divalent transition metal cation homeostasis. Most CDF proteins contain two domains, the cation transporting transmembrane domain and the regulatory cytoplasmic C-terminal domain (CTD). MamM is a magnetosome-associated CDF protein essential for the biomineralization of magnetic iron-oxide particles in magnetotactic bacteria. To investigate the structure-function relationship of CDF cytoplasmic domains, we characterized a MamM M250P mutation that is synonymous with the disease-related mutation L349P of the human CDF protein ZnT-10. Our results show that the M250P exchange in MamM causes severe structural changes in its CTD resulting in abnormal reduced function. Our in vivo, in vitro and in silico studies indicate that the CTD fold is critical for CDF proteins’ proper function and support the previously suggested role of the CDF cytoplasmic domain as a CDF regulatory element. Based on our results, we also suggest a mechanism for the effects of the ZnT-10 L349P mutation in human. PMID:27550551

The C-terminal domain of Tetrahymena thermophila telomerase holoenzyme protein p65 induces multiple structural changes in telomerase RNA

PubMed Central

Akiyama, Benjamin M.; Loper, John; Najarro, Kevin; Stone, Michael D.

2012-01-01

The unique cellular activity of the telomerase reverse transcriptase ribonucleoprotein (RNP) requires proper assembly of protein and RNA components into a functional complex. In the ciliate model organism Tetrahymena thermophila, the La-domain protein p65 is required for in vivo assembly of telomerase. Single-molecule and biochemical studies have shown that p65 promotes efficient RNA assembly with the telomerase reverse transcriptase (TERT) protein, in part by inducing a bend in the conserved stem IV region of telomerase RNA (TER). The domain architecture of p65 consists of an N-terminal domain, a La-RRM motif, and a C-terminal domain (CTD). Using single-molecule Förster resonance energy transfer (smFRET), we demonstrate the p65CTD is necessary for the RNA remodeling activity of the protein and is sufficient to induce a substantial conformational change in stem IV of TER. Moreover, nuclease protection assays directly map the site of p65CTD interaction to stem IV and reveal that, in addition to bending stem IV, p65 binding reorganizes nucleotides that comprise the low-affinity TERT binding site within stem–loop IV. PMID:22315458

CTD Observations on the North Brazil Shelf During A Multidisciplinary Amazon Shelf SEDiment Study (AMASSEDS)

DTIC Science & Technology

1992-06-01

Milligan, H. Morganne, W. Moore, M. Veiga , G. Negreiros, A. Ogston, R. Portugal, H. Oliveira, R. Paiva, R. Pope, A. Rodrigues, K. Ruttenberg, J. Sarmento...34fCL -12 f ~l -12 1 -16 -20 -20 -2 -L L L - 241 L L0 4 B 12 16 20 24 0 4 8 U2 16 20 24 Time (hr) Time (hr) 57 i i i I 27 tI 6I fL * t *. 2 * . 1 I...Guard R&D Center University of Miami Aver Point Gu4600 Rickenbacker Causewayvery Point Miami, FL 33149 Groton, CT 06340I Maury Oceanographic Library

Monitoring hypoxia: approaches to addressing a complex phenomenon in the Black Sea

NASA Astrophysics Data System (ADS)

Friedrich, Jana; Janssen, Felix; He, Yunchang; Holtappels, Moritz; Konovalov, Sergey; Prien, Ralf; Rehder, Gregor; Stanev, Emil

2014-05-01

In this contribution we present an overview of results and share experiences from monitoring and assessing various hypoxia phenomena in the Black Sea. The focus is on approaches and technologies for monitoring of, e.g., mesoscale seasonal patterns in water column oxygenation, multi-decadal trends in oxycline boundary shifts, fast oxygen fluctuations at the pelagic redoxcline and the sediment-water interface, and seasonal changes in bottom-water oxygen. The various temporal scales (from hours to decades) and spatial patterns (from local to basin-scale) in water column oxygenation were addressed using state-of-the-art technologies, e.g., a free-falling pump CTD, a profiling instrumentation platform, ARGO floats equipped with oxygen optodes, static moorings equipped with oxygen optodes, and long-term monitoring programs based on standard CTD casts. Examples from four study sites in the Black Sea and one in the Baltic Sea are presented. Oxygen sensor equipped ARGO type profiling floats proved to be powerful tools to resolve seasonal changes in water column oxygenation and emphasize the importance of mesoscale processes for oxygen distribution in the Black Sea basin. Existing multi-decadal time-series monitoring data based on standard CTD measurements revealed the imprint of climate change and eutrophication on long-term oxygen distributions in the central Black Sea and hence, highlight the importance of maintaining long-term commitments to oxygen monitoring programs. Monitoring data from the last 90 years reflect the rising of the upper boundary of the suboxic zone in the 1970s and 1980s due to eutrophication, and again in the 1990s and 2000s due to NAO forcing, while eutrophication relaxed. Such long time series data allow separating out the effects that climatic forcing and eutrophication exert on oxygen depletion i.e., in the Black Sea. A free-falling pump-CTD provided high-resolution profiles of oxygen and reduced compounds in the Bosporus outflow to the Black Sea, and proved highly suitable to resolve oxygen intrusions into highly stratified systems and hence, to identify and localize processes in complex redoxclines. We also present an example of novel technology applied in the Baltic Sea, which would be highly suitable for the Black Sea. The time series recordings of the profiling instrumentation platform GODESS in the Gotland Basin allowed a thorough characterization of oscillating redoxclines as temporally dynamic, three-dimensional systems. Stand-alone static moorings equipped with optical oxygen sensors, current meters, and turbidity sensors allowed to resolve fast oxygen fluctuations at the sediment-water interface due to, e.g., internal waves and Ekman pumping on the Crimean shelf and identified the formation of seasonal (summer) hypoxia as an highly dynamic process on the north-western Black Sea shelf. This comprehensive study within the EU-FP7 project HYPOX ("In situ monitoring of oxygen depletion in hypoxic ecosystems of coastal and open seas, and land-locked water bodies", www.hypox.net) was able to address many aspects of hypoxia, e.g., in the Black Sea, and revealed the vital need for dedicated oxygen monitoring programs to adequately address the risk of hypoxia formation and ecosystem response. The challenge in any kind of monitoring is to choose the appropriate approach and technology that is suited to resolve the temporal and spatial scales on which the phenomenon occurs.

Exploration of health perceptions and assistive technology use by driving status as related to transportation independence in New Delhi, India.

PubMed

Beyene, Nahom M; Steinfeld, Aaron; Pearlman, Jon; Cooper, Rory A

2012-07-01

This study investigates travel tendencies among people with disabilities and senior citizens in New Delhi, India to reveal relationships between the desire for transportation independence, use of assistive technology for mobility, travel frequency, and satisfaction with available modes of transportation. Study volunteers received invitations to complete a one-time, three-part questionnaire. The survey included an assessment battery developed by the Quality of Life Technology Engineering Research Center, questions featured in the 2002 National Transportation Availability and Use Survey, and a variation on the PARTS/M and FABS/M questionnaires. 80 study participants completed the questionnaire, and were grouped according to driving status as No Driving Experience (NDE), Ceased Driving (CD), and Continue To Drive (CTD). Participants in the NDE group were less likely to use transportation more than twice daily. However, the CD group had the lowest perceived value for available transportation options, with transportation use comparable to the CTD group and an enduring desire to continue driving. Study findings suggest an inner drive for transportation independence. The rise of driving culture internationally presents driver rehabilitation services with challenges due to the need for vehicle modifications and driving assessment using manual transmission automobiles, scooters, and motorcycles.

RNA Seeds Higher Order Assembly of FUS Protein

PubMed Central

Schwartz, Jacob C.; Wang, Xueyin; Podell, Elaine R.; Cech, Thomas R.

2014-01-01

SUMMARY The abundant nuclear RNA-binding protein FUS binds the CTD of RNA polymerase II in an RNA-dependent manner, affecting Ser2 phosphorylation and transcription. Here we examine the mechanism of this process and find that RNA binding nucleates the formation of higher order FUS RNP assemblies that bind the CTD. Both the low-complexity domain and the RGG domain of FUS contribute to assembly. The assemblies appear fibrous by electron microscopy and have characteristics of beta-zipper structures. These results support the emerging view that the pathologic protein aggregation seen in neurodegenerative diseases such as ALS may occur by exaggeration of functionally important assemblies of RNA-binding proteins. PMID:24268778

[Effectiveness of commercial repellents against Aedes aegypti (L.) in Yucatan, México].

PubMed

Uc-Puc, Valentín; Herrera-Bojórquez, Josué; Carmona-Carballo, Carolina; Che-Mendoza, Azael; Medina-Barreiro, Anuar; Chablé-Santos, Juan; Arredondo-Jiménez, Juan I; Flores-Suárez, Adriana E; Manrique-Saide, Pablo

2016-08-01

We assessed the efficacy of commercial repellents available in Yucatan against Aedes aegypti, vector of dengue, Chikungunya and Zika. Protection time was determined based on WHO/CTD/ WHOPES/IC y la NOM-032-SSA2-20I4. Products with DEET (N, N-diethyl-3-methylbenzamide) at 25% met the recommended protection. Efficacy was directly proportional to the concentration of DEET; botanicals repellents resulted no protective. Repellents with DEET provided more protection against Ae. aegypti and botanical repellents, including impregnated wristbands, provided no protection.

Acquisition of Oceanographic Measurements from Baleen Whales: Field Deployments of Tags Developed Under Grant ONR (N00014-13-1-0854)

DTIC Science & Technology

2014-09-30

and on blue and humpback whales in Iceland. • To evaluate the reliability and quality of CTD data collected in arctic ice covered waters by slow...swimming bowhead whales and from the open ocean by fast swimming blue and humpback whales . APPROACH Diving ocean predators can act as “real-time...2014: Deployment of tags on bowhead whales in Disko Bay. June-July 2015: Deployment of tags on blue and humpback whales in Iceland. April-December

Hand cumulative trauma disorders in Nigerian custom tailors: the need for redesign of manual scissors.

PubMed

Adeleye, Adedoyin Abiodun; Akanbi, Olusegun Gabriel

2015-01-01

Cutting scissors are important working tools for Nigerian custom tailors (CTs) but its usage apparently does not meet the ergonomics need of these artisans. A survey was carried out amongst CTs using questionnaires to obtain their background social-occupational demographics and observation methods to study their work performance, use of scissors and any cumulative trauma disorder (CTD) in their hands. Thicknesses of various fabrics were measured and comparison between Western world's custom tailoring job and the Nigerian type was done. The results showed some CTD risk factors with finger contusions on the 71 CTs evaluated. The right-hand contusions were traced to the constant usage of unpadded manual scissors with ungloved hands. Disparity between Western and Nigerian tailoring practice may account for the high occurrence of disorders in Nigerian CTs. Since hand dimensions are crucial in the design of hand tools, it is therefore concluded that hand anthropometry of Nigerian CTs and soft padding of manual scissors may mitigate CTD burdens on CTs' hands. Cumulative trauma disorders on the hands of low-income Nigerian CTs needed investigation. This was done via self-assessment and observational methods of the artisans’ work system. Frequent usage of unpadded manual scissors with un-gloved hands cause and exacerbate the problem. Hand anthropometry of users is crucial in scissors manufacturing.

The premonitory urge to tic: measurement, characteristics, and correlates in older adolescents and adults.

PubMed

Reese, Hannah E; Scahill, Lawrence; Peterson, Alan L; Crowe, Katherine; Woods, Douglas W; Piacentini, John; Walkup, John T; Wilhelm, Sabine

2014-03-01

In addition to motor and/or vocal tics, many individuals with Tourette syndrome (TS) or chronic tic disorder (CTD) report frequent, uncomfortable sensory phenomena that immediately precede the tics. To date, examination of these premonitory sensations or urges has been limited by inconsistent assessment tools. In this paper, we examine the psychometric properties of a nine-item self-report measure, the Premonitory Urge to Tic Scale (PUTS) and examine the characteristics and correlates of the premonitory urge to tic in a clinical sample of 122 older adolescents and adults with TS or CTD. The PUTS demonstrated adequate internal consistency, temporal stability, and concurrent validity. Premonitory urges were endorsed by the majority of individuals. Most individuals reported some relief from the urges after completing a tic and being able to stop their tics even if only temporarily. Degree of premonitory urges was not significantly correlated with age, and we did not observe any gender differences. Degree of premonitory urges was significantly correlated with estimated IQ and tic severity, but not severity of comorbid obsessive-compulsive disorder or attention-deficit hyperactivity disorder. Also, it was not related to concomitant medication status. These findings represent another step forward in our understanding of the premonitory sensations associated with TS and CTD. © 2013.

Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

PubMed Central

Chen, Fei; Zhou, Yu; Qi, Yingchuan B.; Khivansara, Vishal; Li, Hairi; Chun, Sang Young; Kim, John K.; Fu, Xiang-Dong; Jin, Yishi

2015-01-01

Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system. PMID:26588990

Development of Clinical Trial Assessments for the Study of Interstitial Lung Disease in Patients who have Connective Tissue Diseases-Methodological Considerations.

PubMed

Huscher, Dörte; Saketkoo, Lesley Ann; Pittrow, David; Khanna, Dinesh

2010-05-01

This review article discusses the proposed methodology that will be utilized to develop core set items for connective tissue disease-associated interstitial lung disease (CTD-ILD). CTD-ILD remain an important enigma in clinical medicine. No consensus exists on measurement of disease activity or what constitutes a significant response to therapeutic interventions. Lack of appropriate measures inhibit effective drug development and hamper regulatory evaluation of candidate therapies.An interdisciplinary and international Steering Committee (SC) will oversee the execution of a 3-tier Delphi exercise involving experts in CTD and ILD. In parallel to the Delphi, qualitative information will be gathered from patients with ILD using focus groups. These data will subsequently be used to construct surveys to collect quantitative response from patients with ILD. The final Delphi and Patient Perspective results are to be scrutinized by SC and specialty sub-groups (including patient advocates) for truth, discrimination and feasibility - the OMERACT filters. Through application of Nominal Group technique, a core set of outcome measures will be proposed. Subsequent exercises will evaluate the applicability of a proposed core set to the unique issues posed by individual CTDs in addition to guidelines on screening, prognostication and damage scoring.

Methylation of RNA polymerase II non-consensus Lysine residues marks early transcription in mammalian cells

PubMed Central

Dias, João D; Rito, Tiago; Torlai Triglia, Elena; Kukalev, Alexander; Ferrai, Carmelo; Chotalia, Mita; Brookes, Emily; Kimura, Hiroshi; Pombo, Ana

2015-01-01

Dynamic post-translational modification of RNA polymerase II (RNAPII) coordinates the co-transcriptional recruitment of enzymatic complexes that regulate chromatin states and processing of nascent RNA. Extensive phosphorylation of serine residues at the largest RNAPII subunit occurs at its structurally-disordered C-terminal domain (CTD), which is composed of multiple heptapeptide repeats with consensus sequence Y1-S2-P3-T4-S5-P6-S7. Serine-5 and Serine-7 phosphorylation mark transcription initiation, whereas Serine-2 phosphorylation coincides with productive elongation. In vertebrates, the CTD has eight non-canonical substitutions of Serine-7 into Lysine-7, which can be acetylated (K7ac). Here, we describe mono- and di-methylation of CTD Lysine-7 residues (K7me1 and K7me2). K7me1 and K7me2 are observed during the earliest transcription stages and precede or accompany Serine-5 and Serine-7 phosphorylation. In contrast, K7ac is associated with RNAPII elongation, Serine-2 phosphorylation and mRNA expression. We identify an unexpected balance between RNAPII K7 methylation and acetylation at gene promoters, which fine-tunes gene expression levels. DOI: http://dx.doi.org/10.7554/eLife.11215.001 PMID:26687004

Birth outcomes of cases with conotruncal defects of heart - a population-based case-control study.

PubMed

Vereczkey, Attila; Kósa, Zsolt; Csáky-Szunyogh, Melinda; Gerencsér, Balázs; Czeizel, Andrew E

2015-03-01

The aim of this study was to evaluate the birth outcomes of cases with four types of conotruncal defects (CTDs), i.e. common truncus, transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle. Birth outcomes of 597 live-born cases with CTD and 38,151 population controls without any defects were compared in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities completed by socio-demographic variables of their mothers. There was a male excess in cases with CTD (56.8%) with the same mean gestational age (39.4 versus 39.4 weeks) and preterm birth rate (8.2 versus 9.2%), but their mean birth weight was smaller (3077 versus 3276 g) with a high rate of low birthweight (14.6 versus 5.7%) compared to the birth outcomes of population controls. These data indicate intrauterine growth restriction of fetuses affected with transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle particularly in females, while there were a shorter mean gestational age and smaller mean birth weigh in cases with common truncus. In general CTD, except common truncus, had no effect for gestational age but associated with a high risk for intrauterine fetal growth restriction particularly in female cases.

Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease

PubMed Central

Girgis, Reda E; Frost, Adaani E; Hill, Nicholas S; Horn, Evelyn M; Langleben, David; McLaughlin, Vallerie V; Oudiz, Ronald J; Robbins, Ivan M; Seibold, James R; Shapiro, Shelley; Tapson, Victor F; Barst, Robyn J

2007-01-01

Introduction Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ETA receptor, in a cohort of patients with PAH and CTD. Short‐term clinical and haemodynamic effects and longer‐term follow‐up data are presented. Methods A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12‐week, double‐blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo‐treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily. Results Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo‐subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12‐week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I–II than in III–IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients. Conclusions Sitaxsentan appears to be efficacious in patients with PAH associated with CTD. PMID:17472992

An integrative data mining approach to identifying adverse outcome pathway signatures.

PubMed

Oki, Noffisat O; Edwards, Stephen W

2016-03-28

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP network with the AHR gene, an interesting subnetwork including glaucoma was identified. While substantial literature exists to support the potential for AHR ligands to elicit glaucoma, it was not explicitly captured in the public annotation information in CTD. The subnetwork from this analysis suggests a cpAOP that includes changes in CYP1B1 expression, which has been previously established in the literature as a primary cause of glaucoma. These case studies highlight the value in integrating multiple data sources when defining cpAOPs for HTS data. Copyright © 2016. Published by Elsevier Ireland Ltd.

Breast reconstruction in the high risk patient with systemic connective tissue disease: a case series.

PubMed

Chin, K Y; Chalmers, C R; Bryson, A V; Weiler-Mithoff, E M

2013-01-01

The presence of severe underlying connective tissue disease may restrict the reconstructive options offered to a woman in the event of mastectomy. Putative concerns about reconstructive surgery include the effects of connective tissue disease and immunosuppression on wound healing and donor site morbidity, and increased risks of deranged clotting and thrombophilia after free tissue transfer. There is also the possibility of an unpredictable tissue reaction after oncological resection surgery and adjuvant radiotherapy. Here we present a review of the current sparse evidence regarding reconstructive breast surgery in this challenging group of patients. In addition we present a series of six consecutive patients with a spectrum of connective tissue disorders including combinations of longstanding Systemic Lupus Erythematosis (SLE), Rheumatoid arthritis and Raynaud's Disease who underwent successful post-mastectomy reconstruction with an extended autologous latissimus dorsi flap, along with subsequent successful correction of asymmetry and/or nipple reconstruction. There is a paucity of literature on this subject perhaps suggesting that surgeons are reluctant to offer reconstruction or that uptake is poor in this group. Complications related to radiotherapy and free tissue transfer in patients with severe CTD is less than may be expected. The most common complications experienced by our patients with CTD after extended ALD breast reconstruction were persistent donor site seroma, wound dehiscence and delayed haematoma formation, reflecting the abnormal inflammatory response and deranged haemostatic cascade common to connective tissue disease. However, all six patients made a full recovery from surgery without residual donor site morbidity and with an acceptable aesthetic breast reconstruction. Careful peri-operative management is crucial in this group of patients, but good outcomes are possible using a variety of reconstructive techniques. This is the first reported series of patients with severe connective tissue disease who have been managed with extended ALD breast reconstruction. The majority of complications relate to the donor site but the favourable outcomes demonstrate that the extended ALD flap remains a reliable reconstructive option for this group. Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

--No Title--

Science.gov Websites

Properties (CTD/profile data) Trawl Survey Data (including oceanographic profiles) Shiptrack Surface Properties (hull-mounted sensor data) Temperature & Salinity Anomalies (by region) Drifter Tracks eMOLT

MULTIMERMAID: A dedicated multichannel seismic/weather/zoological float for monitoring of the oceans

NASA Astrophysics Data System (ADS)

Hello, Y. M.; Bonnieux, S.; Joubert, C.; Sukhovich, A.; Argentino, J.; Yegikyan, M.; Nolet, G.

2013-12-01

Delays of seismic P waves are used to make scans or 3D images of the variations in seismic wave speed in the Earth's interior using the techniques of seismic tomography. Observations of such delays are ubiquitous on the continents but rare in oceanic regions, mostly because of the large cost associated with deploying ocean-bottom seismometers. At the same time, several thousand free-drifting profiling floats measure the temperature, salinity and current of the upper 2000 m of the ocean in the Argo program, but are incapable to record and transmit seismic signals. Simons et al. (JGR, 2009) developed the idea to use such floats in order to compensate for the lack of seismic delay observations, especially in the southern hemisphere. We built and tested a prototype of such a seismological sensor using an Apex float from Teledyne Webb Research, a Rafos hydrophone, and electronics developed in collaboration with Osean, a small engineering firm in France. This `MERMAID', for `Mobile Earthquake Recorder in Marine Areas by Independent Divers', has concluded its final design stage and a fleet of 20 units is available for experiments. Since 2012, half of these floats have been deployed in the Mediterranean and in the South Indian Ocean. 10 more will be deployed early in 2014 near the Galapagos islands in the Pacific. Analysis of the first data is allowing us to sharpen the wavelet-based algorithm parameters used to discriminate P-waves from the continuous input signal and adapt it to specific noise conditions. A new multidisciplinary version of Mermaid using a dedicated hydrophone is designed to enlarge the band pass for acoustic signals with much higher frequency than seismic. By combining the same algorithm using wavelet transforms, and by adopting a different monitoring strategy with a dedicated processing, Mermaid is able to continuously analyzes acoustic signals to detect major seismic events, while at the same time regularly checking for weather phenomena such rain, drizzle, open sea and ice, or whale migration. This extension to multi-purpose applications makes the Mermaid very attractive for the Argo program. In fact, Mermaids using passive low cost sensors form a very light and complementary solution that can easily be integrated with an Argo float since CTD data are taken during ascent. Such multidisciplinary approach should allow seismologists to participate in international programs such as Argo and obtain the dense ocean coverage needed to image the deep structure of the Earth. We estimate that about 300 Mermaids, operated over a time span of five years, can provide a ray coverage beneath the oceans comparable to that now available beneath the continents with the Global Seismic Network (GSN). To compensate for the extra energy needed for multidisciplinary applications, Geoazur and Osean are developing a new float, called Multimermaid, that uses the same 17' glass sphere as the Ocean Bottom Seismometers constructed by Geoazur. The Multimermaid can navigate up to a depth of 3000 m and hold 2.5 times more battery power than a conventional float.

Effect of greater trochanteric epiphysiodesis after femoral varus osteotomy for lateral pillar classification B and B/C border Legg-Calvé-Perthes disease: A retrospective observational study.

PubMed

Kwon, Keun-Sang; Wang, Sung Il; Lee, Ju-Hyung; Moon, Young Jae; Kim, Jung Ryul

2017-08-01

This is a retrospective observational study. Greater trochanteric epiphysiodesis (GTE) has been recommended to prevent Trendelenburg gait and limitation of the hip joint motion due to trochanteric overgrowth after femoral varus osteotomy (FVO) in Legg-Calvé-Perthes disease (LCPD). However, capital femoral physeal arrest frequently occurs in patients with severe disease (lateral pillar C), so GTE might not be as effective in these patients. The aim of this study was to compare trochanteric growth inhibition due to GTE after FVO between 2 age groups (<8 or >8 years) in patients with lateral pillar B and B/C border LCPD and evaluate the effectiveness of GTE compared with the normal, unaffected hip.This study included 19 children with lateral pillar B and B/C border LCPD in 1 leg who underwent FVO followed by GTE. Of the 19 children, 9 underwent GTE before the age of 8 years and 10 underwent GTE after 8 years of age. On radiographs taken at the immediate postoperative period and at skeletal maturity, the articulo-trochanteric distance (ATD), center-trochanteric distance (CTD), and neck-shaft angle (NSA) were compared between the 2 age groups. The amount of correction was compared between groups. The contralateral, unaffected hip was used as a control for trochanteric growth. The patients were clinically evaluated with Iowa hip score at the final follow-up.There was no significant difference between the 2 age groups in terms of time to GTE, length of follow-up, or lateral pillar classification. In the affected hip, the amount of correction of the ATD, CTD, and NSA was significantly greater in patients < 8 years than in patients > 8 years. However, in the unaffected hip, the change in the ATD, CTD, and NSA did not differ significantly between the 2 groups.We suggest that FVO followed by GTE for lateral pillar B and B/C border LCPD in patients under the age of 8 years can affect growth of the greater trochanter. However, effective growth inhibition due to GTE was not achieved after 8 years of age.

A Small Diameter Rosette for Sampling Ice Covered Waters

NASA Astrophysics Data System (ADS)

Chayes, D. N.; Smethie, W. M.; Perry, R. S.; Schlosser, P.; Friedrich, R.

2011-12-01

A gas tight, small diameter, lightweight rosette, supporting equipment and an effective operational protocol has been developed for aircraft supported sampling of sea water across the Lincoln Sea. The system incorporates a commercial off the shelf CTD electronics (SBE19+ sensor package and SBE33 deck unit) to provide real-time measurement data at the surface. We designed and developed modular water sample units and custom electronics to decode the bottle firing commands and close the sample bottles. For a typical station, we land a ski-equipped deHaviland Twin Otter (DHC-6) aircraft on a suitable piece of sea-ice, drill a 12" diameter hole through the ice next to the cargo door and set up a tent to provide a reasonable working environment over the hole. A small winch with 0.1" diameter single conductor cable is mounted in the aircraft by the cargo door and a tripod supports a sheave above the hole. The CTD module is connected to the end of the wire and the water sampling modules are stacked on top as the system is lowered. For most stations, three sample modules are used to provide 12 four (4) liter sample bottles. Data collected during the down-cast is used to formulate the sampling plan which is executed on the up-cast. The system is powered by a 3,700 Watt, 120VAC gasoline generator. After collection, the sample modules are stored in passively temperature stabilized ice chests during the flight back to the logistics facility at Alert where a broad range of samples are drawn and stored for future analysis. The transport mechanism has a good track record of maintaining water samples within about two degrees of the original collection temperature which minimizes out-gassing. The system has been successfully deployed during a field program each spring starting in 2004 along a transect between the north end of Ellesmere Island (Alert, Nunavut) and the North Pole. During the eight field programs we have taken 48 stations with twelve bottles at most stations (eight at some shallow stations) and with a miss-fire rate within two percent of those achieved with traditional over-the-side CTD/rosette systems.

Seasonal, Oceanographic and Atmospheric Drivers of Diving Behaviour in a Temperate Seal Species Living in the High Arctic

PubMed Central

Blanchet, Marie-Anne; Lydersen, Christian; Ims, Rolf A.; Kovacs, Kit M.

2015-01-01

The harbour seal (Phoca vitulina) population in Svalbard marks the northernmost limit of the species’ range. This small population experiences environmental extremes in sea and air temperatures, sea ice cover and also in light regime for this normally temperate species. This study deployed Conductivity Temperature Depth Satellite Relay Data Loggers (CTD-SRDLs) on 30 adult and juvenile harbour seals in 2009 and 2010 to study their foraging behaviour across multiple seasons. A total of 189,104 dives and 16,640 CTD casts (mean depth 72 m ± 59) were recorded. Individuals dove to a mean depth of 41 m ± 24 with a maximum dive depth range of 24 – 403 m. Dives lasted on average 204 sec ± 120 with maximum durations ranging between 240 – 2,220 sec. Average daily depth and duration of dives, number of dives, time spent diving and dive time/surface time were influenced by date, while sex, age, sea-ice concentration and their interactions were not particularly influential. Dives were deeper (~150 m), longer (~480 sec), less numerous (~250 dives/day) and more pelagic during the winter/early spring compared to the fall and animals spent proportionally less time at the bottom of their dives during the winter. Influxes of warm saline water, corresponding to Atlantic Water characteristics, were observed intermittently at depths ~100 m during both winters in this study. The seasonal changes in diving behaviour were linked to average weekly wind stresses from the north or north-east, which induced upwelling events onto the shelf through offshore Ekman transport. During these events the shelf became flooded with AW from the West Spitsbergen Current, which presumably brought Atlantic fish species close to shore and within the seals’ foraging depth-range. Predicted increased in the influx of AW in this region are likely going to favour the growth and geographic expansion of this harbour seal population in the future. PMID:26196289

hLARP7 C-terminal domain contains an xRRM that binds the 3' hairpin of 7SK RNA

DOE PAGES

Eichhorn, Catherine D.; Chug, Rahul; Feigon, Juli

2016-09-26

The 7SK small nuclear ribonucleoprotein (snRNP) sequesters and inactivates the positive transcription elongation factor b (P-TEFb), an essential eukaryotic mRNA transcription factor. The human La-related protein group 7 (hLARP7) is a constitutive component of the 7SK snRNP and localizes to the 3' terminus of the 7SK long noncoding RNA. hLARP7, and in particular its C-terminal domain (CTD), is essential for 7SK RNA stability and assembly with P-TEFb. The hLARP7 N-terminal Lamodule binds and protects the 3' end from degradation, but the structural and functional role of its CTD is unclear.We report the solution NMR structure of the hLARP7 CTD andmore » show that this domain contains an xRRM, a class of atypical RRM first identified in the Tetrahymena thermophila telomerase LARP7 protein p65. The xRRM binds the 3' end of 7SK RNA at the top of stem-loop 4 (SL4) and interacts with both unpaired and base-paired nucleotides. This study thus confirms that the xRRM is general to the LARP7 family of proteins and defines the binding site for hLARP7 on the 7SK RNA, providing insight into function.« less

High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders

PubMed Central

Abonia, J. Pablo; Wen, Ting; Stucke, Emily M.; Grotjan, Tommie; Griffith, Molly S.; Kemme, Katherine A.; Collins, Margaret H.; Putnam, Philip E.; Franciosi, James P.; von Tiehl, Karl F.; Tinkle, Brad T.; Marsolo, Keith A.; Martin, Lisa J.; Ware, Stephanie M.; Rothenberg, Marc E.

2013-01-01

Background Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. Objective We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). Methods We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. Results We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ21 = 112.0; P < 10−3) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. Conclusion There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD. PMID:23608731

Characterizing turbulent overturns in CTD-data

NASA Astrophysics Data System (ADS)

van Haren, Hans; Gostiaux, Louis

2014-06-01

We are concerned with the shape of overturns due to irreversible effects of turbulent mixing through internal wave breaking in the ocean. Vertical (z) overturn displacements (d) are computed from ship-borne SeaBird-911 CTD-data using the well-established method of reordering unstable portions in vertical density profiles. When displayed as a function of z, the displacements d(z) reveal a characteristic zigzag shape. Here, we primarily investigate the particular slope (z/d) of this zigzag signature after assigning the displacements to the end-point depths. Using model-overturns we show that this slope equals ½ for a solid-body-rotation, while a more sophisticated Rankine-vortex overturn-model, here employed in the vertical, has slopes slightly >½ in the interior and >1 along the sides. In the case of a near-homogeneous layer, displacement-points fill a parallelogram with side-edges having a slope of 1. The models are used to interpret overturn shapes in NE-Atlantic-Ocean-data from moderately deep, turbulent waters above Rockall Bank (off Ireland) and from deep, weakly stratified waters above Mount Josephine (off Portugal). These are compared with salinity-compensated intrusion data in Mediterranean-outflow-waters in the Canary Basin. Dynamically, most overturns are found to resemble the half-turn Rankine-vortex model and very few a, small-only, solid-body-rotation. Additionally, the usefulness and uselessness of upcast-CTD-data are discussed for overturn characterization.

Cdk7 mediates RPB1-driven mRNA synthesis in Toxoplasma gondii

PubMed Central

Deshmukh, Abhijit S.; Mitra, Pallabi; Maruthi, Mulaka

2016-01-01

Cyclin-dependent kinase 7 in conjunction with CyclinH and Mat1 activates cell cycle CDKs and is a part of the general transcription factor TFIIH. Role of Cdk7 is well characterized in model eukaryotes however its relevance in protozoan parasites has not been investigated. This important regulator of key processes warrants closer examination particularly in this parasite given its unique cell cycle progression and flexible mode of replication. We report functional characterization of TgCdk7 and its partners TgCyclinH and TgMat1. Recombinant Cdk7 displays kinase activity upon binding its cyclin partner and this activity is further enhanced in presence of Mat1. The activated kinase phosphorylates C-terminal domain of TgRPB1 suggesting its role in parasite transcription. Therefore, the function of Cdk7 in CTD phosphorylation and RPB1 mediated transcription was investigated using Cdk7 inhibitor. Unphosphorylated CTD binds promoter DNA while phosphorylation by Cdk7 triggers its dissociation from DNA with implications for transcription initiation. Inhibition of Cdk7 in the parasite led to strong reduction in Serine 5 phosphorylation of TgRPB1-CTD at the promoters of constitutively expressed actin1 and sag1 genes with concomitant reduction of both nascent RNA synthesis and 5′-capped transcripts. Therefore, we provide compelling evidence for crucial role of TgCdk7 kinase activity in mRNA synthesis. PMID:27759017

An Integrative data mining approach to identifying Adverse ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP

hLARP7 C-terminal domain contains an xRRM that binds the 3' hairpin of 7SK RNA

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

Eichhorn, Catherine D.; Chug, Rahul; Feigon, Juli

The 7SK small nuclear ribonucleoprotein (snRNP) sequesters and inactivates the positive transcription elongation factor b (P-TEFb), an essential eukaryotic mRNA transcription factor. The human La-related protein group 7 (hLARP7) is a constitutive component of the 7SK snRNP and localizes to the 3' terminus of the 7SK long noncoding RNA. hLARP7, and in particular its C-terminal domain (CTD), is essential for 7SK RNA stability and assembly with P-TEFb. The hLARP7 N-terminal Lamodule binds and protects the 3' end from degradation, but the structural and functional role of its CTD is unclear.We report the solution NMR structure of the hLARP7 CTD andmore » show that this domain contains an xRRM, a class of atypical RRM first identified in the Tetrahymena thermophila telomerase LARP7 protein p65. The xRRM binds the 3' end of 7SK RNA at the top of stem-loop 4 (SL4) and interacts with both unpaired and base-paired nucleotides. This study thus confirms that the xRRM is general to the LARP7 family of proteins and defines the binding site for hLARP7 on the 7SK RNA, providing insight into function.« less

Local Stability of AIDS Epidemic Model Through Treatment and Vertical Transmission with Time Delay

NASA Astrophysics Data System (ADS)

Novi W, Cascarilla; Lestari, Dwi

2016-02-01

This study aims to explain stability of the spread of AIDS through treatment and vertical transmission model. Human with HIV need a time to positively suffer AIDS. The existence of a time, human with HIV until positively suffer AIDS can be delayed for a time so that the model acquired is the model with time delay. The model form is a nonlinear differential equation with time delay, SIPTA (susceptible-infected-pre AIDS-treatment-AIDS). Based on SIPTA model analysis results the disease free equilibrium point and the endemic equilibrium point. The disease free equilibrium point with and without time delay are local asymptotically stable if the basic reproduction number is less than one. The endemic equilibrium point will be local asymptotically stable if the time delay is less than the critical value of delay, unstable if the time delay is more than the critical value of delay, and bifurcation occurs if the time delay is equal to the critical value of delay.

Coupling mRNA processing with transcription in time and space

PubMed Central

Bentley, David L.

2015-01-01

Maturation of mRNA precursors often occurs simultaneously with their synthesis by RNA polymerase II (Pol II). The co-transcriptional nature of mRNA processing has permitted the evolution of coupling mechanisms that coordinate transcription with mRNA capping, splicing, editing and 3′ end formation. Recent experiments using sophisticated new methods for analysis of nascent RNA have provided important insights into the relative amount of co-transcriptional and post-transcriptional processing, the relationship between mRNA elongation and processing, and the role of the Pol II carboxy-terminal domain (CTD) in regulating these processes. PMID:24514444

Studies on the wintertime current structure and T-S fine-structure in the Taiwan Strait

NASA Astrophysics Data System (ADS)

Hu, Jianyu; Fu, Zilang; Wu, Lianxing

1990-12-01

A cruise through the western sea area of the Taiwan Strait was carried out by the R/V Dong Fang Hong in December, 1987. Eight anchored and 10 not anchored stations were set up. Over 25 time-series current observations were made at each station and CTD (Conductivity-temperature-depth) measurements were made at 5 anchored and 10 not anchored stations. Based on the measured data. fine-structures and step-like vertical structures of temperature and salinity were analysed and a tentative wintertime current structure in the Taiwan Strait was described.

Hydrothermal exploration of the Mariana Back Arc Basin: Chemical Characterization

NASA Astrophysics Data System (ADS)

Resing, J. A.; Chadwick, B.; Baker, E. T.; Butterfield, D. A.; Baumberger, T.; Buck, N. J.; Walker, S. L.; Merle, S. G.; Michael, S.

2016-12-01

In November and December 2015, we visited the Southern Mariana back-arc on R/V Falkor (cruise FK151121) to explore for hydrothermal and volcanic activity. We conducted our study using the SENTRY AUV, a CTD rosette designed to do tows and vertical casts into the deep back-arc, and a trace metal CTD-package for the upper 1000m of the water column to examine transport form the nearby arc. We conducted 7 SENTRY dives, 12 tow-yos, 7 vertical casts, and 14 trace metal casts. We also mapped 24,050 km2 of the seafloor using the Falkor EM 302 multibeam. We discovered four new hydrothermal vent sites, and at one of them we found that some of the venting was coming from recently erupted lava flows. That lava flow is the deepest contemporary eruption yet discovered (at 4100-4450 m), and the first to be documented on a slow-spreading ridge. In addition, we were able to map the previously known Alice Springs hydrothermal site in unprecedented detail with AUV Sentry. The distribution of hydrothermal activity as well as chemistry of the plumes above them will be discussed. Plume chemistry data will include , Fe, Mn, CH4, H2, and 3He. The ship time for this project was provided by the Schmidt Ocean Institute with science funding provided by NOAA-Ocean Exploration.

Structure and variability of the Western Maine Coastal Current

USGS Publications Warehouse

Churchill, J.H.; Pettigrew, N.R.; Signell, R.P.

2005-01-01

Analyses of CTD and moored current meter data from 1998 and 2000 reveal a number of mechanisms influencing the flow along the western coast of Maine. On occasions, the Eastern Maine Coastal Current extends into the western Gulf of Maine where it takes the form of a deep (order 100 m deep) and broad (order 20 km wide) southwestward flow with geostrophic velocities exceeding 20 cm s -1. This is not a coastally trapped flow, however. In fields of geostrophic velocity, computed from shipboard-CTD data, the core of this current is roughly centered at the 100 m isobath and its onshore edge is no closer than 10 km from the coast. Geostrophic velocity fields also reveal a relatively shallow (order 10 m deep) baroclinic flow adjacent to the coast. This flow is also directed to the southwest and appears to be principally comprised of local river discharge. Analyses of moored current meter data reveal wind-driven modulations of the coastal flow that are consistent with expectations from simple theoretical models. However, a large fraction of the near-shore current variance does not appear to be directly related to wind forcing. Sea-surface temperature imagery, combined with analysis of the moored current meter data, suggests that eddies and meanders within the coastal flow may at times dominate the near-shore current variance. ?? 2005 Elsevier Ltd. All rights reserved.

The effects of the framing of time on delay discounting.

PubMed

DeHart, William Brady; Odum, Amy L

2015-01-01

We examined the effects of the framing of time on delay discounting. Delay discounting is the process by which delayed outcomes are devalued as a function of time. Time in a titrating delay discounting task is often framed in calendar units (e.g., as 1 week, 1 month, etc.). When time is framed as a specific date, delayed outcomes are discounted less compared to the calendar format. Other forms of framing time; however, have not been explored. All participants completed a titrating calendar unit delay-discounting task for money. Participants were also assigned to one of two delay discounting tasks: time as dates (e.g., June 1st, 2015) or time in units of days (e.g., 5000 days), using the same delay distribution as the calendar delay-discounting task. Time framed as dates resulted in less discounting compared to the calendar method, whereas time framed as days resulted in greater discounting compared to the calendar method. The hyperboloid model fit best compared to the hyperbola and exponential models. How time is framed may alter how participants attend to the delays as well as how the delayed outcome is valued. Altering how time is framed may serve to improve adherence to goals with delayed outcomes. © Society for the Experimental Analysis of Behavior.

The role of parental perceptions of tic frequency and intensity in predicting tic-related functional impairment in youth with chronic tic disorders.

PubMed

Espil, Flint M; Capriotti, Matthew R; Conelea, Christine A; Woods, Douglas W

2014-12-01

Tic severity is composed of several dimensions. Tic frequency and intensity are two such dimensions, but little empirical data exist regarding their relative contributions to functional impairment in those with chronic tic disorders (CTD). The present study examined the relative contributions of these dimensions in predicting tic-related impairment across several psychosocial domains. Using data collected from parents of youth with CTD, multivariate regression analyses revealed that both tic frequency and intensity predicted tic-related impairment in several areas; including family and peer relationships, school interference, and social endeavors, even when controlling for the presence of comorbid anxiety symptoms and Attention Deficit Hyperactivity Disorder diagnostic status. Results showed that tic intensity predicted more variance across more domains than tic frequency.

Synthesis of IgM, IgG and IgA in rheumatoid arthritis.

PubMed Central

Poikonen, K; Oka, M; Möttönen, T; Jokinen, I; Arvilommi, H

1982-01-01

We studied the production of immunoglobulins by lymphocytes separated from the blood of 15 rheumatoid arthritis (RA) patients, of 12 patients suffering from other connective tissue diseases (CTD), and of 18 healthy controls. The production of IgM, IgG and IgA in pokeweed-mitogen-stimulated cultures was measured by counting the number of plaque-forming cells (PFC) and by determining the concentration of secreted immunoglobulins by means of an enzyme immunoassay. Synthesis of immunoglobulins, particularly IgM and IgG, was lower than in other CTD patients or controls. The IgM response of RA patients was 20% and 29% (PFC and Ig concentrations) that of the controls. The respective figures for IgG were 33% and 53% and for IgA 61% and 72%. PMID:6756322

Dynamics of scroll waves with time-delay propagation in excitable media

NASA Astrophysics Data System (ADS)

Chen, Jiang-Xing; Xiao, Jie; Qiao, Li-Yan; Xu, Jiang-Rong

2018-06-01

Information transmission delay can be widely observed in various systems. Here, we study the dynamics of scroll waves with time-delay propagation among slices in excitable media. Weak time delay induces scroll waves to meander. Through increasing the time delay, we find a series of dynamical transitions. Firstly, the straight filament of a scroll wave becomes twisted. Then, the scroll wave breaks and forms interesting patterns. With long time delay, loosed scroll waves are maintained while their period are greatly decreased. Also, cylinder waves appears. The influences of diffusively coupling strength on the time-delay-induced scroll waves are studied. It is found that the critical time delay characterizing those transitions decreases as the coupling strength is increased. A phase diagram in the diffusive coupling-time delay plane is presented.

49 CFR 236.563 - Delay time.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Delay time. 236.563 Section 236.563 Transportation... Cab Signal Systems Rules and Instructions; Locomotives § 236.563 Delay time. Delay time of automatic... requirements of § 236.24 shall take into consideration the delay time. ...

49 CFR 236.563 - Delay time.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 4 2014-10-01 2014-10-01 false Delay time. 236.563 Section 236.563 Transportation... Cab Signal Systems Rules and Instructions; Locomotives § 236.563 Delay time. Delay time of automatic... requirements of § 236.24 shall take into consideration the delay time. ...

Wigner time delay in photodetachment of Tm-and in photoionization of Yb: A comparative study

NASA Astrophysics Data System (ADS)

Saha, Soumyajit; Jose, Jobin; Deshmukh, Pranawa; Dolmatov, Valeriy; Kheifets, Anatoli; Manson, Steven

2017-04-01

Preliminary studies of Wigner time delay in photodetachment spectra of negative ions have been reported. Photodetachment time delay for some dipole channels of Tm- and of Cl- were calculated using relativistic random phase approximation (RRPA). Comparisons between photodetachment time delay of Cl- and photoionization time delay of Ar were made. We investigate the photodetachment time delay for all three relativistically split nd -> ɛ f channels of Tm- and for nd -> ɛ f channels of Yb (isoelectronic to Tm-) using RRPA. We study the effect of the shape resonance, brought about by the centrifugal barrier potential, on photodetachment time delay. A negative ion is a good laboratory for studying the effects of shape resonances on time delay since the phase is unaffected by the Coulomb component. Wigner time delay in photodetachment of Tm- and in photoionization of Yb: A comparative study.

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions.

PubMed

Pannek, Kerstin; Boyd, Roslyn N; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E

2014-01-01

Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Data of 50 children with unilateral CP caused by periventricular white matter lesions (5-17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7-16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm(2)) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment-AHA) was assessed in connections that showed significant differences in FA compared to CTD. FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r(2) = 0.16-0.44; p < 0.05). This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention.

Effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks.

PubMed

Sun, Xiaojuan; Perc, Matjaž; Kurths, Jürgen

2017-05-01

In this paper, we study effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks. Our focus is on the impact of two parameters, namely the time delay τ and the probability of partial time delay p delay , whereby the latter determines the probability with which a connection between two neurons is delayed. Our research reveals that partial time delays significantly affect phase synchronization in this system. In particular, partial time delays can either enhance or decrease phase synchronization and induce synchronization transitions with changes in the mean firing rate of neurons, as well as induce switching between synchronized neurons with period-1 firing to synchronized neurons with period-2 firing. Moreover, in comparison to a neuronal network where all connections are delayed, we show that small partial time delay probabilities have especially different influences on phase synchronization of neuronal networks.

Delay-range-dependent chaos synchronization approach under varying time-lags and delayed nonlinear coupling.

PubMed

Zaheer, Muhammad Hamad; Rehan, Muhammad; Mustafa, Ghulam; Ashraf, Muhammad

2014-11-01

This paper proposes a novel state feedback delay-range-dependent control approach for chaos synchronization in coupled nonlinear time-delay systems. The coupling between two systems is esteemed to be nonlinear subject to time-lags. Time-varying nature of both the intrinsic and the coupling delays is incorporated to broad scope of the present study for a better-quality synchronization controller synthesis. Lyapunov-Krasovskii (LK) functional is employed to derive delay-range-dependent conditions that can be solved by means of the conventional linear matrix inequality (LMI)-tools. The resultant control approach for chaos synchronization of the master-slave time-delay systems considers non-zero lower bound of the intrinsic as well as the coupling time-delays. Further, the delay-dependent synchronization condition has been established as a special case of the proposed LK functional treatment. Furthermore, a delay-range-dependent condition, independent of the delay-rate, has been provided to address the situation when upper bound of the delay-derivative is unknown. A robust state feedback control methodology is formulated for synchronization of the time-delay chaotic networks against the L2 norm bounded perturbations by minimizing the L2 gain from the disturbance to the synchronization error. Numerical simulation results are provided for the time-delay chaotic networks to show effectiveness of the proposed delay-range-dependent chaos synchronization methodologies. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

Downhole delay assembly for blasting with series delay

DOEpatents

Ricketts, Thomas E.

1982-01-01

A downhole delay assembly is provided which can be placed into a blasthole for initiation of explosive in the blasthole. The downhole delay assembly includes at least two detonating time delay devices in series in order to effect a time delay of longer than about 200 milliseconds in a round of explosions. The downhole delay assembly provides a protective housing to prevent detonation of explosive in the blasthole in response to the detonation of the first detonating time delay device. There is further provided a connection between the first and second time delay devices. The connection is responsive to the detonation of the first detonating time delay device and initiates the second detonating time delay device. A plurality of such downhole delay assemblies are placed downhole in unfragmented formation and are initiated simultaneously for providing a round of explosive expansions. The explosive expansions can be used to form an in situ oil shale retort containing a fragmented permeable mass of formation particles.

Parenting Predictors of Delay Inhibition in Socioeconomically Disadvantaged Preschoolers

PubMed Central

Merz, Emily C.; Landry, Susan H.; Zucker, Tricia A.; Barnes, Marcia A.; Assel, Michael; Taylor, Heather B.; Lonigan, Christopher J.; Phillips, Beth M.; Clancy-Menchetti, Jeanine; Eisenberg, Nancy; Spinrad, Tracy L.; Valiente, Carlos; de Villiers, Jill; Consortium, the School Readiness Research

2016-01-01

This study examined longitudinal associations between specific parenting factors and delay inhibition in socioeconomically disadvantaged preschoolers. At Time 1, parents and 2- to 4-year-old children (mean age = 3.21 years; N = 247) participated in a videotaped parent-child free play session, and children completed delay inhibition tasks (gift delay-wrap, gift delay-bow, and snack delay tasks). Three months later, at Time 2, children completed the same set of tasks. Parental responsiveness was coded from the parent-child free play sessions, and parental directive language was coded from transcripts of a subset of 127 of these sessions. Structural equation modeling was used, and covariates included age, gender, language skills, parental education, and Time 1 delay inhibition. Results indicated that in separate models, Time 1 parental directive language was significantly negatively associated with Time 2 delay inhibition, and Time 1 parental responsiveness was significantly positively associated with Time 2 delay inhibition. When these parenting factors were entered simultaneously, Time 1 parental directive language significantly predicted Time 2 delay inhibition whereas Time 1 parental responsiveness was no longer significant. Findings suggest that parental language that modulates the amount of autonomy allotted the child may be an important predictor of early delay inhibition skills. PMID:27833461

Time-delayed feedback control of diffusion in random walkers.

PubMed

Ando, Hiroyasu; Takehara, Kohta; Kobayashi, Miki U

2017-07-01

Time delay in general leads to instability in some systems, while specific feedback with delay can control fluctuated motion in nonlinear deterministic systems to a stable state. In this paper, we consider a stochastic process, i.e., a random walk, and observe its diffusion phenomenon with time-delayed feedback. As a result, the diffusion coefficient decreases with increasing delay time. We analytically illustrate this suppression of diffusion by using stochastic delay differential equations and justify the feasibility of this suppression by applying time-delayed feedback to a molecular dynamics model.

The Role of Parental Perceptions of Tic Frequency and Intensity in Predicting Tic-Related Functional Impairment in Youth with Chronic Tic Disorders

PubMed Central

Espil, Flint M.; Capriotti, Matthew R.; Conelea, Christine A.; Woods, Douglas W.

2014-01-01

Tic severity is composed of several dimensions. Tic frequency and intensity are two such dimensions, but little empirical data exist regarding their relative contributions to functional impairment in those with Chronic Tic Disorders (CTD). The present study examined the relative contributions of these dimensions in predicting tic-related impairment across several psychosocial domains. Using data collected from parents of youth with CTD, multivariate regression analyses revealed that both tic frequency and intensity predicted tic-related impairment in several areas; including family and peer relationships, school interference, and social endeavors, even when controlling for the presence of comorbid anxiety symptoms and Attention Deficit Hyperactivity Disorder diagnostic status. Results showed that tic intensity predicted more variance across more domains than tic frequency. PMID:24395287

International Conference on Harmonisation; guidance on the M4 Common Technical Document--Quality: Questions and Answers/Location Issues; availability. Notice.

PubMed

2004-06-09

The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "M4: The CTD--Quality: Questions and Answers/Location Issues." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance provides further clarification for preparing the quality components of an application file in the common technical document (CTD) format. The guidance addresses the relationship between linked sections for certain parameters (such as polymorphism and particle size), and it addresses location issues (by indicating the section in which to place requested information). The guidance is intended to ease the preparation of paper and electronic submissions, facilitate regulatory reviews, and simplify the exchange of regulatory information among regulatory authorities.

National Air Space (NAS) Data Exchange Environment Through 2060

NASA Technical Reports Server (NTRS)

Roy, Aloke

2015-01-01

NASA's NextGen Concepts and Technology Development (CTD) Project focuses on capabilities to improve safety, capacity and efficiency of the National Air Space (NAS). In order to achieve those objectives, NASA sought industry-Government partnerships to research and identify solutions for traffic flow management, dynamic airspace configuration, separation assurance, super density operations, airport surface operations and similar forward-looking air-traffic modernization (ATM) concepts. Data exchanges over NAS being the key enabler for most of these ATM concepts, the Sub-Topic area 3 of the CTD project sought to identify technology candidates that can satisfy air-to-air and air/ground communications needs of the NAS in the year 2060 timeframe. Honeywell, under a two-year contract with NASA, is working on this communications technology research initiative. This report summarizes Honeywell's research conducted during the second year of the study task.

Retrieving the CTD:Rosette

NASA Image and Video Library

2017-12-08

On June 28, 2011, Holley Kelly, a teacher from Farragut High School, helped retrieve the CTD/Rosette ensemble from the Bering Strait, east of the Diomede Islands. The ICESCAPE mission, or "Impacts of Climate on Ecosystems and Chemistry of the Arctic Pacific Environment," is a NASA shipborne investigation to study how changing conditions in the Arctic affect the ocean's chemistry and ecosystems. The bulk of the research took place in the Beaufort and Chukchi seas in summer 2010 and 2011. Credit: NASA/Kathryn Hansen NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials.

PubMed

Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

2014-05-01

Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Stability, folding dynamics, and long-range conformational transition of the synaptic t-SNARE complex

PubMed Central

Zhang, Xinming; Rebane, Aleksander A.; Ma, Lu; Li, Feng; Jiao, Junyi; Qu, Hong; Pincet, Frederic; Rothman, James E.

2016-01-01

Synaptic soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) couple their stepwise folding to fusion of synaptic vesicles with plasma membranes. In this process, three SNAREs assemble into a stable four-helix bundle. Arguably, the first and rate-limiting step of SNARE assembly is the formation of an activated binary target (t)-SNARE complex on the target plasma membrane, which then zippers with the vesicle (v)-SNARE on the vesicle to drive membrane fusion. However, the t-SNARE complex readily misfolds, and its structure, stability, and dynamics are elusive. Using single-molecule force spectroscopy, we modeled the synaptic t-SNARE complex as a parallel three-helix bundle with a small frayed C terminus. The helical bundle sequentially folded in an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a central ionic layer, with total unfolding energy of ∼17 kBT, where kB is the Boltzmann constant and T is 300 K. Peptide binding to the CTD activated the t-SNARE complex to initiate NTD zippering with the v-SNARE, a mechanism likely shared by the mammalian uncoordinated-18-1 protein (Munc18-1). The NTD zippering then dramatically stabilized the CTD, facilitating further SNARE zippering. The subtle bidirectional t-SNARE conformational switch was mediated by the ionic layer. Thus, the t-SNARE complex acted as a switch to enable fast and controlled SNARE zippering required for synaptic vesicle fusion and neurotransmission. PMID:27911771

[Stomach cancer in patients with systemic non-differentiated connective tissue dysplasia].

PubMed

Zil'ber, V S

2014-01-01

The study was designed as a comparative analysis of clinical and anamnestic data and results of morphological studies of surgically obtained tissues from 61 patients with stomach cancer (SC) aged 29-78 yr with (group 1) and without (group 2) signs of connective tissue dysplasia (CTD). The groups had an identical structure of SC hystological types, but in group 1 the tumours were localized mainly in the stomach body (60.6%, p < 0.05) and in group 2 in the cardia (32.1%, p < 0.05). In group 1, SC was more frequently associated with chronic (sometimes multiple) ulcers outside the tumor (18.2 compared with 7.1% in group 2). Comparative analysis revealed the following features of SC in patients with CTD: predominance of stigmatization signs in the urogenital system (57.6%) and gastrointestinal tract (42.4%), cyst formation in different organs (75.8%) especially in kidneys (48.5%), high frequency of gastric problems in medical history (chronic gastritis, ulcer disease) (72.7 and 35.7% in groups 1 and 2 respectively, p < 0.05) and concomitant pathology of urogenital system (42.4%, p < 0.05). These peculiarities may be used as the marker for the inclusion of patients in the risk group for SC. Taking into account plastic, morphogenetic, and protective functions of connective tissue under physiological conditions, the above epithelial-stromal relationships and peculiarities of reparative processes in gastric mucosa one can not exclude effect of CTD on gastric cancerogenesis. This implies the necessity of further studies.

Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy

PubMed Central

Valieva, Maria E.; Gerasimova, Nadezhda S.; Kudryashova, Kseniya S.; Kozlova, Anastasia L.; Kirpichnikov, Mikhail P.; Hu, Qi; Botuyan, Maria Victoria; Mer, Georges; Feofanov, Alexey V.; Studitsky, Vasily M.

2017-01-01

A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes were studied with single-particle Förster resonance energy transfer (spFRET) microscopy using nucleosomes labeled with a donor-acceptor pair of fluorophores, which were attached to the adjacent gyres of DNA near the contact between H2A-H2B dimers. Human FACT and its version without the C-terminal domain (CTD) and the high mobility group (HMG) domain of the structure-specific recognition protein 1 (SSRP1) subunit did not change the structure of the nucleosomes, while FACT without the acidic C-terminal domains of the suppressor of Ty 16 (Spt16) and the SSRP1 subunits caused nucleosome aggregation. Proteolytic removal of histone tails significantly disturbed the nucleosome structure, inducing partial unwrapping of nucleosomal DNA. Human FACT reduced DNA unwrapping and stabilized the structure of tailless nucleosomes. CTD and/or HMG domains of SSRP1 are required for this FACT activity. In contrast, previously it has been shown that yeast FACT unfolds (reorganizes) nucleosomes using the CTD domain of SSRP1-like Pol I-binding protein 3 subunit (Pob3). Thus, yeast and human FACT complexes likely utilize the same domains for nucleosome reorganization and stabilization, respectively, and these processes are mechanistically similar. PMID:28067802

Stabilization of Nucleosomes by Histone Tails and by FACT Revealed by spFRET Microscopy.

PubMed

Valieva, Maria E; Gerasimova, Nadezhda S; Kudryashova, Kseniya S; Kozlova, Anastasia L; Kirpichnikov, Mikhail P; Hu, Qi; Botuyan, Maria Victoria; Mer, Georges; Feofanov, Alexey V; Studitsky, Vasily M

2017-01-06

A correct chromatin structure is important for cell viability and is tightly regulated by numerous factors. Human protein complex FACT (facilitates chromatin transcription) is an essential factor involved in chromatin transcription and cancer development. Here FACT-dependent changes in the structure of single nucleosomes were studied with single-particle Förster resonance energy transfer (spFRET) microscopy using nucleosomes labeled with a donor-acceptor pair of fluorophores, which were attached to the adjacent gyres of DNA near the contact between H2A-H2B dimers. Human FACT and its version without the C-terminal domain (CTD) and the high mobility group (HMG) domain of the structure-specific recognition protein 1 (SSRP1) subunit did not change the structure of the nucleosomes, while FACT without the acidic C-terminal domains of the suppressor of Ty 16 (Spt16) and the SSRP1 subunits caused nucleosome aggregation. Proteolytic removal of histone tails significantly disturbed the nucleosome structure, inducing partial unwrapping of nucleosomal DNA. Human FACT reduced DNA unwrapping and stabilized the structure of tailless nucleosomes. CTD and/or HMG domains of SSRP1 are required for this FACT activity. In contrast, previously it has been shown that yeast FACT unfolds (reorganizes) nucleosomes using the CTD domain of SSRP1-like Pol I-binding protein 3 subunit (Pob3). Thus, yeast and human FACT complexes likely utilize the same domains for nucleosome reorganization and stabilization, respectively, and these processes are mechanistically similar.

Tetramerization and interdomain flexibility of the replication initiation controller YabA enables simultaneous binding to multiple partners

PubMed Central

Felicori, Liza; Jameson, Katie H.; Roblin, Pierre; Fogg, Mark J.; Garcia-Garcia, Transito; Ventroux, Magali; Cherrier, Mickaël V.; Bazin, Alexandre; Noirot, Philippe; Wilkinson, Anthony J.; Molina, Franck; Terradot, Laurent; Noirot-Gros, Marie-Françoise

2016-01-01

YabA negatively regulates initiation of DNA replication in low-GC Gram-positive bacteria. The protein exerts its control through interactions with the initiator protein DnaA and the sliding clamp DnaN. Here, we combined X-ray crystallography, X-ray scattering (SAXS), modeling and biophysical approaches, with in vivo experimental data to gain insight into YabA function. The crystal structure of the N-terminal domain (NTD) of YabA solved at 2.7 Å resolution reveals an extended α-helix that contributes to an intermolecular four-helix bundle. Homology modeling and biochemical analysis indicates that the C-terminal domain (CTD) of YabA is a small Zn-binding domain. Multi-angle light scattering and SAXS demonstrate that YabA is a tetramer in which the CTDs are independent and connected to the N-terminal four-helix bundle via flexible linkers. While YabA can simultaneously interact with both DnaA and DnaN, we found that an isolated CTD can bind to either DnaA or DnaN, individually. Site-directed mutagenesis and yeast-two hybrid assays identified DnaA and DnaN binding sites on the YabA CTD that partially overlap and point to a mutually exclusive mode of interaction. Our study defines YabA as a novel structural hub and explains how the protein tetramer uses independent CTDs to bind multiple partners to orchestrate replication initiation in the bacterial cell. PMID:26615189

Hydrographic Conditions in the Gulf of Carpentaria During Australian Monsoon Experiment

NASA Astrophysics Data System (ADS)

Inoue, M.; Steinberg, C.; Wolanski, E.; Ridd, P.

2002-12-01

Gulf of Carpentaria located in the northern Australia, is a shallow wide basin with the deepest bottom depths of approximately 60 m. It is connected to Arafura Sea to the north and west, and to the Torres Strait to the east. Hydrographic surveys of the Gulf of Carpentaria were carried out in January and March, 1987 as part of Australian Monsoon Experiment. During the January survey, Tropical Cyclone (TC) Irma was formed in the Gulf of Carpentaria. An east-west CTD section at 13o52'S was occupied twice, one prior to and during, and the other after the formation of TC Irma. In addition, two post-Irma east-west sections were occupied at 12o40'S and 11o30'S. The pre-cyclone section indicates a well-defined stratified two-layer system, while the post-cyclone sections show deepening of the surface warm layer due to significant mixing by TC Irma. Overall, significant cooling of near surface warm water on the order of more than 1oC was observed. Significant heat loss estimated for the water column has presumably contributed toward the development of TC Irma. In February 1987, TC Jason was formed in the gulf. During the March survey, two east-west CTD sections were occupied at 11o30'S and 13o52'S. The March survey reveals notable warming of the bottom water. Detailed discussion of the CTD data from the two cruises will be presented.

[The diagnostic significance of nailfold video-capillaroscopy in systemic sclerosis].

PubMed

Li, Lin-Guang; Zhang, Jiang-Lin; Liu, Xiu-Hua; Huang, Feng

2012-05-01

To observe nailfold capillary changes in a cohort of connective tissue disease (CTD) with Raynaud's phenomenon (RP) and to explore the diagnostic value of nailfold video-capillaroscopy (NVC) in systemic sclerosis (SSc). Sixty CTD patients with RP divided into SSc group (n = 36) and non-SSc group (n = 24) were referred to an experienced operator for NVC. The patients had decreased capillary loops in SSc group with the capillary diameter more enlarged in SSc group than non-SSc group. The number of patients in SSc group with giant capillaries was 14, while 3 in non-SSc group. There were 23 patients with haemorrhages in SSc group and 9 in non-SSc group. The number of patients with severe effusion was 15 in SSc group, while 2 in non-SSc group. By using the ROC curves, indexes with AUC at least 0.7 of the input capillary diameter, the output capillary diameter, the middle capillary diameter, blood color and effusion for the diagnostic cutoff points were 18.5 µm, 24.5 µm, 19.5µm, deep red and severe effusion. With at least 2 out of the top 3 indexes, the diagnostic sensitivity and specificity of SSc were higher. CTD Patients with RP of SSc have less capillary loops, more enlarged capillaries, more giant capillaries, more severe effusion and more haemorrhages than non-SSc patients. The characteristics of nailfold capillary changes in SSc patients with RP can be helpful for the diagnosis and the differential diagnosis of SSc.

Hydrothermal venting on the flanks of Heard and McDonald islands, southern Indian Ocean

NASA Astrophysics Data System (ADS)

Lupton, J. E.; Arculus, R. J.; Coffin, M.; Bradney, A.; Baumberger, T.; Wilkinson, C.

2017-12-01

Heard Island and the nearby McDonald Islands are two sites of active volcanism associated with the so-called Kerguelen mantle plume or hot spot. In fact, it has been proposed that the Kerguelen hot spot is currently located beneath Heard Island. During its maiden maximum endurance voyage (IN2016_V01), the recently commissioned Australian R/V Investigator conducted a detailed bathymetric and water column survey of the waters around Heard Island and the McDonald Islands as well as other sites on the Kerguelen Plateau. Some 50 hydrographic profiles were completed using the CTD/rosette system equipped with trace metal sampling and a nephelometer for suspended particle concentrations. In addition to the hydrographic profiles, 244 bubble plumes were detected in the vicinity of the Heard and McDonald Islands using the ship's multibeam system. It is thought that the bubble plumes observed on sea knolls and other seafloor surrounding the McDonald Islands are likely hydrothermal in origin, while plumes northeast of Heard Island may be biogenic methane from cold seeps. At 29 of the hydrographic stations water samples for helium isotope measurements were drawn from the CTD rosette and hermetically sealed into copper tubing for subsequent shorebased mass spectrometer and gas chromatograph analysis. In this paper we report results for 3He/4He ratios and CO2 and CH4 concentrations in water samples collected with the CTD/rosette, and discuss how these results are correlated with suspended particle concentrations and temperature anomalies.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

PubMed Central

Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

2014-01-01

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. PMID:24368713

3.3 Å structure of Niemann–Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport

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

Li, Xiaochun; Lu, Feiran; Trinh, Michael N.

Niemann–Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann–Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314–1,278), which—in contrast to previous lower resolution structures—features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfidemore » bonds, one of which (C909–C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD–NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.« less

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair

PubMed Central

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M.; Friedhoff, Peter; Plotz, Guido

2010-01-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome which predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased co-expression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations. PMID:20533529

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

PubMed

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M; Friedhoff, Peter; Plotz, Guido

2010-08-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome that predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased coexpression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations.

Effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks

NASA Astrophysics Data System (ADS)

Sun, Xiaojuan; Perc, Matjaž; Kurths, Jürgen

2017-05-01

In this paper, we study effects of partial time delays on phase synchronization in Watts-Strogatz small-world neuronal networks. Our focus is on the impact of two parameters, namely the time delay τ and the probability of partial time delay pdelay, whereby the latter determines the probability with which a connection between two neurons is delayed. Our research reveals that partial time delays significantly affect phase synchronization in this system. In particular, partial time delays can either enhance or decrease phase synchronization and induce synchronization transitions with changes in the mean firing rate of neurons, as well as induce switching between synchronized neurons with period-1 firing to synchronized neurons with period-2 firing. Moreover, in comparison to a neuronal network where all connections are delayed, we show that small partial time delay probabilities have especially different influences on phase synchronization of neuronal networks.

Effect of time delay on surgical performance during telesurgical manipulation.

PubMed

Fabrizio, M D; Lee, B R; Chan, D Y; Stoianovici, D; Jarrett, T W; Yang, C; Kavoussi, L R

2000-03-01

Telementoring allows a less experienced surgeon to benefit from an expert surgical consultation, reducing cost, travel, and the learning curve associated with new procedures. However, there are several technical limitations that affect practical applications. One potentially serious problem is the time delay that occurs any time data are transferred across long distances. To date, the effect of time delay on surgical performance has not been studied. A two-phase trial was designed to examine the effect of time delay on surgical performance. In the first phase, a series of tasks was performed, and the numbers of robotic movements required for completion was counted. Programmed incremental time delays were made in audiovisual acquisition and robotic controls. The number of errors made while performing each task at various time delay intervals was noted. In the second phase, a remote surgeon in Baltimore performed the tasks 9000 miles away in Singapore. The number of errors made was recorded. As the time delay increased, the number of operator errors increased. The accuracy needed to perform remote robotic procedures was diminished as the time delay increased. A learning curve did exist for each task, but as the time delay interval increased, it took longer to complete the task. Time delay does affect surgical performance. There is an acceptable delay of <700 msec in which surgeons can compensate for this phenomenon. Clinical studies will be needed to evaluate the true impact of time delay.

Finite time synchronization of memristor-based Cohen-Grossberg neural networks with mixed delays.

PubMed

Chen, Chuan; Li, Lixiang; Peng, Haipeng; Yang, Yixian

2017-01-01

Finite time synchronization, which means synchronization can be achieved in a settling time, is desirable in some practical applications. However, most of the published results on finite time synchronization don't include delays or only include discrete delays. In view of the fact that distributed delays inevitably exist in neural networks, this paper aims to investigate the finite time synchronization of memristor-based Cohen-Grossberg neural networks (MCGNNs) with both discrete delay and distributed delay (mixed delays). By means of a simple feedback controller and novel finite time synchronization analysis methods, several new criteria are derived to ensure the finite time synchronization of MCGNNs with mixed delays. The obtained criteria are very concise and easy to verify. Numerical simulations are presented to demonstrate the effectiveness of our theoretical results.

Time-delayed chameleon: Analysis, synchronization and FPGA implementation

NASA Astrophysics Data System (ADS)

Rajagopal, Karthikeyan; Jafari, Sajad; Laarem, Guessas

2017-12-01

In this paper we report a time-delayed chameleon-like chaotic system which can belong to different families of chaotic attractors depending on the choices of parameters. Such a characteristic of self-excited and hidden chaotic flows in a simple 3D system with time delay has not been reported earlier. Dynamic analysis of the proposed time-delayed systems are analysed in time-delay space and parameter space. A novel adaptive modified functional projective lag synchronization algorithm is derived for synchronizing identical time-delayed chameleon systems with uncertain parameters. The proposed time-delayed systems and the synchronization algorithm with controllers and parameter estimates are then implemented in FPGA using hardware-software co-simulation and the results are presented.

The time delay in strong gravitational lensing with Gauss-Bonnet correction

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

Man, Jingyun; Cheng, Hongbo, E-mail: jingyunman@mail.ecust.edu.cn, E-mail: hbcheng@ecust.edu.cn

2014-11-01

The time delay between two relativistic images in the strong gravitational lensing governed by Gauss-Bonnet gravity is studied. We make a complete analytical derivation of the expression of time delay in presence of Gauss-Bonnet coupling. With respect to Schwarzschild, the time delay decreases as a consequence of the shrinking of the photon sphere. As the coupling increases, the second term in the time delay expansion becomes more relevant. Thus time delay in strong limit encodes some new information about geometry in five-dimensional spacetime with Gauss-Bonnet correction.

Combination of ORP and pH sensors in tow-yo studies to map redox and acid-base anomalies in seawater due to hydrothermal activity in shallow areas

NASA Astrophysics Data System (ADS)

Santana-Casiano, J. M.; González-Dávila, M.; Fraile-Nuez, E.; Santana-González, C.; Baker, E. T.; Resing, J. A.; Walker, S. L.

2016-12-01

The detection of activity from low-temperature hydrothermal vents, where the increase in temperature is not evident, requires the utilization of alternative sensors that respond to emissions of certain chemical species. The character of both reduced and acid fluids in the volcanic emissions in the El Hierro submarine volcano allowed us to detect anomalies related with changes in the chemical potential and the proton concentration using ORP and pH sensors, respectively. Tow-yos with these sensors provided the approximate locations of the emissions plotting δ(ORP)/δt and ΔpH versus the latitude or longitude. The ORP sensor responds very quickly to the presence of reduced chemicals in the water column. The magnitude of this change is examined by the time derivative of ORP, δ(ORP)/δt. For pH changes, ΔpH, the mean pH for each depth at a reference station in an area not affected by the vent emission is subtracted from each point measured near the volcanic edifice. The submarine volcano of El Hierro, in its degasification stage, provided an excellent opportunity to apply CTD-pH-ORP tow-yo methodology and to study the effect of CO2 emission on the seawater carbonate system, the global carbon flux, and local ocean acidification. Detailed surveys of the volcanic edifice were carried out during VULCANO 0314 and VULCANA0615 cruises using several CTD-pH-ORP tow-yo studies, localizing the redox and acidic changes, which were used to obtain surface maps of anomalies. CTD-pH-ORP yo-yo studies were also conducted that included discrete sampling for carbonate system parameters and total dissolved Fe(II), TDFe(II). The inputs of CO2 along multiple sections combined with measurements of oceanic currents produced an estimated volcanic CO2 flux = 6.0 105 ± 1.1 105 kg d-1and increases the acidity above the volcano by 20%. From the yo-yo studies important anomalies in both pHT and TDFe(II) were observed. The increased TDFe(II) concentrations and the low associated pHT values may be acting as an important fertilization event in the seawater around the volcano at the Island of El Hierro providing optimal conditions for the regeneration of the area.

Effect of Time Delay on Recognition Memory for Pictures: The Modulatory Role of Emotion

PubMed Central

Wang, Bo

2014-01-01

This study investigated the modulatory role of emotion in the effect of time delay on recognition memory for pictures. Participants viewed neutral, positive and negative pictures, and took a recognition memory test 5 minutes, 24 hours, or 1 week after learning. The findings are: 1) For neutral, positive and negative pictures, overall recognition accuracy in the 5-min delay did not significantly differ from that in the 24-h delay. For neutral and positive pictures, overall recognition accuracy in the 1-week delay was lower than in the 24-h delay; for negative pictures, overall recognition in the 24-h and 1-week delay did not significantly differ. Therefore negative emotion modulates the effect of time delay on recognition memory, maintaining retention of overall recognition accuracy only within a certain frame of time. 2) For the three types of pictures, recollection and familiarity in the 5-min delay did not significantly differ from that in the 24-h and the 1-week delay. Thus emotion does not appear to modulate the effect of time delay on recollection and familiarity. However, recollection in the 24-h delay was higher than in the 1-week delay, whereas familiarity in the 24-h delay was lower than in the 1-week delay. PMID:24971457

Using Performance Assessment Model in Physics Laboratory to Increase Students’ Critical Thinking Disposition

NASA Astrophysics Data System (ADS)

Emiliannur, E.; Hamidah, I.; Zainul, A.; Wulan, A. R.

2017-09-01

Performance Assessment Model (PAM) has been developed to represent the physics concepts which able to be devided into five experiments: 1) acceleration due to gravity; 2) Hooke’s law; 3) simple harmonic motion; 4) work-energy concepts; and 5) the law of momentum conservation. The aim of this study was to determine the contribution of PAM in physics laboratory to increase students’ Critical Thinking Disposition (CTD) at senior high school. Subject of the study were 11th grade consist 32 students of a senior high school in Lubuk Sikaping, West Sumatera. The research used one group pretest-postest design. Data was collected through essay test and questionnaire about CTD. Data was analyzed using quantitative way with N-gain value. This study concluded that performance assessmet model effectively increases the N-gain at medium category. It means students’ critical thinking disposition significant increase after implementation of performance assessment model in physics laboratory.

C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis

PubMed Central

Harriss, June; Das, Chhaya; Zhu, Li; Edwards, Melissa; Shaaban, Salam; Tucker, Haley

2015-01-01

The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3′s oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors. PMID:25738358

An acoustic charge transport imager for high definition television applications

NASA Technical Reports Server (NTRS)

Hunt, William D.; Brennan, Kevin F.; Summers, Christopher J.

1993-01-01

This report covers: (1) invention of a new, ultra-low noise, low operating voltage APD which is expected to offer far better performance than the existing volume doped APD device; (2) performance of a comprehensive series of experiments on the acoustic and piezoelectric properties of ZnO films sputtered on GaAs which can possibly lead to a decrease in the required rf drive power for ACT devices by 15dB; (3) development of an advanced, hydrodynamic, macroscopic simulator used for evaluating the performance of ACT and CTD devices and aiding in the development of the next generation of devices; (4) experimental development of CTD devices which utilize a p-doped top barrier demonstrating charge storage capacity and low leakage currents; (5) refinements in materials growth techniques and in situ controls to lower surface defect densities to record levels as well as increase material uniformity and quality.

Angular dependence of EWS time delay for photoionization of @Xe

NASA Astrophysics Data System (ADS)

Mandal, Ankur; Deshmukh, Pranawa; Kheifets, Anatoli; Dolmatov, Valeriy; Manson, Steven

2017-04-01

Interference between photoionization channels leads to angular dependence in photoionization time delay. Angular dependence is found to be a common effect for two-photon absorption experiments very recently. The effect of confinement on the time delay where each partial wave contributions to the ionization are studied. In this work we report angular dependence and confinement effects on Eisenbud-Wigner-Smith (EWS) time delay in atomic photoionization. Using and we computed the EWS time delay for free and confined Xe atom for photoionization from inner 4d3/2 and 4d5/2 and outer 5p1/2 and 5p3/2 subshells at various angles. The calculated EWS time delay is few tens to few hundreds of attoseconds (10-18 second). The photoionization time delay for @Xe follows that in the free Xe atom on which the confinement oscillations are built. The present work reveals the effect of confinement on the photoionization time delay at different angles between photoelectron ejection and the photon polarization.

Crash testing difference-smoothing algorithm on a large sample of simulated light curves from TDC1

NASA Astrophysics Data System (ADS)

Rathna Kumar, S.

2017-09-01

In this work, we propose refinements to the difference-smoothing algorithm for the measurement of time delay from the light curves of the images of a gravitationally lensed quasar. The refinements mainly consist of a more pragmatic approach to choose the smoothing time-scale free parameter, generation of more realistic synthetic light curves for the estimation of time delay uncertainty and using a plot of normalized χ2 computed over a wide range of trial time delay values to assess the reliability of a measured time delay and also for identifying instances of catastrophic failure. We rigorously tested the difference-smoothing algorithm on a large sample of more than thousand pairs of simulated light curves having known true time delays between them from the two most difficult 'rungs' - rung3 and rung4 - of the first edition of Strong Lens Time Delay Challenge (TDC1) and found an inherent tendency of the algorithm to measure the magnitude of time delay to be higher than the true value of time delay. However, we find that this systematic bias is eliminated by applying a correction to each measured time delay according to the magnitude and sign of the systematic error inferred by applying the time delay estimator on synthetic light curves simulating the measured time delay. Following these refinements, the TDC performance metrics for the difference-smoothing algorithm are found to be competitive with those of the best performing submissions of TDC1 for both the tested 'rungs'. The MATLAB codes used in this work and the detailed results are made publicly available.

Comparison of delay enhancement mechanisms for SBS-based slow light systems.

PubMed

Schneider, Thomas; Henker, Ronny; Lauterbach, Kai-Uwe; Junker, Markus

2007-07-23

We compare two simple mechanisms for the enhancement of the time delay in slow light systems. Both are based on the superposition of the Brillouin gain with additional loss. As we will show in theory and experiment if two losses are placed at the wings of a SBS gain, contrary to other methods, the loss power increases the time delay. This leads to higher delay times at lower optical powers and to an increase of the zero gain delay of more than 50%. With this method we achieved a time delay of more than 120ns for pulses with a temporal width of 30ns. To the best of our knowledge, this is the highest time delay in just one fiber spool. Beside the enhancement of the time delay the method could have the potential to decrease the pulse distortions for high bit rate signals.

Impact of Partial Time Delay on Temporal Dynamics of Watts-Strogatz Small-World Neuronal Networks

NASA Astrophysics Data System (ADS)

Yan, Hao; Sun, Xiaojuan

2017-06-01

In this paper, we mainly discuss effects of partial time delay on temporal dynamics of Watts-Strogatz (WS) small-world neuronal networks by controlling two parameters. One is the time delay τ and the other is the probability of partial time delay pdelay. Temporal dynamics of WS small-world neuronal networks are discussed with the aid of temporal coherence and mean firing rate. With the obtained simulation results, it is revealed that for small time delay τ, the probability pdelay could weaken temporal coherence and increase mean firing rate of neuronal networks, which indicates that it could improve neuronal firings of the neuronal networks while destroying firing regularity. For large time delay τ, temporal coherence and mean firing rate do not have great changes with respect to pdelay. Time delay τ always has great influence on both temporal coherence and mean firing rate no matter what is the value of pdelay. Moreover, with the analysis of spike trains and histograms of interspike intervals of neurons inside neuronal networks, it is found that the effects of partial time delays on temporal coherence and mean firing rate could be the result of locking between the period of neuronal firing activities and the value of time delay τ. In brief, partial time delay could have great influence on temporal dynamics of the neuronal networks.

Piloted simulator study of allowable time delay in pitch flight control system of a transport airplane with negative static stability

NASA Technical Reports Server (NTRS)

Grantham, William D.; Smith, Paul M.; Person, Lee H., Jr.; Meyer, Robert T.; Tingas, Stephen A.

1987-01-01

A piloted simulation study was conducted to determine the permissible time delay in the flight control system of a 10-percent statically unstable transport airplane during cruise flight conditions. The math model used for the simulation was a derivative Lockheed L-1011 wide-body jet transport. Data were collected and analyzed from a total of 137 cruising flights in both calm- and turbulent-air conditions. Results of this piloted simulation study verify previous findings that show present military specifications for allowable control-system time delay may be too stringent when applied to transport-size airplanes. Also, the degree of handling-qualities degradation due to time delay is shown to be strongly dependent on the source of the time delay in an advanced flight control system. Maximum allowable time delay for each source of time delay in the control system, in addition to a less stringent overall maximum level of time delay, should be considered for large aircraft. Preliminary results also suggest that adverse effects of control-system time delay may be at least partially offset by variations in control gearing. It is recommended that the data base include different airplane baselines, control systems, and piloting tasks with many pilots participating, so that a reasonable set of limits for control-system time delay can be established to replace the military specification limits currently being used.

Exercise training in pulmonary arterial hypertension associated with connective tissue diseases

PubMed Central

2012-01-01

Introduction The objective of this prospective study was to assess short- and long-term efficacy of exercise training (ET) as add-on to medical therapy in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-APAH). Methods Patients with invasively confirmed CTD-APAH received ET in-hospital for 3 weeks and continued at home for 12 weeks. Efficacy parameters have been evaluated at baseline and after 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of 2.9 ± 1.9 years. Results Twenty-one consecutive patients were included and assessed at baseline, and after 3 weeks, 14 after 15 weeks. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 67 ± 52 meters after 3 weeks (p < 0.001) and by 71 ± 35 meters after 15 weeks (p = 0.003), scores of quality of life (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET. The 1- and 2-year overall-survival rates were 100%, the 3-year survival 73%. In one patient lung transplantation was performed 6 months after ET. Conclusion ET as add-on to medical therapy is highly effective in patients with CTD-APAH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further randomized controlled studies are needed to confirm these results. Trial registration ClinicalTrials.gov: NCT00491309. PMID:22709477

Structural basis for ribosome protein S1 interaction with RNA in trans-translation of Mycobacterium tuberculosis.

PubMed

Fan, Yi; Dai, Yazhuang; Hou, Meijing; Wang, Huilin; Yao, Hongwei; Guo, Chenyun; Lin, Donghai; Liao, Xinli

2017-05-27

Ribosomal protein S1 (RpsA), the largest 30S protein in ribosome, plays a significant role in translation and trans-translation. In Mycobacterium tuberculosis, the C-terminus of RpsA is known as tuberculosis drug target of pyrazinoic acid, which inhibits the interaction between MtRpsA and tmRNA in trans-translation. However, the molecular mechanism underlying the interaction of MtRpsA with tmRNA remains unknown. We herein analyzed the interaction of the C-terminal domain of MtRpsA with three RNA fragments poly(A), sMLD and pre-sMLD. NMR titration analysis revealed that the RNA binding sites on MtRpsA CTD are mainly located in the β2, β3 and β5 strands and the adjacent L3 loop of the S1 domain. Fluorescence experiments determined the MtRpsA CTD binding to RNAs are in the micromolar affinity range. Sequence analysis also revealed conserved residues in the mapped RNA binding region. Residues L304, V305, G308, F310, H322, I323, R357 and I358 were verified to be the key residues influencing the interaction between MtRpsA CTD and pre-sMLD. Molecular docking further confirmed that the poly(A)-like sequence and sMLD of tmRNA are all involved in the protein-RNA interaction, through charged interaction and hydrogen bonds. The results will be beneficial for designing new anti-tuberculosis drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Attention bias for social threat in youth with tic disorders: Links with tic severity and social anxiety.

PubMed

Pile, Victoria; Robinson, Sally; Topor, Marta; Hedderly, Tammy; Lau, Jennifer Y F

2018-06-07

Many individuals with Tourette syndrome and chronic tic disorders (TS/CTDs) report poor social functioning and comorbid social anxiety. Yet limited research has investigated the role of cognitive factors that highlight social threats in youth with TS/CTD, and whether these biases underlie tic severity and co-occurring social anxiety. This study examined whether selective attention to social threat is enhanced young people with TS/CTDs compared to healthy controls, and whether attention biases are associated with tic severity and social anxiety. Twenty seven young people with TS/CTDs and 25 matched control participants completed an experimental measure of attention bias toward/away from threat stimuli. A clinician-rated interview measuring tic severity/impairment (YGTSS Total Score) and questionnaire measures of social anxiety were completed by participants and their parents. Young people with TS/CTD showed an attention bias to social threat words (relative to benign words) compared to controls but no such bias for social threat faces. Attention bias for social threat words was associated with increasing YGTSS Total Score and parent-reported social anxiety in the TS/CTDs group. Mediation analysis revealed a significant indirect path between YGTSS Total Score and social anxiety, via attention to social threat. Tentatively, these associations appeared to be driven by impairment rather than tic severity scores. Preliminary data suggests that youth with TS/CTD have enhanced attention to threat, compared to controls, and this is associated with impairment and social anxiety. Attention to threat could offer a cognitive mechanism connecting impairment and social anxiety, and so be a valuable trans-diagnostic treatment target.

Funding oncology clinical trials: are cooperative group trials sustainable?

PubMed

Seow, Hsien-Yeang; Whelan, Patrick; Levine, Mark N; Cowan, Kathryn; Lysakowski, Barbara; Kowaleski, Brenda; Snider, Anne; Xu, Rebecca Y; Arnold, Andrew

2012-05-01

Many oncology clinical trials departments (CTDs) are in serious fiscal deficit and their sustainability is in jeopardy. This study investigates whether the payment models used to fund industry versus cooperative group trials contribute to the fiscal deficit of a CTD. We examined the lifetime costs of all cooperative group and industry trials activated in the CTD of a cancer center between 2007 and 2011. A trial's lifetime is defined as being from the date the first patient was accrued until the last patient's actual or projected final follow-up visit. For each trial, we calculated the lifetime monthly net income, which was defined as monthly revenue minus monthly costs. Data sources included study protocols, trial budgets, and accrual data. Of the 97 trials analyzed, 64 (66%) were cooperative group trials. The pattern of lifetime net income for cooperative group trials has a positive peak during patient accrual followed by a negative trough during follow-up. In contrast, the pattern for industry trials resembled an "l" shape. The patterns reflect the differing payment models: upfront lump-sum payments (cooperative group) versus milestone payments (industry). The negative trough in the lifetime net income of a cooperative group trial occurs because follow-up costs are typically not funded or are underfunded. CTDs accrue more patients in new trials to offset that deficit. The CTD uses revenue from accrual to existing trials to cross-subsidize past trials in follow-up. As the number of patients on follow-up increases, the fiscal deficit grows larger each year, perpetuating the cycle.

The Clinical Features of Myositis-Associated Autoantibodies: a Review.

PubMed

Gunawardena, Harsha

2017-02-01

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases traditionally defined by clinical manifestations including skeletal muscle weakness, skin rashes, elevated skeletal muscle enzymes, and neurophysiological and/or histological evidence of muscle inflammation. Patients with myositis overlap can develop other features including parenchymal lung disease, inflammatory arthritis, gastrointestinal manifestations and marked constitutional symptoms. Although patients may be diagnosed as having polymyositis (PM) or dermatomyositis (DM) under the IIM spectrum, it is quite clear that disease course between subgroups of patients is different. For example, interstitial lung disease may predominate in some, whereas cutaneous complications, cancer risk, or severe refractory myopathy may be a significant feature in others. Therefore, tools that facilitate diagnosis and indicate which patients require more detailed investigation for disease complications are invaluable in clinical practice. The expanding field of autoantibodies (autoAbs) associated with connective tissue disease (CTD)-myositis overlap has generated considerable interest over the last few years. Using an immunological diagnostic approach, this group of heterogeneous conditions can be separated into a number of distinct clinical phenotypes. Rather than diagnose a patient as simply having PM, DM or overlap CTD, we can define syndromes to differentiate disease subsets that emphasise clinical outcomes and guide management. There are now over 15 CTD-myositis overlap autoAbs found in patients with a range of clinical manifestations including interstitial pneumonia, cutaneous disease, cancer-associated myositis and autoimmune-mediated necrotising myopathy. This review describes their diagnostic utility, potential role in disease monitoring and response to treatment. In the future, routine use of these autoAb will allow a stratified approach to managing this complex set of conditions.

76 FR 68734 - Taking and Importing Marine Mammals: Taking Marine Mammals Incidental to Navy Training Exercises...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-07

... marine mammal is likely to travel during the time associated with the TDFD's time delay, and that... Navy provided the approximate distance that an animal would typically travel within a given time-delay... Speed and Length of Time-Delay Potential distance Species group Swim speed Time-delay traveled Delphinid...

Researchers use Modified CRISPR Systems to Modulate Gene Expression on a Genomic Scale

Cancer.gov

Cancer Target Discovery and Development Network (CTD2) researchers at the University of California, San Francisco, developed a CRISPR system that can regulate both gene repression and activation with fewer off-target effects.

Structure of the Paramyxovirus Parainfluenza Virus 5 Nucleoprotein in Complex with an Amino-Terminal Peptide of the Phosphoprotein

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

Aggarwal, Megha; Leser, George P.; Kors, Christopher A.

Parainfluenza virus 5 (PIV5) belongs to the familyParamyxoviridae, which consists of enveloped viruses with a nonsegmented negative-strand RNA genome encapsidated by the nucleoprotein (N). Paramyxovirus replication is regulated by the phosphoprotein (P) through protein-protein interactions with N and the RNA polymerase (L). The chaperone activity of P is essential to maintain the unassembled RNA-free form of N in order to prevent nonspecific RNA binding and premature N oligomerization. Here, we determined the crystal structure of unassembled PIV5 N in complex with a P peptide (N 0P) derived from the N terminus of P (P50) at 2.65 Å. The PIV5 Nmore » 0P consists of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a hinge region. The cleft at the hinge region of RNA-bound PIV5 N was previously shown to be an RNA binding site. The N 0P structure shows that the P peptide binds to the CTD of N and extends toward the RNA binding site to inhibit N oligomerization and, hence, RNA binding. Binding of P peptide also keeps the PIV5 N in the open form. A molecular dynamics (MD) analysis of both the open and closed forms of N shows the flexibility of the CTD and the preference of the N protein to be in an open conformation. The gradual opening of the hinge region, to release the RNA, was also observed. Together, these results advance our knowledge of the conformational swapping of N required for the highly regulated paramyxovirus replication. IMPORTANCEParamyxovirus replication is regulated by the interaction of P with N and L proteins. Here, we report the crystal structure of unassembled parainfluenza virus 5 (PIV5) N chaperoned with P peptide. Our results provide a detailed understanding of the binding of P to N. The conformational switching of N between closed and open forms during its initial interaction with P, as well as during RNA release, was analyzed. Our data also show the plasticity of the CTD and the importance of domain movement for conformational switching. The results improve our understanding of the mechanism of interchanging N conformations for RNA replication and release.« less

Structure of the Paramyxovirus Parainfluenza Virus 5 Nucleoprotein in Complex with an Amino-Terminal Peptide of the Phosphoprotein.

PubMed

Aggarwal, Megha; Leser, George P; Kors, Christopher A; Lamb, Robert A

2018-03-01

Parainfluenza virus 5 (PIV5) belongs to the family Paramyxoviridae , which consists of enveloped viruses with a nonsegmented negative-strand RNA genome encapsidated by the nucleoprotein (N). Paramyxovirus replication is regulated by the phosphoprotein (P) through protein-protein interactions with N and the RNA polymerase (L). The chaperone activity of P is essential to maintain the unassembled RNA-free form of N in order to prevent nonspecific RNA binding and premature N oligomerization. Here, we determined the crystal structure of unassembled PIV5 N in complex with a P peptide (N 0 P) derived from the N terminus of P (P50) at 2.65 Å. The PIV5 N 0 P consists of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a hinge region. The cleft at the hinge region of RNA-bound PIV5 N was previously shown to be an RNA binding site. The N 0 P structure shows that the P peptide binds to the CTD of N and extends toward the RNA binding site to inhibit N oligomerization and, hence, RNA binding. Binding of P peptide also keeps the PIV5 N in the open form. A molecular dynamics (MD) analysis of both the open and closed forms of N shows the flexibility of the CTD and the preference of the N protein to be in an open conformation. The gradual opening of the hinge region, to release the RNA, was also observed. Together, these results advance our knowledge of the conformational swapping of N required for the highly regulated paramyxovirus replication. IMPORTANCE Paramyxovirus replication is regulated by the interaction of P with N and L proteins. Here, we report the crystal structure of unassembled parainfluenza virus 5 (PIV5) N chaperoned with P peptide. Our results provide a detailed understanding of the binding of P to N. The conformational switching of N between closed and open forms during its initial interaction with P, as well as during RNA release, was analyzed. Our data also show the plasticity of the CTD and the importance of domain movement for conformational switching. The results improve our understanding of the mechanism of interchanging N conformations for RNA replication and release. Copyright © 2018 American Society for Microbiology.

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data.

PubMed

Hettne, Kristina M; Boorsma, André; van Dartel, Dorien A M; Goeman, Jelle J; de Jong, Esther; Piersma, Aldert H; Stierum, Rob H; Kleinjans, Jos C; Kors, Jan A

2013-01-29

Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect.

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions

PubMed Central

Pannek, Kerstin; Boyd, Roslyn N.; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E.

2014-01-01

Background Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. Aim The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Methods Data of 50 children with unilateral CP caused by periventricular white matter lesions (5–17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7–16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm2) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment—AHA) was assessed in connections that showed significant differences in FA compared to CTD. Results FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r2 = 0.16–0.44; p < 0.05). Conclusion This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention. PMID:25003031

Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data

PubMed Central

2013-01-01

Background Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. Methods We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Results Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Conclusions Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect. PMID:23356878

Probability of Loss of Assured Safety in Systems with Multiple Time-Dependent Failure Modes: Incorporation of Delayed Link Failure in the Presence of Aleatory Uncertainty.

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

Helton, Jon C.; Brooks, Dusty Marie; Sallaberry, Cedric Jean-Marie.

Probability of loss of assured safety (PLOAS) is modeled for weak link (WL)/strong link (SL) systems in which one or more WLs or SLs could potentially degrade into a precursor condition to link failure that will be followed by an actual failure after some amount of elapsed time. The following topics are considered: (i) Definition of precursor occurrence time cumulative distribution functions (CDFs) for individual WLs and SLs, (ii) Formal representation of PLOAS with constant delay times, (iii) Approximation and illustration of PLOAS with constant delay times, (iv) Formal representation of PLOAS with aleatory uncertainty in delay times, (v) Approximationmore » and illustration of PLOAS with aleatory uncertainty in delay times, (vi) Formal representation of PLOAS with delay times defined by functions of link properties at occurrence times for failure precursors, (vii) Approximation and illustration of PLOAS with delay times defined by functions of link properties at occurrence times for failure precursors, and (viii) Procedures for the verification of PLOAS calculations for the three indicated definitions of delayed link failure.« less

Time delay can facilitate coherence in self-driven interacting-particle systems

NASA Astrophysics Data System (ADS)

Sun, Yongzheng; Lin, Wei; Erban, Radek

2014-12-01

Directional switching in a self-propelled particle model with delayed interactions is investigated. It is shown that the average switching time is an increasing function of time delay. The presented results are applied to studying collective animal behavior. It is argued that self-propelled particle models with time delays can explain the state-dependent diffusion coefficient measured in experiments with locust groups. The theory is further generalized to heterogeneous groups where each individual can respond to its environment with a different time delay.

Delay banking for air traffic management

NASA Technical Reports Server (NTRS)

Green, Steven M. (Inventor)

2007-01-01

A method and associated system for time delay banking for aircraft arrival time, aircraft departure time and/or en route flight position. The delay credit value for a given flight may decrease with passage of time and may be transferred to or traded with other flights having the same or a different user (airline owner or operator). The delay credit value for a given aircraft flight depends upon an initial delay credit value, which is determined by a central system and depends upon one or more other flight characteristics. Optionally, the delay credit value decreases with passage of time. Optionally, a transaction cost is assessed against a delay credit value that is used on behalf of another flight with the same user or is traded with a different user.

General relation between the group delay and dwell time in multicomponent electron systems

NASA Astrophysics Data System (ADS)

Zhai, Feng; Lu, Junqiang

2016-10-01

For multicomponent electron scattering states, we derive a general relation between the Wigner group delay and the Bohmian dwell time. It is found that the definition of group delay should account for the phase of the spinor wave functions of propagating modes. The difference between the group delay and dwell time comes from both the interference delay and the decaying modes. For barrier tunneling of helical electrons on a surface of topological insulators, our calculations including the trigonal-warping term show that the decaying modes can contribute greatly to the group delay. The derived relation between the group delay and the dwell time is helpful to unify the two definitions of tunneling time in a quite general situation.

CAN LARGE TIME DELAYS OBSERVED IN LIGHT CURVES OF CORONAL LOOPS BE EXPLAINED IN IMPULSIVE HEATING?

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

Lionello, Roberto; Linker, Jon A.; Mikić, Zoran

The light curves of solar coronal loops often peak first in channels associated with higher temperatures and then in those associated with lower temperatures. The delay times between the different narrowband EUV channels have been measured for many individual loops and recently for every pixel of an active region observation. The time delays between channels for an active region exhibit a wide range of values. The maximum time delay in each channel pair can be quite large, i.e., >5000 s. These large time delays make-up 3%–26% (depending on the channel pair) of the pixels where a trustworthy, positive time delaymore » is measured. It has been suggested that these time delays can be explained by simple impulsive heating, i.e., a short burst of energy that heats the plasma to a high temperature, after which the plasma is allowed to cool through radiation and conduction back to its original state. In this paper, we investigate whether the largest observed time delays can be explained by this hypothesis by simulating a series of coronal loops with different heating rates, loop lengths, abundances, and geometries to determine the range of expected time delays between a set of four EUV channels. We find that impulsive heating cannot address the largest time delays observed in two of the channel pairs and that the majority of the large time delays can only be explained by long, expanding loops with photospheric abundances. Additional observations may rule out these simulations as an explanation for the long time delays. We suggest that either the time delays found in this manner may not be representative of real loop evolution, or that the impulsive heating and cooling scenario may be too simple to explain the observations, and other potential heating scenarios must be explored.« less

Cognitive person variables in the delay of gratification of older children at risk.

PubMed

Rodriguez, M L; Mischel, W; Shoda, Y

1989-08-01

The components of self-regulation were analyzed, extending the self-imposed delay of gratification paradigm to older children with social adjustment problems. Delay behavior was related to a network of conceptually relevant cognitive person variables, consisting of attention deployment strategies during delay, knowledge of delay rules, and intelligence. A positive relationship was demonstrated between concurrent indexes of intelligence, attention deployment, and actual delay time. Moreover, attention deployment, measured as an individual differences variable during the delay process, had a direct, positive effect on delay behavior. Specifically, as the duration of delay and the frustration of the situation increased, children who spent a higher proportion of the time distracting themselves from the tempting elements of the delay situation were able to delay longer. The effect of attention deployment on delay behavior was significant even when age, intelligence, and delay rule knowledge were controlled. Likewise, delay rule knowledge significantly predicted delay time, even when age, attention deployment, and intelligence were controlled.

Firing patterns transition and desynchronization induced by time delay in neural networks

NASA Astrophysics Data System (ADS)

Huang, Shoufang; Zhang, Jiqian; Wang, Maosheng; Hu, Chin-Kun

2018-06-01

We used the Hindmarsh-Rose (HR) model (Hindmarsh and Rose, 1984) to study the effect of time delay on the transition of firing behaviors and desynchronization in neural networks. As time delay is increased, neural networks exhibit diversity of firing behaviors, including regular spiking or bursting and firing patterns transitions (FPTs). Meanwhile, the desynchronization of firing and unstable bursting with decreasing amplitude in neural system, are also increasingly enhanced with the increase of time delay. Furthermore, we also studied the effect of coupling strength and network randomness on these phenomena. Our results imply that time delays can induce transition and desynchronization of firing behaviors in neural networks. These findings provide new insight into the role of time delay in the firing activities of neural networks, and can help to better understand the firing phenomena in complex systems of neural networks. A possible mechanism in brain that can cause the increase of time delay is discussed.

Delay time in a single barrier for a movable quantum shutter

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

Hernandez, Alberto

2010-05-15

The transient solution and delay time for a {delta} potential scatterer with a movable quantum shutter is calculated by solving analytically the time-dependent Schroedinger equation. The delay time is analyzed as a function of the distance between the shutter and the potential barrier and also as a function of the distance between the potential barrier and the detector. In both cases, it is found that the delay time exhibits a dynamical behavior and that it tends to a saturation value {Delta}t{sub sat} in the limit of very short distances, which represents the maximum delay produced by the potential barrier nearmore » the interaction region. The phase time {tau}{sub {theta},} on the other hand, is not an appropriate time scale for measuring the time delay near the interaction region, except if the shutter is moved far away from the potential. The role played by the antibound state of the system on the behavior of the delay time is also discussed.« less

LiDAR-IMU Time Delay Calibration Based on Iterative Closest Point and Iterated Sigma Point Kalman Filter.

PubMed

Liu, Wanli

2017-03-08

The time delay calibration between Light Detection and Ranging (LiDAR) and Inertial Measurement Units (IMUs) is an essential prerequisite for its applications. However, the correspondences between LiDAR and IMU measurements are usually unknown, and thus cannot be computed directly for the time delay calibration. In order to solve the problem of LiDAR-IMU time delay calibration, this paper presents a fusion method based on iterative closest point (ICP) and iterated sigma point Kalman filter (ISPKF), which combines the advantages of ICP and ISPKF. The ICP algorithm can precisely determine the unknown transformation between LiDAR-IMU; and the ISPKF algorithm can optimally estimate the time delay calibration parameters. First of all, the coordinate transformation from the LiDAR frame to the IMU frame is realized. Second, the measurement model and time delay error model of LiDAR and IMU are established. Third, the methodology of the ICP and ISPKF procedure is presented for LiDAR-IMU time delay calibration. Experimental results are presented that validate the proposed method and demonstrate the time delay error can be accurately calibrated.

On Time Delay Margin Estimation for Adaptive Control and Optimal Control Modification

NASA Technical Reports Server (NTRS)

Nguyen, Nhan T.

2011-01-01

This paper presents methods for estimating time delay margin for adaptive control of input delay systems with almost linear structured uncertainty. The bounded linear stability analysis method seeks to represent an adaptive law by a locally bounded linear approximation within a small time window. The time delay margin of this input delay system represents a local stability measure and is computed analytically by three methods: Pade approximation, Lyapunov-Krasovskii method, and the matrix measure method. These methods are applied to the standard model-reference adaptive control, s-modification adaptive law, and optimal control modification adaptive law. The windowing analysis results in non-unique estimates of the time delay margin since it is dependent on the length of a time window and parameters which vary from one time window to the next. The optimal control modification adaptive law overcomes this limitation in that, as the adaptive gain tends to infinity and if the matched uncertainty is linear, then the closed-loop input delay system tends to a LTI system. A lower bound of the time delay margin of this system can then be estimated uniquely without the need for the windowing analysis. Simulation results demonstrates the feasibility of the bounded linear stability method for time delay margin estimation.

Leveraging delay discounting for health: Can time delays influence food choice?

PubMed

Appelhans, Bradley M; French, Simone A; Olinger, Tamara; Bogucki, Michael; Janssen, Imke; Avery-Mamer, Elizabeth F; Powell, Lisa M

2018-07-01

Delay discounting, the tendency to choose smaller immediate rewards over larger delayed rewards, is theorized to promote consumption of immediately rewarding but unhealthy foods at the expense of long-term weight maintenance and nutritional health. An untested implication of delay discounting models of decision-making is that selectively delaying access to less healthy foods may promote selection of healthier (immediately available) alternatives, even if they may be less desirable. The current study tested this hypothesis by measuring healthy versus regular vending machine snack purchasing before and during the implementation of a 25-s time delay on the delivery of regular snacks. Purchasing was also examined under a $0.25 discount on healthy snacks, a $0.25 tax on regular snacks, and the combination of both pricing interventions with the 25-s time delay. Across 32,019 vending sales from three separate vending locations, the 25-s time delay increased healthy snack purchasing from 40.1% to 42.5%, which was comparable to the impact of a $0.25 discount (43.0%). Combining the delay and the discount had a roughly additive effect (46.0%). However, the strongest effects were seen under the $0.25 tax on regular snacks (53.7%) and the combination of the delay and the tax (50.2%). Intervention effects varied substantially between vending locations. Importantly, time delays did not harm overall vending sales or revenue, which is relevant to the real-world feasibility of this intervention. More investigation is needed to better understand how the impact of time delays on food choice varies across populations, evaluate the effects of time delays on beverage vending choices, and extend this approach to food choices in contexts other than vending machines. ClinicalTrials.gov, NCT02359916. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of time delay on flying qualities: An update

NASA Technical Reports Server (NTRS)

Smith, R. E.; Sarrafian, S. K.

1986-01-01

Flying qualities problems of modern, full-authority electronic flight control systems are most often related to the introduction of additional time delay in aircraft response to a pilot input. These delays can have a significant effect on the flying qualities of the aircraft. Time delay effects are reexamined in light of recent flight test experience with aircraft incorporating new technology. Data from the X-29A forward-swept-wing demonstrator, a related preliminary in-flight experiment, and other flight observations are presented. These data suggest that the present MIL-F-8785C allowable-control system time delay specifications are inadequate or, at least, incomplete. Allowable time delay appears to be a function of the shape of the aircraft response following the initial delay. The cockpit feel system is discussed as a dynamic element in the flight control system. Data presented indicate that the time delay associated with a significant low-frequency feel system does not result in the predicted degradation in aircraft flying qualities. The impact of the feel system is discussed from two viewpoints: as a filter in the control system which can alter the initial response shape and, therefore, the allowable time delay, and as a unique dynamic element whose delay contribution can potentially be discounted by special pilot loop closures.

Describing-function analysis of a ripple regulator with slew-rate limits and time delays

NASA Technical Reports Server (NTRS)

Wester, Gene W.

1990-01-01

The effects of time delays and slew-rate limits on the steady-state operating points and performance of a free-running ripple regulator are evaluated using describing-function analysis. The describing function of an ideal comparator (no time delays or slew rate limits) has no phase shift and is independent of frequency. It is found that turn-on delay and turn-off delay have different effects on gain and phase and cannot be combined. Comparator hysteresis affects both gain and phase; likewise, time delays generally affect both gain and phase. It is found that the effective time delay around the feedback loop is one half the sum of turn-on and turn-off delays, regardless of whether the delays are caused by storage time or slew rate limits. Expressions are formulated for the switching frequency, switch duty ratio, dc output, and output ripple. For the case of no hysteresis, a simple, graphical solution for the switching frequency is possible, and the resulting switching frequency is independent of first-order variations of input or load.

Market-based control strategy for long-span structures considering the multi-time delay issue

NASA Astrophysics Data System (ADS)

Li, Hongnan; Song, Jianzhu; Li, Gang

2017-01-01

To solve the different time delays that exist in the control device installed on spatial structures, in this study, discrete analysis using a 2 N precise algorithm was selected to solve the multi-time-delay issue for long-span structures based on the market-based control (MBC) method. The concept of interval mixed energy was introduced from computational structural mechanics and optimal control research areas, and it translates the design of the MBC multi-time-delay controller into a solution for the segment matrix. This approach transforms the serial algorithm in time to parallel computing in space, greatly improving the solving efficiency and numerical stability. The designed controller is able to consider the issue of time delay with a linear controlling force combination and is especially effective for large time-delay conditions. A numerical example of a long-span structure was selected to demonstrate the effectiveness of the presented controller, and the time delay was found to have a significant impact on the results.

Delay time and Hartman effect in strain engineered graphene

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

Chen, Xi, E-mail: xchen@shu.edu.cn; Deng, Zhi-Yong; Ban, Yue, E-mail: yban@shu.edu.cn

2014-05-07

Tunneling times, including group delay and dwell time, are studied for massless Dirac electrons transmitting through a one-dimensional barrier in strain-engineered graphene. The Hartman effect, the independence of group delay on barrier length, is induced by the strain effect, and associated with the transmission gap and the evanescent mode. The influence of barrier height/length and strain modulus/direction on the group delay is also discussed, which provides the flexibility to control the group delay with applications in graphene-based devices. The relationship between group delay and dwell time is finally derived to clarify the nature of the Hartman effect.

Reconstructions of parameters of radiophysical chaotic generator with delayed feedback from short time series

NASA Astrophysics Data System (ADS)

Ishbulatov, Yu. M.; Karavaev, A. S.; Kiselev, A. R.; Semyachkina-Glushkovskaya, O. V.; Postnov, D. E.; Bezruchko, B. P.

2018-04-01

A method for the reconstruction of time-delayed feedback system is investigated, which is based on the detection of synchronous response of a slave time-delay system with respect to the driving from the master system under study. The structure of the driven system is similar to the structure of the studied time-delay system, but the feedback circuit is broken in the driven system. The method efficiency is tested using short and noisy data gained from an electronic chaotic oscillator with time-delayed feedback.

Reconstruction of ensembles of coupled time-delay systems from time series.

PubMed

Sysoev, I V; Prokhorov, M D; Ponomarenko, V I; Bezruchko, B P

2014-06-01

We propose a method to recover from time series the parameters of coupled time-delay systems and the architecture of couplings between them. The method is based on a reconstruction of model delay-differential equations and estimation of statistical significance of couplings. It can be applied to networks composed of nonidentical nodes with an arbitrary number of unidirectional and bidirectional couplings. We test our method on chaotic and periodic time series produced by model equations of ensembles of diffusively coupled time-delay systems in the presence of noise, and apply it to experimental time series obtained from electronic oscillators with delayed feedback coupled by resistors.

Stability of Nonlinear Systems with Unknown Time-varying Feedback Delay

NASA Astrophysics Data System (ADS)

Chunodkar, Apurva A.; Akella, Maruthi R.

2013-12-01

This paper considers the problem of stabilizing a class of nonlinear systems with unknown bounded delayed feedback wherein the time-varying delay is 1) piecewise constant 2) continuous with a bounded rate. We also consider application of these results to the stabilization of rigid-body attitude dynamics. In the first case, the time-delay in feedback is modeled specifically as a switch among an arbitrarily large set of unknown constant values with a known strict upper bound. The feedback is a linear function of the delayed states. In the case of linear systems with switched delay feedback, a new sufficiency condition for average dwell time result is presented using a complete type Lyapunov-Krasovskii (L-K) functional approach. Further, the corresponding switched system with nonlinear perturbations is proven to be exponentially stable inside a well characterized region of attraction for an appropriately chosen average dwell time. In the second case, the concept of the complete type L-K functional is extended to a class of nonlinear time-delay systems with unknown time-varying time-delay. This extension ensures stability robustness to time-delay in the control design for all values of time-delay less than the known upper bound. Model-transformation is used in order to partition the nonlinear system into a nominal linear part that is exponentially stable with a bounded perturbation. We obtain sufficient conditions which ensure exponential stability inside a region of attraction estimate. A constructive method to evaluate the sufficient conditions is presented together with comparison with the corresponding constant and piecewise constant delay. Numerical simulations are performed to illustrate the theoretical results of this paper.

Effect of metrology time delay on overlay APC

NASA Astrophysics Data System (ADS)

Carlson, Alan; DiBiase, Debra

2002-07-01

The run-to-run control strategy of lithography APC is primarily composed of a feedback loop as shown in the diagram below. It is known that the insertion of a time delay in a feedback loop can cause degradation in control performance and could even cause a stable system to become unstable, if the time delay becomes sufficiently large. Many proponents of integrated metrology methods have cited the damage caused by metrology time delays as the primary justification for moving from a stand-alone to integrated metrology. While there is little dispute over the qualitative form of this argument, there has been very light published about the quantitative effects under real fab conditions - precisely how much control is lost due to these time delays. Another issue regarding time delays is that the length of these delays is not typically fixed - they vary from lot to lot and in some cases this variance can be large - from one hour on the short side to over 32 hours on the long side. Concern has been expressed that the variability in metrology time delays can cause undesirable dynamics in feedback loops that make it difficult to optimize feedback filters and gains and at worst could drive a system unstable. By using data from numerous fabs, spanning many sizes and styles of operation, we have conducted a quantitative study of the time delay effect on overlay run- to-run control. Our analysis resulted in the following conclusions: (1) There is a significant and material relationship between metrology time delay and overlay control under a variety of real world production conditions. (2) The run-to-run controller can be configured to minimize sensitivity to time delay variations. (3) The value of moving to integrated metrology can be quantified.

Digital time delay

DOEpatents

Martin, A.D.

1986-05-09

Method and apparatus are provided for generating an output pulse following a trigger pulse at a time delay interval preset with a resolution which is high relative to a low resolution available from supplied clock pulses. A first lumped constant delay provides a first output signal at predetermined interpolation intervals corresponding to the desired high resolution time interval. Latching circuits latch the high resolution data to form a first synchronizing data set. A selected time interval has been preset to internal counters and corrected for circuit propagation delay times having the same order of magnitude as the desired high resolution. Internal system clock pulses count down the counters to generate an internal pulse delayed by an internal which is functionally related to the preset time interval. A second LCD corrects the internal signal with the high resolution time delay. A second internal pulse is then applied to a third LCD to generate a second set of synchronizing data which is complementary with the first set of synchronizing data for presentation to logic circuits. The logic circuits further delay the internal output signal with the internal pulses. The final delayed output signal thereafter enables the output pulse generator to produce the desired output pulse at the preset time delay interval following input of the trigger pulse.

Traversal of electromagnetic pulses through dispersive media with negative refractive index

NASA Astrophysics Data System (ADS)

Nanda, L.; Ramakrishna, S. A.

2017-05-01

We investigate the traversal of electromagnetic pulses through dispersive media with negative refractive index in such a way that no resonant effects come into play. It has been verified that for evanescent waves, the definitions of the group delay and the reshaping delay times get interchanged in comparison to the propagating waves. We show that for a negative refractive index medium (NRM) with ɛ(ω)=μ(ω), the reshaping delay time identically vanishes for propagating waves. The total delay time in NRM is otherwise contributed by both the group and the reshaping delay times, whereas for the case of broadband pulses in NRM the total delay time is always subluminal.

Simulation analysis of the effect of initial delay on flight delay diffusion

NASA Astrophysics Data System (ADS)

Que, Zufu; Yao, Hongguang; Yue, Wei

2018-01-01

The initial delay of the flight is an important factor affecting the spread of flight delays, so clarifying their relationship conduces to control flight delays in the aeronautical network. Through establishing a model of the chain aviation network and making simulation analysis of the effects of initial delay on the delay longitudinal diffusion, it’s found that the number of delayed airports in the air network, the total delay time and the average delay time of the delayed airport are generally positively correlated with the initial delay. This indicates that the occurrence of the initial delay should be avoided or reduced as much as possible to improve the punctuality of the flight.

A snapshot of internal waves and hydrodynamic instabilities in the southern Bay of Bengal

NASA Astrophysics Data System (ADS)

Lozovatsky, Iossif; Wijesekera, Hemantha; Jarosz, Ewa; Lilover, Madis-Jaak; Pirro, Annunziata; Silver, Zachariah; Centurioni, Luca; Fernando, H. J. S.

2016-08-01

Measurements conducted in the southern Bay of Bengal (BoB) as a part of the ASIRI-EBoB Program portray the characteristics of high-frequency internal waves in the upper pycnocline as well as the velocity structure with episodic events of shear instability. A 20 h time series of CTD, ADCP, and acoustic backscatter profiles down to 150 m as well as temporal CTD measurements in the pycnocline at z = 54 m were taken to the east of Sri Lanka. Internal waves of periods ˜10-40 min were recorded at all depths below a shallow (˜20-30 m) surface mixed layer in the background of an 8 m amplitude internal tide. The absolute values of vertical displacements associated with high-frequency waves followed the Nakagami distribution with a median value of 2.1 m and a 95% quintile 6.5 m. The internal wave amplitudes are normally distributed. The tails of the distribution deviate from normality due to episodic high-amplitude displacements. The sporadic appearance of internal waves with amplitudes exceeding ˜5 m usually coincided with patches of low Richardson numbers, pointing to local shear instability as a possible mechanism of internal-wave-induced turbulence. The probability of shear instability in the summer BoB pycnocline based on an exponential distribution of the inverse Richardson number, however, appears to be relatively low, not exceeding 4% for Ri < 0.25 and about 10% for Ri < 0.36 (K-H billows). The probability of the generation of asymmetric breaking internal waves and Holmboe instabilities is above ˜25%.

RIMPAC 08: Naval Oceanographic Office glider operations

NASA Astrophysics Data System (ADS)

Mahoney, Kevin L.; Grembowicz, Ken; Bricker, Bruce; Crossland, Steve; Bryant, Danielle; Torres, Marc; Giddings, Tom

2009-05-01

The Naval Oceanographic Office (NAVOCEANO) Glider Operations Center (GOC) supported its first joint-mission exercise during Rim of the Pacific (RIMPAC) 08, a multi-national naval exercise conducted during July 2008 near the Hawaiian Islands. NAVOCEANO personnel deployed four Seagliders from USNS SUMNER for Anti-submarine Warfare (ASW) operations and four Slocum gliders for Mine Warfare (MIW) operations. Each Seaglider was equipped with a Sea-Bird Electronics (SBE) 41cp CTD and Wet Labs, Inc. bb2fl ECO-puck optical sensor. The instrumentation suite on the Slocum gliders varied, but each Slocum glider had an SBE 41cp CTD combined with one of the following optical sensors: a Wet Labs, Inc. AUVb scattering sensor, a Wet Labs, Inc. bb3slo ECO-puck backscattering sensor, or a Satlantic, Inc. OCR radiometer. Using Iridium communications, the GOC had command and control of all eight gliders, with Department of Defense (DoD) personnel and DoD contractors serving as glider pilots. Raw glider data were transmitted each time a glider surfaced, and the subsequent data flow included processing, quality-control procedures, and the generation of operational and tactical products. The raw glider data were also sent to the Naval Research Laboratory at Stennis Space Center (NRLSSC) for fusion with satellite data and modeled data (currents, tides, etc.) to create optical forecasting, optical volume, and electro-optical identification (EOID) performance surface products. The glider-based products were delivered to the ASW and MIW Reach Back Cells for incorporation into METOC products and for dissemination to the Fleet. Based on the metrics presented in this paper, the inaugural joint-mission operation was a success.

Estimation of coupling between time-delay systems from time series

NASA Astrophysics Data System (ADS)

Prokhorov, M. D.; Ponomarenko, V. I.

2005-07-01

We propose a method for estimation of coupling between the systems governed by scalar time-delay differential equations of the Mackey-Glass type from the observed time series data. The method allows one to detect the presence of certain types of linear coupling between two time-delay systems, to define the type, strength, and direction of coupling, and to recover the model equations of coupled time-delay systems from chaotic time series corrupted by noise. We verify our method using both numerical and experimental data.

LiDAR-IMU Time Delay Calibration Based on Iterative Closest Point and Iterated Sigma Point Kalman Filter

PubMed Central

Liu, Wanli

2017-01-01

The time delay calibration between Light Detection and Ranging (LiDAR) and Inertial Measurement Units (IMUs) is an essential prerequisite for its applications. However, the correspondences between LiDAR and IMU measurements are usually unknown, and thus cannot be computed directly for the time delay calibration. In order to solve the problem of LiDAR-IMU time delay calibration, this paper presents a fusion method based on iterative closest point (ICP) and iterated sigma point Kalman filter (ISPKF), which combines the advantages of ICP and ISPKF. The ICP algorithm can precisely determine the unknown transformation between LiDAR-IMU; and the ISPKF algorithm can optimally estimate the time delay calibration parameters. First of all, the coordinate transformation from the LiDAR frame to the IMU frame is realized. Second, the measurement model and time delay error model of LiDAR and IMU are established. Third, the methodology of the ICP and ISPKF procedure is presented for LiDAR-IMU time delay calibration. Experimental results are presented that validate the proposed method and demonstrate the time delay error can be accurately calibrated. PMID:28282897

The Miniaturized Autonomous Moored Profiler

DTIC Science & Technology

2004-07-20

power sleep mode. All collected data is stored on a flashcard memory module for later retrieval or remote transmission. With the optical telemetry...board flashcard for later retrieval or remote transmission. Although the descent operation ultimately depends upon the cable-pay, the CTD remains on

EVALUATION OF SUPERCRITICAL CARBON DIOXIDE TECHNOLOGY TO REDUCE SOLVENT IN SPRAY COATING APPLICATIONS

EPA Science Inventory

This evaluation, part of the Pollution Prevention Clean Technology Demonstration (CTD) Program, addresses the product quality, waste reduction, and economic issues of spray paint application using supercritical carbon dioxide (CO2). Anion Carbide has developed this technology and...

[Time perception in depressed and manic patients].

PubMed

Zhao, Qi-yuan; Ji, Yi-fu; Wang, Kai; Zhang, Lei; Liu, Ping; Jiang, Yu-bao

2010-02-02

To investigate the time perception in affective disorders by using neuropsychological tests and to try to elucidate its neurobiochemical mechanism. Using a time reproduction task, a comparative study was conducted for 28 depressive patients, 22 manic patients, and 26 age and education level matched healthy persons as healthy controls. Both depressive patients and manic patients are abnormal (P < 0.001), depressive patients over-reproduced the time interval than healthy controls (600 ms/delay 1 s: 1.6 +/- 0.6, P < 0.001; 600 ms/delay 5 s: 1.7 +/- 0.6, P < 0.001; 3 s/delay 1 s: 3.9 +/- 0.9, P < 0.001; 3 s/delay 5 s: 3.9 +/- 0.7, P < 0.001; 5 s/delay 1 s: 5.9 +/- 1.3, P < 0.001; 5 s/delay 5 s: 6.1 +/- 1.3, P < 0.001), yet manic patients under-reproduced the time interval (600 ms/delay 1 s: 0.7 +/- 0.2, P < 0.01; 600 ms/delay 5 s: 0.6 +/- 0.3, P < 0.001; 3 s/delay 1 s: 1.7 +/- 0.5, P < 0.001; 3 s/delay 5 s: 1.8 +/- 0.6, P < 0.001; 5 s/delay 1 s: 2.9 +/- 0.7, P < 0.001; 5 s/delay 5 s: 3.0 +/- 0.8, P < 0.001). The results of time reproduction task in patients were not related to age, education, duration of illness, number of admission (P > 0.05), but had some relation to severity of illness.And the results were positively correlated with the score of HAMD in depressive patients (six times: r = 0.44, 0.46, 0.73, 0.61, 0.55, 0.50, P < 0.05), but negatively with the score of BRMS in manic patients (six times: r = -0.57, -0.54, -0.71, -0.69, -0.80, -0.71, P < 0.05). Emotion will affect one's time perception. And the neurotransmitter in brain may participate in the processes of time perception.

Bounded Linear Stability Analysis - A Time Delay Margin Estimation Approach for Adaptive Control

NASA Technical Reports Server (NTRS)

Nguyen, Nhan T.; Ishihara, Abraham K.; Krishnakumar, Kalmanje Srinlvas; Bakhtiari-Nejad, Maryam

2009-01-01

This paper presents a method for estimating time delay margin for model-reference adaptive control of systems with almost linear structured uncertainty. The bounded linear stability analysis method seeks to represent the conventional model-reference adaptive law by a locally bounded linear approximation within a small time window using the comparison lemma. The locally bounded linear approximation of the combined adaptive system is cast in a form of an input-time-delay differential equation over a small time window. The time delay margin of this system represents a local stability measure and is computed analytically by a matrix measure method, which provides a simple analytical technique for estimating an upper bound of time delay margin. Based on simulation results for a scalar model-reference adaptive control system, both the bounded linear stability method and the matrix measure method are seen to provide a reasonably accurate and yet not too conservative time delay margin estimation.

Broadband true time delay for microwave signal processing, using slow light based on stimulated Brillouin scattering in optical fibers.

PubMed

Chin, Sanghoon; Thévenaz, Luc; Sancho, Juan; Sales, Salvador; Capmany, José; Berger, Perrine; Bourderionnet, Jérôme; Dolfi, Daniel

2010-10-11

We experimentally demonstrate a novel technique to process broadband microwave signals, using all-optically tunable true time delay in optical fibers. The configuration to achieve true time delay basically consists of two main stages: photonic RF phase shifter and slow light, based on stimulated Brillouin scattering in fibers. Dispersion properties of fibers are controlled, separately at optical carrier frequency and in the vicinity of microwave signal bandwidth. This way time delay induced within the signal bandwidth can be manipulated to correctly act as true time delay with a proper phase compensation introduced to the optical carrier. We completely analyzed the generated true time delay as a promising solution to feed phased array antenna for radar systems and to develop dynamically reconfigurable microwave photonic filters.

Finite-Time Stabilization and Adaptive Control of Memristor-Based Delayed Neural Networks.

PubMed

Wang, Leimin; Shen, Yi; Zhang, Guodong

Finite-time stability problem has been a hot topic in control and system engineering. This paper deals with the finite-time stabilization issue of memristor-based delayed neural networks (MDNNs) via two control approaches. First, in order to realize the stabilization of MDNNs in finite time, a delayed state feedback controller is proposed. Then, a novel adaptive strategy is applied to the delayed controller, and finite-time stabilization of MDNNs can also be achieved by using the adaptive control law. Some easily verified algebraic criteria are derived to ensure the stabilization of MDNNs in finite time, and the estimation of the settling time functional is given. Moreover, several finite-time stability results as our special cases for both memristor-based neural networks (MNNs) without delays and neural networks are given. Finally, three examples are provided for the illustration of the theoretical results.Finite-time stability problem has been a hot topic in control and system engineering. This paper deals with the finite-time stabilization issue of memristor-based delayed neural networks (MDNNs) via two control approaches. First, in order to realize the stabilization of MDNNs in finite time, a delayed state feedback controller is proposed. Then, a novel adaptive strategy is applied to the delayed controller, and finite-time stabilization of MDNNs can also be achieved by using the adaptive control law. Some easily verified algebraic criteria are derived to ensure the stabilization of MDNNs in finite time, and the estimation of the settling time functional is given. Moreover, several finite-time stability results as our special cases for both memristor-based neural networks (MNNs) without delays and neural networks are given. Finally, three examples are provided for the illustration of the theoretical results.

The effect of visual-motion time delays on pilot performance in a pursuit tracking task

NASA Technical Reports Server (NTRS)

Miller, G. K., Jr.; Riley, D. R.

1976-01-01

A study has been made to determine the effect of visual-motion time delays on pilot performance of a simulated pursuit tracking task. Three interrelated major effects have been identified: task difficulty, motion cues, and time delays. As task difficulty, as determined by airplane handling qualities or target frequency, increases, the amount of acceptable time delay decreases. However, when relatively complete motion cues are included in the simulation, the pilot can maintain his performance for considerably longer time delays. In addition, the number of degrees of freedom of motion employed is a significant factor.

Hemodynamic heterogeneity of connective tissue disease patients with borderline mean pulmonary artery pressure and its distinctive characters from those with normal pulmonary artery pressure: a retrospective study.

PubMed

Asari, Yusa; Yamasaki, Yoshioki; Tsuchida, Kosei; Suzuki, Kengo; Akashi, Yoshihiro J; Okazaki, Takahiro; Ozaki, Shoichi; Yamada, Hidehiro; Kawahata, Kimito

2018-05-18

To clarify whether patients with connective tissue disease (CTD)-associated borderline mean pulmonary artery pressure (mPAP) have distinctive hemodynamic characteristics from those with normal mPAP and whether pathogenesis is as heterogeneous as manifest pulmonary hypertension (PH). Seventy-five CTD patients who underwent right heart catheterization (RHC) from 2008 through 2016 were retrospectively analyzed. We compared between-group differences in clinical and hemodynamic findings: normal mPAP (n = 35), borderline mPAP (n = 15), and PH (n = 25). A therapeutic intervention trial based on RHC results was performed in nine patients. The values of tricuspid regurgitation pressure gradient (TRPG) in patients with borderline mPAP were comparable at rest but became higher after exercise compared to those with a normal mPAP (P = 0.01). Pulmonary artery wedge pressure in patients with borderline mPAP was higher than in those with normal mPAP (P < 0.0001) and comparable to those with PH. Each of the three patients was treated for pre-capillary and post-capillary disease and two for interstitial lung disease (ILD). During the mean follow-up period of 40 months, mPAP or TRPG normalized in all patients treated for pre-capillary and post-capillary disease. One patient with severe ILD developed to PH and died from it. CTD patients with borderline mPAP, the underlining pathogenesis of which is heterogeneous as PH, have distinctive hemodynamic characteristics from those with normal mPAP. Whether a specific treatment targeting the inflammatory process or local hemodynamics may alter the clinical course to PH is a topic for future research.

A portable digital microphotography unit for rapid documentation of periungual nailfold capillary changes in autoimmune connective tissue diseases.

PubMed

Sontheimer, Richard D

2004-03-01

While employing a DermLite dermoscopy unit to assess pigment pattern networks in melanocytic skin lesions, it was observed that this compact, portable dermoscopy unit can also be used to quickly detect nailfold capillary changes when entertaining a diagnosis of autoimmune connective tissue diseases (CTD) such as dermatomyositis (DM), scleroderma/systemic sclerosis (SSc), or systemic lupus erythematosus. Aware that the suppliers of the DermLite dermoscopy unit also market a portable digital microphotography unit based on the DermLite optical principles for efficiently documenting cutaneous pigment network patterns, we investigated whether this unit (DermLite Foto flash unit attached to a Nikon Coolpix digital camera) might be used to photographically document nailfold capillary changes in patients with autoimmune CTD. A DermLite Foto flash unit attached to a Nikon Coolpix digital camera was used in a controlled observational study to obtain digital photographs of nailfold capillaries in a small sequential sample of patients with autoimmune CTD attending a rheumatic skin disease subspecialty clinic in an academic department of dermatology. The digital microphotography system proved to be highly useful in documenting the nailfold vascular changes observed in a small sample of patients with DM. We observed that the nailfold capillary changes seen in patients with clinically amyopathic DM were qualitatively and quantitatively similar to those seen in patients with classical DM. Digital microphotography systems designed for examining pigmented skin lesions can be used easily to document nailfold capillary changes often observed in DM and SSc. Nailfold capillary changes documented in this manner appear to be indistinguishable in clinically amyopathic DM and classical DM.

Structure of the paramyxovirus parainfluenza virus 5 nucleoprotein–RNA complex

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

Alayyoubi, Maher; Leser, George P.; Kors, Christopher A.

Parainfluenza virus 5 (PIV5) is a member of the Paramyxoviridae family of membrane-enveloped viruses with a negative-sense RNA genome that is packaged and protected by long filamentous nucleocapsid-helix structures (RNPs). These RNPs, consisting of ~2,600 protomers of nucleocapsid (N) protein, form the template for viral transcription and replication. In this paper, we have determined the 3D X-ray crystal structure of the nucleoprotein (N)-RNA complex from PIV5 to 3.11-Å resolution. The structure reveals a 13-mer nucleocapsid ring whose diameter, cavity, and pitch/height dimensions agree with EM data from early studies on the Paramyxovirinae subfamily of native RNPs, indicating that it closelymore » represents one-turn in the building block of the RNP helices. The PIV5-N nucleocapsid ring encapsidates a nuclease resistant 78-nt RNA strand in its positively charged groove formed between the N-terminal (NTD) and C-terminal (CTD) domains of its successive N protomers. Six nucleotides precisely are associated with each N protomer, with alternating three-base-in three-base-out conformation. The binding of six nucleotides per protomer is consistent with the “rule of six” that governs the genome packaging of the Paramyxovirinae subfamily of viruses. PIV5-N protomer subdomains are very similar in structure to the previously solved Nipah-N structure, but with a difference in the angle between NTD/CTD at the RNA hinge region. Based on the Nipah-N structure we modeled a PIV5-N open conformation in which the CTD rotates away from the RNA strand into the inner spacious nucleocapsid-ring cavity. Finally, this rotation would expose the RNA for the viral polymerase activity without major disruption of the nucleocapsid structure.« less

Regulation of RIG-I Activation by K63-Linked Polyubiquitination.

PubMed

Okamoto, Masaaki; Kouwaki, Takahisa; Fukushima, Yoshimi; Oshiumi, Hiroyuki

2017-01-01

RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5'-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection.

Regulation of RIG-I Activation by K63-Linked Polyubiquitination

PubMed Central

Okamoto, Masaaki; Kouwaki, Takahisa; Fukushima, Yoshimi; Oshiumi, Hiroyuki

2018-01-01

RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5′-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection. PMID:29354136

A CTD–Pfizer collaboration: manual curation of 88 000 scientific articles text mined for drug–disease and drug–phenotype interactions

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; Roberts, Phoebe M.; King, Benjamin L.; Lay, Jean M.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J.; Enayetallah, Ahmed E.; Mattingly, Carolyn J.

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88 629 articles relating over 1 200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 2 54 173 toxicogenomic interactions (1 52 173 chemical–disease, 58 572 chemical–gene, 5 345 gene–disease and 38 083 phenotype interactions). All chemical–gene–disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer’s text-mining process to collate the articles, and CTD’s curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug–disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades’ worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/ PMID:24288140

Structure of the paramyxovirus parainfluenza virus 5 nucleoprotein–RNA complex

DOE PAGES

Alayyoubi, Maher; Leser, George P.; Kors, Christopher A.; ...

2015-03-23

Parainfluenza virus 5 (PIV5) is a member of the Paramyxoviridae family of membrane-enveloped viruses with a negative-sense RNA genome that is packaged and protected by long filamentous nucleocapsid-helix structures (RNPs). These RNPs, consisting of ~2,600 protomers of nucleocapsid (N) protein, form the template for viral transcription and replication. In this paper, we have determined the 3D X-ray crystal structure of the nucleoprotein (N)-RNA complex from PIV5 to 3.11-Å resolution. The structure reveals a 13-mer nucleocapsid ring whose diameter, cavity, and pitch/height dimensions agree with EM data from early studies on the Paramyxovirinae subfamily of native RNPs, indicating that it closelymore » represents one-turn in the building block of the RNP helices. The PIV5-N nucleocapsid ring encapsidates a nuclease resistant 78-nt RNA strand in its positively charged groove formed between the N-terminal (NTD) and C-terminal (CTD) domains of its successive N protomers. Six nucleotides precisely are associated with each N protomer, with alternating three-base-in three-base-out conformation. The binding of six nucleotides per protomer is consistent with the “rule of six” that governs the genome packaging of the Paramyxovirinae subfamily of viruses. PIV5-N protomer subdomains are very similar in structure to the previously solved Nipah-N structure, but with a difference in the angle between NTD/CTD at the RNA hinge region. Based on the Nipah-N structure we modeled a PIV5-N open conformation in which the CTD rotates away from the RNA strand into the inner spacious nucleocapsid-ring cavity. Finally, this rotation would expose the RNA for the viral polymerase activity without major disruption of the nucleocapsid structure.« less

Critical congenital heart disease--utility of routine screening for chromosomal and other extracardiac malformations.

PubMed

Baker, Kimberly; Sanchez-de-Toledo, Joan; Munoz, Ricardo; Orr, Richard; Kiray, Shareen; Shiderly, Dana; Clemens, Michele; Wearden, Peter; Morell, Victor O; Chrysostomou, Constantinos

2012-01-01

Objective.  Infants with critical congenital heart disease (CHD) can have genetic and other extracardiac malformations, which add to the short- and long-term risk of morbidity and perhaps mortality. We sought to examine our center's practice of screening for extracardiac anomalies and to determine the yield of these tests among specific cardiac diagnostic categories. Design.  Retrospective review of infants admitted to the cardiac intensive care unit with a new diagnosis of CHD. Subjects were categorized into six groups: septal defects (SD), conotruncal defects (CTD), single-ventricle physiology (SV), left-sided obstructive lesions (LSO), right-sided obstructive lesions (RSO), and "other" (anomalous pulmonary venous return, Ebstein's anomaly). Screening modalities included genetic testing (karyotype and fluorescent in situ hybridization for 22q11.2 deletion), renal ultrasound (RUS), and head ultrasound (HUS). Results.  One hundred forty-one patients were identified. The incidence of cardiac anomalies was: CTD (36%), SD (18%), SV (18%), LSO (14%), RSO (3%), and "other" (8%). Overall 14% had an abnormal karyotype, 5% had a deletion for 22q11.2, 28% had an abnormal RUS and 22% had abnormal HUS. Patients in SD and SV had the highest incidence of abnormal karyotype (36% and 17%); 22q11.2 deletion was present only in CTD and LSO groups (9% and 7%, respectively); abnormal RUS and HUS were seen relatively uniformly in all categories. Premature infants had significantly higher incidence of renal 43% vs. 24%, and intracranial abnormalities 46% vs. 16%. Conclusion.  Infants with critical CHD and particularly premature infants have high incidence of genetic and other extracardiac anomalies. Universal screening for these abnormalities with ultrasonographic and genetic testing maybe warranted because early detection could impact short and long-term outcomes. © 2011 Wiley Periodicals, Inc.

Solution structure of the c-terminal dimerization domain of SARS coronavirus nucleocapsid protein solved by the SAIL-NMR method.

PubMed

Takeda, Mitsuhiro; Chang, Chung-ke; Ikeya, Teppei; Güntert, Peter; Chang, Yuan-hsiang; Hsu, Yen-lan; Huang, Tai-huang; Kainosho, Masatsune

2008-07-18

The C-terminal domain (CTD) of the severe acute respiratory syndrome coronavirus (SARS-CoV) nucleocapsid protein (NP) contains a potential RNA-binding region in its N-terminal portion and also serves as a dimerization domain by forming a homodimer with a molecular mass of 28 kDa. So far, the structure determination of the SARS-CoV NP CTD in solution has been impeded by the poor quality of NMR spectra, especially for aromatic resonances. We have recently developed the stereo-array isotope labeling (SAIL) method to overcome the size problem of NMR structure determination by utilizing a protein exclusively composed of stereo- and regio-specifically isotope-labeled amino acids. Here, we employed the SAIL method to determine the high-quality solution structure of the SARS-CoV NP CTD by NMR. The SAIL protein yielded less crowded and better resolved spectra than uniform (13)C and (15)N labeling, and enabled the homodimeric solution structure of this protein to be determined. The NMR structure is almost identical with the previously solved crystal structure, except for a disordered putative RNA-binding domain at the N-terminus. Studies of the chemical shift perturbations caused by the binding of single-stranded DNA and mutational analyses have identified the disordered region at the N-termini as the prime site for nucleic acid binding. In addition, residues in the beta-sheet region also showed significant perturbations. Mapping of the locations of these residues onto the helical model observed in the crystal revealed that these two regions are parts of the interior lining of the positively charged helical groove, supporting the hypothesis that the helical oligomer may form in solution.

Interstitial Lung Disease in India. Results of a Prospective Registry.

PubMed

Singh, Sheetu; Collins, Bridget F; Sharma, Bharat B; Joshi, Jyotsna M; Talwar, Deepak; Katiyar, Sandeep; Singh, Nishtha; Ho, Lawrence; Samaria, Jai Kumar; Bhattacharya, Parthasarathi; Gupta, Rakesh; Chaudhari, Sudhir; Singh, Tejraj; Moond, Vijay; Pipavath, Sudhakar; Ahuja, Jitesh; Chetambath, Ravindran; Ghoshal, Aloke G; Jain, Nirmal K; Devi, H J Gayathri; Kant, Surya; Koul, Parvaiz; Dhar, Raja; Swarnakar, Rajesh; Sharma, Surendra K; Roy, Dhrubajyoti J; Sarmah, Kripesh R; Jankharia, Bhavin; Schmidt, Rodney; Katiyar, Santosh K; Jindal, Arpita; Mangal, Daya K; Singh, Virendra; Raghu, Ganesh

2017-03-15

Interstitial lung disease (ILD) is a heterogeneous group of acute and chronic inflammatory and fibrotic lung diseases. Existing ILD registries have had variable findings. Little is known about the clinical profile of ILDs in India. To characterize new-onset ILDs in India by creating a prospective ILD using multidisciplinary discussion (MDD) to validate diagnoses. Adult patients of Indian origin living in India with new-onset ILD (27 centers, 19 Indian cities, March 2012-June 2015) without malignancy or infection were included. All had connective tissue disease (CTD) serologies, spirometry, and high-resolution computed tomography chest. ILD pattern was defined by high-resolution computed tomography images. Three groups independently made diagnoses after review of clinical data including that from prompted case report forms: local site investigators, ILD experts at the National Data Coordinating Center (NDCC; Jaipur, India) with MDD, and experienced ILD experts at the Center for ILD (CILD; Seattle, WA) with MDD. Cohen's κ was used to assess reliability of interobserver agreement. A total of 1,084 patients were recruited. Final diagnosis: hypersensitivity pneumonitis in 47.3% (n = 513; exposure, 48.1% air coolers), CTD-ILD in 13.9%, and idiopathic pulmonary fibrosis in 13.7%. Cohen's κ: 0.351 site investigator/CILD, 0.519 site investigator/NDCC, and 0.618 NDCC/CILD. Hypersensitivity pneumonitis was the most common new-onset ILD in India, followed by CTD-ILD and idiopathic pulmonary fibrosis; diagnoses varied between site investigators and CILD experts, emphasizing the value of MDD in ILD diagnosis. Prompted case report forms including environmental exposures in prospective registries will likely provide further insight into the etiology and management of ILD worldwide.

Structure of the paramyxovirus parainfluenza virus 5 nucleoprotein-RNA complex.

PubMed

Alayyoubi, Maher; Leser, George P; Kors, Christopher A; Lamb, Robert A

2015-04-07

Parainfluenza virus 5 (PIV5) is a member of the Paramyxoviridae family of membrane-enveloped viruses with a negative-sense RNA genome that is packaged and protected by long filamentous nucleocapsid-helix structures (RNPs). These RNPs, consisting of ∼2,600 protomers of nucleocapsid (N) protein, form the template for viral transcription and replication. We have determined the 3D X-ray crystal structure of the nucleoprotein (N)-RNA complex from PIV5 to 3.11-Å resolution. The structure reveals a 13-mer nucleocapsid ring whose diameter, cavity, and pitch/height dimensions agree with EM data from early studies on the Paramyxovirinae subfamily of native RNPs, indicating that it closely represents one-turn in the building block of the RNP helices. The PIV5-N nucleocapsid ring encapsidates a nuclease resistant 78-nt RNA strand in its positively charged groove formed between the N-terminal (NTD) and C-terminal (CTD) domains of its successive N protomers. Six nucleotides precisely are associated with each N protomer, with alternating three-base-in three-base-out conformation. The binding of six nucleotides per protomer is consistent with the "rule of six" that governs the genome packaging of the Paramyxovirinae subfamily of viruses. PIV5-N protomer subdomains are very similar in structure to the previously solved Nipah-N structure, but with a difference in the angle between NTD/CTD at the RNA hinge region. Based on the Nipah-N structure we modeled a PIV5-N open conformation in which the CTD rotates away from the RNA strand into the inner spacious nucleocapsid-ring cavity. This rotation would expose the RNA for the viral polymerase activity without major disruption of the nucleocapsid structure.

Measurement of Antinuclear Antibodies: Assessment of Different Test Systems

PubMed Central

Kern, P.; Kron, M.; Hiesche, K.

2000-01-01

The performance of rat liver and HEp-2 in the detection of antinuclear antibodies (ANA) was studied by two independent sites and compared against an ANA enzyme immunoassay (EIA) screen and EIA systems for the measurement of antibodies to double-stranded DNA (dsDNA) and ENA. Sixty-two sera from patients with connective tissue disease (CTD) and 398 from controls suffering from other disorders were included. The level of agreement was, for HEp-2 and rat liver (within one site), 82.0% (ANA positive/ANA negative) and 51.0% (ANA pattern); and for HEp2- and HEp-2 (between sites), 71.8 and 86.5%. On sera with the ANA homogeneous pattern, the measurement of anti-ENA EIA added little to the detection rate with anti-dsDNA EIA alone. On ANA speckled sera, the EIA reactivity depended on the reaction of the mitotic cells: while sera with positive mitoses reacted similarly to ANA homogeneous sera, in those with negative mitoses the measurement of anti-ENA added about 10% to the detection rate achieved with anti-dsDNA alone. The measurement of anti-Scl-70 and anti-Jo-1 did not markedly improve the positive rate with classical ENA (anti-SSA, -SSB, -Sm, and -RNP) alone, raising doubts about the cost efficiency of including these measurements in unselected sera. The ANA EIA identified patients with CTD at a rate similar to that for rat liver and HEp-2. However, up to 98% of the sera found to be negative by ANA EIA but positive by use of rat liver and HEp-2 were from controls. Thus, the ANA EIA may possible be used as an alternative screen, particularly in laboratories with a high frequency of sera from patients not suffering from CTD. PMID:10618281

Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability*

PubMed Central

Aman, Teresa K.; Maki, Bruce A.; Ruffino, Thomas J.; Kasperek, Eileen M.; Popescu, Gabriela K.

2014-01-01

Protein kinase A (PKA) enhances synaptic plasticity in the central nervous system by increasing NMDA receptor current amplitude and Ca2+ flux in an isoform-dependent yet poorly understood manner. PKA phosphorylates multiple residues on GluN1, GluN2A, and GluN2B subunits in vivo, but the functional significance of this multiplicity is unknown. We examined gating and permeation properties of recombinant NMDA receptor isoforms and of receptors with altered C-terminal domain (CTDs) prior to and after pharmacological inhibition of PKA. We found that PKA inhibition decreased GluN1/GluN2B but not GluN1/GluN2A gating; this effect was due to slower rates for receptor activation and resensitization and was mediated exclusively by the GluN2B CTD. In contrast, PKA inhibition reduced NMDA receptor-relative Ca2+ permeability (PCa/PNa) regardless of the GluN2 isoform and required the GluN1 CTD; this effect was due primarily to decreased unitary Ca2+ conductance, because neither Na+ conductance nor Ca2+-dependent block was altered substantially. Finally, we show that both the gating and permeation effects can be reproduced by changing the phosphorylation state of a single residue: GluN2B Ser-1166 and GluN1 Ser-897, respectively. We conclude that PKA effects on NMDA receptor gating and Ca2+ permeability rely on distinct phosphorylation sites located on the CTD of GluN2B and GluN1 subunits. This separate control of NMDA receptor properties by PKA may account for the specific effects of PKA on plasticity during synaptic development and may lead to drugs targeted to alter NMDA receptor gating or Ca2+ permeability. PMID:24847051

Longitudinal Changes in Segmental Aortic Stiffness Determined by Cardiac Magnetic Resonance in Children and Young Adults With Connective Tissue Disorders (the Marfan, Loeys-Dietz, and Ehlers-Danlos Syndromes, and Nonspecific Connective Tissue Disorders).

PubMed

Merlocco, Anthony; Lacro, Ronald V; Gauvreau, Kimberlee; Rabideau, Nicole; Singh, Michael N; Prakash, Ashwin

2017-10-01

Aortic stiffness measured by cardiac magnetic resonance (CMR) in connective tissue disorder (CTD) patients has been previously shown to be abnormal and to be associated with adverse aortic outcomes. The rate of increase in aortic stiffness with normal aging has been previously described. However, longitudinal changes in aortic stiffness have not been characterized in CTD patients. We examined longitudinal changes in CMR-derived aortic stiffness in children and young adults with CTDs. A retrospective analysis of 50 children and young adults (median age, 20 years; range, 0.2 to 49; 40% < 18 years old) with a CTD, and with at least 2 CMR examinations (total 152 examinations) over a median duration of 3.9 (1 to 13.2) years was performed. Aortic stiffness measures (strain, distensibility, and β stiffness index) were calculated on each examination at the aortic root (AoR), ascending aorta, and descending aorta. Longitudinal changes in parameters were analyzed using linear mixed-effects models. Aortic strain and distensibility decreased with age, whereas the β stiffness index increased at all aortic segments. The average rates of decline in distensibility (x10 -3  mm Hg -1 per 10-year increase in age) were 0.7, 1.3, and 1 at the AoR, ascending aorta, and descending aorta, respectively. The rates of decline in distensibility were not associated with the rates of AoR dilation or surgical AoR replacement. In conclusion, on serial CMR measurements in children and young adults with CTDs, aortic stiffness progressively increased with age, with rates of change only slightly higher than those previously reported in healthy adults. Copyright © 2017 Elsevier Inc. All rights reserved.

The NMR solution structure of Mycobacterium tuberculosis F-ATP synthase subunit ε provides new insight into energy coupling inside the rotary engine.

PubMed

Joon, Shin; Ragunathan, Priya; Sundararaman, Lavanya; Nartey, Wilson; Kundu, Subhashri; Manimekalai, Malathy S S; Bogdanović, Nebojša; Dick, Thomas; Grüber, Gerhard

2018-03-01

Mycobacterium tuberculosis (Mt) F 1 F 0 ATP synthase (α 3 :β 3 :γ:δ:ε:a:b:b':c 9 ) is essential for the viability of growing and nongrowing persister cells of the pathogen. Here, we present the first NMR solution structure of Mtε, revealing an N-terminal β-barrel domain (NTD) and a C-terminal domain (CTD) composed of a helix-loop-helix with helix 1 and -2 being shorter compared to their counterparts in other bacteria. The C-terminal amino acids are oriented toward the NTD, forming a domain-domain interface between the NTD and CTD. The Mtε structure provides a novel mechanistic model of coupling c-ring- and ε rotation via a patch of hydrophobic residues in the NTD and residues of the CTD to the bottom of the catalytic α 3 β 3 -headpiece. To test our model, genome site-directed mutagenesis was employed to introduce amino acid changes in these two parts of the epsilon subunit. Inverted vesicle assays show that these mutations caused an increase in ATP hydrolysis activity and a reduction in ATP synthesis. The structural and enzymatic data are discussed in light of the transition mechanism of a compact and extended state of Mtε, which provides the inhibitory effects of this coupling subunit inside the rotary engine. Finally, the employment of these data with molecular docking shed light into the second binding site of the drug Bedaquiline. Structural data are available in the PDB under the accession number 5YIO. © 2018 Federation of European Biochemical Societies.

Core Mediator structure at 3.4 Å extends model of transcription initiation complex.

PubMed

Nozawa, Kayo; Schneider, Thomas R; Cramer, Patrick

2017-05-11

Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. The architecture of Mediator and its position on the PIC are known, but atomic details are limited to Mediator subcomplexes. Here we report the crystal structure of the 15-subunit cMed from Schizosaccharomyces pombe at 3.4 Å resolution. The structure shows an unaltered head module, and reveals the intricate middle module, which we show is globally required for transcription. Sites of known Mediator mutations cluster at the interface between the head and middle modules, and in terminal regions of the head subunits Med6 (ref. 16) and Med17 (ref. 17) that tether the middle module. The structure led to a model for Saccharomyces cerevisiae cMed that could be combined with the 3.6 Å cryo-electron microscopy structure of the core PIC (cPIC). The resulting atomic model of the cPIC-cMed complex informs on interactions of the submodules forming the middle module, called beam, knob, plank, connector, and hook. The hook is flexibly linked to Mediator by a conserved hinge and contacts the transcription initiation factor IIH (TFIIH) kinase that phosphorylates the carboxy (C)-terminal domain (CTD) of Pol II and was recently positioned on the PIC. The hook also contains residues that crosslink to the CTD and reside in a previously described cradle. These results provide a framework for understanding Mediator function, including its role in stimulating CTD phosphorylation by TFIIH.

Essential role of the flexible linker on the conformational equilibrium of bacterial peroxiredoxin reductase for effective regeneration of peroxiredoxin

PubMed Central

Kamariah, Neelagandan; Eisenhaber, Birgit; Eisenhaber, Frank; Grüber, Gerhard

2017-01-01

Reactive oxygen species (ROS) can damage DNA, proteins, and lipids, so cells have antioxidant systems that regulate ROS. In many bacteria, a dedicated peroxiredoxin reductase, alkyl hydroperoxide reductase subunit F (AhpF), catalyzes the rapid reduction of the redox-active disulfide center of the antioxidant protein peroxiredoxin (AhpC) to detoxify ROS such as hydrogen peroxide, organic hydroperoxide, and peroxynitrite. AhpF is a flexible multidomain protein that enables a series of electron transfers among the redox centers by accepting reducing equivalents from NADH. A flexible linker connecting the N-terminal domain (NTD) and C-terminal domain (CTD) of AhpF suggests that the enzyme adopts a large-scale domain motion that alternates between the closed and open states to shuttle electrons from the CTD via the NTD to AhpC. Here, we conducted comprehensive mutational, biochemical, and biophysical analyses to gain insights into the role of the flexible linker and the residues critical for the domain motions of Escherichia coli AhpF (EcAhpF) during electron transfer. Small-angle X-ray scattering studies of linker mutants revealed that a group of charged residues, 200EKR202, is crucial for the swiveling motion of the NTD. Moreover, NADH binding significantly affected EcAhpF flexibility and the movement of the NTD relative to the CTD. The mutants also exhibited a decrease in H2O2 reduction by the AhpF-AhpC ensemble. We propose that a concerted movement involving the NTD, C-terminal NADH, and FAD domains, and the flexible linker between them is essential for optimal intra-domain cross-talk and for efficient electron transfer to the redox partner AhpC required for peroxidation. PMID:28270505

Identification and Molecular Characterization of the Chloroplast Targeting Domain of Turnip yellow mosaic virus Replication Proteins

PubMed Central

Moriceau, Lucille; Jomat, Lucile; Bressanelli, Stéphane; Alcaide-Loridan, Catherine; Jupin, Isabelle

2017-01-01

Turnip yellow mosaic virus (TYMV) is a positive-strand RNA virus infecting plants. The TYMV 140K replication protein is a key organizer of viral replication complex (VRC) assembly, being responsible for recruitment of the viral polymerase and for targeting the VRCs to the chloroplast envelope where viral replication takes place. However, the structural requirements determining the subcellular localization and membrane association of this essential viral protein have not yet been defined. In this study, we investigated determinants for the in vivo chloroplast targeting of the TYMV 140K replication protein. Subcellular localization studies of deletion mutants identified a 41-residue internal sequence as the chloroplast targeting domain (CTD) of TYMV 140K; this sequence is sufficient to target GFP to the chloroplast envelope. The CTD appears to be located in the C-terminal extension of the methyltransferase domain—a region shared by 140K and its mature cleavage product 98K, which behaves as an integral membrane protein during infection. We predicted the CTD to fold into two amphipathic α-helices—a folding that was confirmed in vitro by circular dichroism spectroscopy analyses of a synthetic peptide. The importance for subcellular localization of the integrity of these amphipathic helices, and the function of 140K/98K, was demonstrated by performing amino acid substitutions that affected chloroplast targeting, membrane association and viral replication. These results establish a short internal α-helical peptide as an unusual signal for targeting proteins to the chloroplast envelope membrane, and provide new insights into membrane targeting of viral replication proteins—a universal feature of positive-strand RNA viruses. PMID:29312393

Robust stability bounds for multi-delay networked control systems

NASA Astrophysics Data System (ADS)

Seitz, Timothy; Yedavalli, Rama K.; Behbahani, Alireza

2018-04-01

In this paper, the robust stability of a perturbed linear continuous-time system is examined when controlled using a sampled-data networked control system (NCS) framework. Three new robust stability bounds on the time-invariant perturbations to the original continuous-time plant matrix are presented guaranteeing stability for the corresponding discrete closed-loop augmented delay-free system (ADFS) with multiple time-varying sensor and actuator delays. The bounds are differentiated from previous work by accounting for the sampled-data nature of the NCS and for separate communication delays for each sensor and actuator, not a single delay. Therefore, this paper expands the knowledge base in multiple inputs multiple outputs (MIMO) sampled-data time delay systems. Bounds are presented for unstructured, semi-structured, and structured perturbations.

Discrete-time BAM neural networks with variable delays

NASA Astrophysics Data System (ADS)

Liu, Xin-Ge; Tang, Mei-Lan; Martin, Ralph; Liu, Xin-Bi

2007-07-01

This Letter deals with the global exponential stability of discrete-time bidirectional associative memory (BAM) neural networks with variable delays. Using a Lyapunov functional, and linear matrix inequality techniques (LMI), we derive a new delay-dependent exponential stability criterion for BAM neural networks with variable delays. As this criterion has no extra constraints on the variable delay functions, it can be applied to quite general BAM neural networks with a broad range of time delay functions. It is also easy to use in practice. An example is provided to illustrate the theoretical development.

Local Bifurcations and Optimal Theory in a Delayed Predator-Prey Model with Threshold Prey Harvesting

NASA Astrophysics Data System (ADS)

Tankam, Israel; Tchinda Mouofo, Plaire; Mendy, Abdoulaye; Lam, Mountaga; Tewa, Jean Jules; Bowong, Samuel

2015-06-01

We investigate the effects of time delay and piecewise-linear threshold policy harvesting for a delayed predator-prey model. It is the first time that Holling response function of type III and the present threshold policy harvesting are associated with time delay. The trajectories of our delayed system are bounded; the stability of each equilibrium is analyzed with and without delay; there are local bifurcations as saddle-node bifurcation and Hopf bifurcation; optimal harvesting is also investigated. Numerical simulations are provided in order to illustrate each result.

A Strain-Sonde Technique for the Measurement of Mechanical Time-Delay Fuze Function Times and Performance

DTIC Science & Technology

1983-09-01

AD IV) MEMORANDUM REPORT ARBRL-MR-03309 N(Supersedes IMR No. 760) A STRAIN -SONDE TECHNIQUE FOR THE MEASUREMENT OF MECHANICAL TIME- DELAY FUZE...and BkuWel) S. TYPE OF REPORT & PERIOD COVERED A STRAIN -SONDE TECHNIQUE FOR THE MEASUREMENT OF Final MECHANICAL TIME-DELAY FUZE FUNCTION TIMES AND S...nmber) M577 Mechanical Time-Delay Fuze F"/FM Telemeter Interlock Pin Release Semiconductor Strain Gage Rotor Signal Condition Amplifier Firing Pin In

Robust optimization for nonlinear time-delay dynamical system of dha regulon with cost sensitivity constraint in batch culture

NASA Astrophysics Data System (ADS)

Yuan, Jinlong; Zhang, Xu; Liu, Chongyang; Chang, Liang; Xie, Jun; Feng, Enmin; Yin, Hongchao; Xiu, Zhilong

2016-09-01

Time-delay dynamical systems, which depend on both the current state of the system and the state at delayed times, have been an active area of research in many real-world applications. In this paper, we consider a nonlinear time-delay dynamical system of dha-regulonwith unknown time-delays in batch culture of glycerol bioconversion to 1,3-propanediol induced by Klebsiella pneumonia. Some important properties and strong positive invariance are discussed. Because of the difficulty in accurately measuring the concentrations of intracellular substances and the absence of equilibrium points for the time-delay system, a quantitative biological robustness for the concentrations of intracellular substances is defined by penalizing a weighted sum of the expectation and variance of the relative deviation between system outputs before and after the time-delays are perturbed. Our goal is to determine optimal values of the time-delays. To this end, we formulate an optimization problem in which the time delays are decision variables and the cost function is to minimize the biological robustness. This optimization problem is subject to the time-delay system, parameter constraints, continuous state inequality constraints for ensuring that the concentrations of extracellular and intracellular substances lie within specified limits, a quality constraint to reflect operational requirements and a cost sensitivity constraint for ensuring that an acceptable level of the system performance is achieved. It is approximated as a sequence of nonlinear programming sub-problems through the application of constraint transcription and local smoothing approximation techniques. Due to the highly complex nature of this optimization problem, the computational cost is high. Thus, a parallel algorithm is proposed to solve these nonlinear programming sub-problems based on the filled function method. Finally, it is observed that the obtained optimal estimates for the time-delays are highly satisfactory via numerical simulations.

Time delay and noise explaining the behaviour of the cell growth in fermentation process

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

Ayuobi, Tawfiqullah; Rosli, Norhayati; Bahar, Arifah

2015-02-03

This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process.

Time delay and noise explaining the behaviour of the cell growth in fermentation process

NASA Astrophysics Data System (ADS)

Ayuobi, Tawfiqullah; Rosli, Norhayati; Bahar, Arifah; Salleh, Madihah Md

2015-02-01

This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process.

The Effects of Financial Education on Impulsive Decision Making

PubMed Central

DeHart, William B.; Friedel, Jonathan E.; Lown, Jean M.; Odum, Amy L.

2016-01-01

Delay discounting, as a behavioral measure of impulsive choice, is strongly related to substance abuse and other risky behaviors. Therefore, effective techniques that alter delay discounting are of great interest. We explored the ability of a semester long financial education course to change delay discounting. Participants were recruited from a financial education course (n = 237) and an abnormal psychology course (n = 80). Both groups completed a delay-discounting task for $100 during the first two weeks (Time 1) of the semester as well as during the last two weeks (Time 2) of the semester. Participants also completed a personality inventory and financial risk tolerance scale both times and a delay-discounting task for $1,000 during Time 2. Delay discounting decreased in the financial education group at the end of the semester whereas there was no change in delay discounting in the abnormal psychology group. Financial education may be an effective method for reducing delay discounting. PMID:27442237

The Effects of Financial Education on Impulsive Decision Making.

PubMed

DeHart, William B; Friedel, Jonathan E; Lown, Jean M; Odum, Amy L

2016-01-01

Delay discounting, as a behavioral measure of impulsive choice, is strongly related to substance abuse and other risky behaviors. Therefore, effective techniques that alter delay discounting are of great interest. We explored the ability of a semester long financial education course to change delay discounting. Participants were recruited from a financial education course (n = 237) and an abnormal psychology course (n = 80). Both groups completed a delay-discounting task for $100 during the first two weeks (Time 1) of the semester as well as during the last two weeks (Time 2) of the semester. Participants also completed a personality inventory and financial risk tolerance scale both times and a delay-discounting task for $1,000 during Time 2. Delay discounting decreased in the financial education group at the end of the semester whereas there was no change in delay discounting in the abnormal psychology group. Financial education may be an effective method for reducing delay discounting.

Delay-induced stochastic bifurcations in a bistable system under white noise

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

Sun, Zhongkui, E-mail: sunzk@nwpu.edu.cn; Fu, Jin; Xu, Wei

2015-08-15

In this paper, the effects of noise and time delay on stochastic bifurcations are investigated theoretically and numerically in a time-delayed Duffing-Van der Pol oscillator subjected to white noise. Due to the time delay, the random response is not Markovian. Thereby, approximate methods have been adopted to obtain the Fokker-Planck-Kolmogorov equation and the stationary probability density function for amplitude of the response. Based on the knowledge that stochastic bifurcation is characterized by the qualitative properties of the steady-state probability distribution, it is found that time delay and feedback intensity as well as noise intensity will induce the appearance of stochasticmore » P-bifurcation. Besides, results demonstrated that the effects of the strength of the delayed displacement feedback on stochastic bifurcation are accompanied by the sensitive dependence on time delay. Furthermore, the results from numerical simulations best confirm the effectiveness of the theoretical analyses.« less

The rates and time-delay distribution of multiply imaged supernovae behind lensing clusters

NASA Astrophysics Data System (ADS)

Li, Xue; Hjorth, Jens; Richard, Johan

2012-11-01

Time delays of gravitationally lensed sources can be used to constrain the mass model of a deflector and determine cosmological parameters. We here present an analysis of the time-delay distribution of multiply imaged sources behind 17 strong lensing galaxy clusters with well-calibrated mass models. We find that for time delays less than 1000 days, at z = 3.0, their logarithmic probability distribution functions are well represented by P(log Δt) = 5.3 × 10-4Δttilde beta/M2502tilde beta, with tilde beta = 0.77, where M250 is the projected cluster mass inside 250 kpc (in 1014M⊙), and tilde beta is the power-law slope of the distribution. The resultant probability distribution function enables us to estimate the time-delay distribution in a lensing cluster of known mass. For a cluster with M250 = 2 × 1014M⊙, the fraction of time delays less than 1000 days is approximately 3%. Taking Abell 1689 as an example, its dark halo and brightest galaxies, with central velocity dispersions σ>=500kms-1, mainly produce large time delays, while galaxy-scale mass clumps are responsible for generating smaller time delays. We estimate the probability of observing multiple images of a supernova in the known images of Abell 1689. A two-component model of estimating the supernova rate is applied in this work. For a magnitude threshold of mAB = 26.5, the yearly rate of Type Ia (core-collapse) supernovae with time delays less than 1000 days is 0.004±0.002 (0.029±0.001). If the magnitude threshold is lowered to mAB ~ 27.0, the rate of core-collapse supernovae suitable for time delay observation is 0.044±0.015 per year.

Elapsed Time Between the First Symptoms of Breast Cancer and Medical Help-Seeking Behavior and the Affecting Factors.

PubMed

Gözüm, Sebahat; Tuzcu, Ayla

Many studies have determined that the time between women's realization of first symptoms and seeking help from a healthcare professional is more than 1 month. The situation is defined as delay in medical help-seeking behavior (MHSB). The purpose of this study was to determine the time elapsed between the first symptoms of breast cancer and MHSB, as well as the factors contributing to the delay. In this descriptive study, the data were collected from 132 patients who received a diagnosis of breast cancer and are receiving treatment in the Oncology Clinic of Akdeniz University Hospital. The questionnaire used in the study was structured in 3 parts: sociodemographic characteristics, breast cancer history/screening behaviors, and psychological factors affecting MHSB. The elapsed time between patients' first symptoms and MHSB was classified into "normal" when it was less than 1 month, "delay" when it was between 1 and 3 months, "long-term delay" when it was more than 3 months, and "very serious delay" when it was more than 6 months. A total of 59.8% were classified as normal, 16.7% as delayed, 5.3% as a long-term delay, and 18.2% as a very serious delay after first symptoms. The delay in MHSB time was affected 18.55 times by "not caring/minding," 10.73 times by "fear," 7.13 times by "having more important problems," and 4.23 times by "realization of first symptoms" by themselves. Psychological factors were the most important determinants in delay. The MHSB time was less if those first realizing the symptoms were healthcare professionals. Healthcare professionals should direct women to screenings and train them to interpret symptoms correctly.

Effects of computing time delay on real-time control systems

NASA Technical Reports Server (NTRS)

Shin, Kang G.; Cui, Xianzhong

1988-01-01

The reliability of a real-time digital control system depends not only on the reliability of the hardware and software used, but also on the speed in executing control algorithms. The latter is due to the negative effects of computing time delay on control system performance. For a given sampling interval, the effects of computing time delay are classified into the delay problem and the loss problem. Analysis of these two problems is presented as a means of evaluating real-time control systems. As an example, both the self-tuning predicted (STP) control and Proportional-Integral-Derivative (PID) control are applied to the problem of tracking robot trajectories, and their respective effects of computing time delay on control performance are comparatively evaluated. For this example, the STP (PID) controller is shown to outperform the PID (STP) controller in coping with the delay (loss) problem.

The influences of delay time on the stability of a market model with stochastic volatility

NASA Astrophysics Data System (ADS)

Li, Jiang-Cheng; Mei, Dong-Cheng

2013-02-01

The effects of the delay time on the stability of a market model are investigated, by using a modified Heston model with a cubic nonlinearity and cross-correlated noise sources. These results indicate that: (i) There is an optimal delay time τo which maximally enhances the stability of the stock price under strong demand elasticity of stock price, and maximally reduces the stability of the stock price under weak demand elasticity of stock price; (ii) The cross correlation coefficient of noises and the delay time play an opposite role on the stability for the case of the delay time <τo and the same role for the case of the delay time >τo. Moreover, the probability density function of the escape time of stock price returns, the probability density function of the returns and the correlation function of the returns are compared with other literatures.

Fred Hutchinson Cancer Research Center (FHCRC1): Genetic Disruption of CTCF Destabilizes DNA Methylation | Office of Cancer Genomics

Cancer.gov

The CTD2 Center at Fred Hutchinson Cancer Research Center identified the DNA binding protein CTCF as a tumor suppressor and regulator of DNA methylation. Read the abstract Experimental Approaches Read the detailed Experimental Approaches

Fred Hutchinson Cancer Research Center (FHCRC-1): Genetic Disruption of CTCF Destabilizes DNA Methylation | Office of Cancer Genomics

Cancer.gov

The CTD2 Center at Fred Hutchinson Cancer Research Center identified the DNA binding protein CTCF as a tumor suppressor and regulator of DNA methylation. Read the abstract Experimental Approaches Read the detailed Experimental Approaches

Protein-Protein Interactions (PPI) reagents: | Office of Cancer Genomics

Cancer.gov

The CTD2 Center at Emory University has a library of genes used to study protein-protein interactions in mammalian cells. These genes are cloned in different mammalian expression vectors. A list of available cancer-associated genes can be accessed below.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRi) plasmids | Office of Cancer Genomics

Cancer.gov

CTD2 researchers at the University of California in San Francisco developed a modified Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) CRISPR/dCas9 system. Catalytically inactive dCas9 enables modular and programmable RNA-guided genome regulation in eukaryotes.

University of California San Francisco (UCSF-2): Integrative Genomic Approaches in Neuroblastoma (NBL) | Office of Cancer Genomics

Cancer.gov

The CTD2 Center at University of California San Francisco (UCSF-2) used an integrative genomics approach to reveal unidentified mRNA splicing patterns in neuroblastoma. Read the abstract Experimental Approaches Read the detailed Experimental Approaches

The yeast prefoldin-like URI-orthologue Bud27 associates with the RSC nucleosome remodeler and modulates transcription

PubMed Central

Mirón-García, María Carmen; Garrido-Godino, Ana Isabel; Martínez-Fernández, Verónica; Fernández-Pevida, Antonio; Cuevas-Bermúdez, Abel; Martín-Expósito, Manuel; Chávez, Sebastián; de la Cruz, Jesús; Navarro, Francisco

2014-01-01

Bud27, the yeast orthologue of human URI/RMP, is a member of the prefoldin-like family of ATP-independent molecular chaperones. It has recently been shown to mediate the assembly of the three RNA polymerases in an Rpb5-dependent manner. In this work, we present evidence of Bud27 modulating RNA pol II transcription elongation. We show that Bud27 associates with RNA pol II phosphorylated forms (CTD-Ser5P and CTD-Ser2P), and that its absence affects RNA pol II occupancy of transcribed genes. We also reveal that Bud27 associates in vivo with the Sth1 component of the chromatin remodeling complex RSC and mediates its association with RNA pol II. Our data suggest that Bud27, in addition of contributing to Rpb5 folding within the RNA polymerases, also participates in the correct assembly of other chromatin-associated protein complexes, such as RSC, thereby modulating their activity. PMID:25081216

Structural insights into the mycobacteria transcription initiation complex from analysis of X-ray crystal structures

DOE PAGES

Hubin, Elizabeth A.; Lilic, Mirjana; Darst, Seth A.; ...

2017-07-13

The mycobacteria RNA polymerase (RNAP) is a target for antimicrobials against tuberculosis, motivating structure/function studies. Here we report a 3.2 Å-resolution crystal structure of a Mycobacterium smegmatis (Msm) open promoter complex (RPo), along with structural analysis of the Msm RPo and a previously reported 2.76 Å-resolution crystal structure of an Msm transcription initiation complex with a promoter DNA fragment. We observe the interaction of the Msm RNAP α-subunit C-terminal domain (αCTD) with DNA, and we provide evidence that the a CTD may play a role in Mtb transcription regulation. Here, our results reveal the structure of an Actinobacteria-unique insert ofmore » the RNAP β' subunit. Finally, our analysis reveals the disposition of the N-terminal segment of Msm σ A, which may comprise an intrinsically disordered protein domain unique to mycobacteria. The clade-specific features of the mycobacteria RNAP provide clues to the profound instability of mycobacteria RPo compared with E. coli.« less

Internationalization of regulatory requirements.

PubMed

Juillet, Y

2003-02-01

The aim of harmonisation of medicines regulatory requirements is to allow the patient quicker access to new drugs and to avoid animal and human duplications. Harmonisation in the European Union (EU) is now completed, and has led to the submission of one dossier in one language study leading to European marketing authorizations, thanks in particular to efficacy guidelines published at the European level. With the benefit of the European experience since 1989, more than 40 guidelines have been harmonised amongst the EU, Japan and the USA through the International Conference on Harmonisation (ICH). ICH is a unique process gathering regulators and industry experts from the three regions. Its activity is built on expertise and trust. The Common Technical Document (CTD), an agreed common format for application in the three regions, is a logical follow-up to the ICH first phase harmonising the content of the dossier. The CTD final implementation in July 2003 will have considerable influence on the review process and on the exchange of information in the three regions.

Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis.

PubMed

Ma, Lu; Rebane, Aleksander A; Yang, Guangcan; Xi, Zhiqun; Kang, Yuhao; Gao, Ying; Zhang, Yongli

2015-12-23

Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE C-terminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the half-zippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1.

Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8.

PubMed

Kato, Hidekazu; Miyake, Fuyu; Shimbo, Hiroko; Ohya, Makoto; Sugawara, Hidenori; Aida, Noriko; Anzai, Rie; Takagi, Mariko; Okuda, Mitsuko; Takano, Kyoko; Wada, Takahito; Iai, Mizue; Yamashita, Sumimasa; Osaka, Hitoshi

2014-08-01

Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Structure of the Siz/PIAS SUMO E3 ligase Siz1 and determinants required for SUMO modification of PCNA

PubMed Central

Yunus, Ali A.; Lima, Christopher D.

2009-01-01

Summary Siz1 is a founding member of the Siz/PIAS RING family of SUMO E3 ligases. The x-ray structure of an active Siz1 ligase revealed an elongated tripartite architecture comprised of an N-terminal PINIT domain, a central zinc-containing RING-like SP-RING domain, and a C-terminal domain we term the SP-CTD. Structure-based mutational analysis and biochemical studies show that the SP-RING and SP-CTD are required for activation of the E2~SUMO thioester while the PINIT domain is essential for redirecting SUMO conjugation to the proliferating cell nuclear antigen (PCNA) at lysine 164, a non-consensus lysine residue that is not modified by the SUMO E2 in the absence of Siz1. Mutational analysis of Siz1 and PCNA revealed surfaces on both proteins that are required for efficient SUMO modification of PCNA in vitro and in vivo. PMID:19748360

OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.

PubMed

Samsudin, Firdaus; Ortiz-Suarez, Maite L; Piggot, Thomas J; Bond, Peter J; Khalid, Syma

2016-12-06

The envelope of Gram-negative bacteria is highly complex, containing separate outer and inner membranes and an intervening periplasmic space encompassing a peptidoglycan (PGN) cell wall. The PGN scaffold is anchored non-covalently to the outer membrane via globular OmpA-like domains of various proteins. We report atomically detailed simulations of PGN bound to OmpA in three different states, including the isolated C-terminal domain (CTD), the full-length monomer, or the complete full-length dimeric form. Comparative analysis of dynamics of OmpA CTD from different bacteria helped to identify a conserved PGN-binding mode. The dynamics of full-length OmpA, embedded within a realistic representation of the outer membrane containing full-rough (Ra) lipopolysaccharide, phospholipids, and cardiolipin, suggested how the protein may provide flexible mechanical support to the cell wall. An accurate model of the heterogeneous bacterial cell envelope should facilitate future efforts to develop antibacterial agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Architecture of the RNA polymerase II-Mediator core initiation complex.

PubMed

Plaschka, C; Larivière, L; Wenzeck, L; Seizl, M; Hemann, M; Tegunov, D; Petrotchenko, E V; Borchers, C H; Baumeister, W; Herzog, F; Villa, E; Cramer, P

2015-02-19

The conserved co-activator complex Mediator enables regulated transcription initiation by RNA polymerase (Pol) II. Here we reconstitute an active 15-subunit core Mediator (cMed) comprising all essential Mediator subunits from Saccharomyces cerevisiae. The cryo-electron microscopic structure of cMed bound to a core initiation complex was determined at 9.7 Å resolution. cMed binds Pol II around the Rpb4-Rpb7 stalk near the carboxy-terminal domain (CTD). The Mediator head module binds the Pol II dock and the TFIIB ribbon and stabilizes the initiation complex. The Mediator middle module extends to the Pol II foot with a 'plank' that may influence polymerase conformation. The Mediator subunit Med14 forms a 'beam' between the head and middle modules and connects to the tail module that is predicted to bind transcription activators located on upstream DNA. The Mediator 'arm' and 'hook' domains contribute to a 'cradle' that may position the CTD and TFIIH kinase to stimulate Pol II phosphorylation.

Structural insights into the mycobacteria transcription initiation complex from analysis of X-ray crystal structures

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

Hubin, Elizabeth A.; Lilic, Mirjana; Darst, Seth A.

The mycobacteria RNA polymerase (RNAP) is a target for antimicrobials against tuberculosis, motivating structure/function studies. Here we report a 3.2 Å-resolution crystal structure of a Mycobacterium smegmatis (Msm) open promoter complex (RPo), along with structural analysis of the Msm RPo and a previously reported 2.76 Å-resolution crystal structure of an Msm transcription initiation complex with a promoter DNA fragment. We observe the interaction of the Msm RNAP α-subunit C-terminal domain (αCTD) with DNA, and we provide evidence that the αCTD may play a role in Mtb transcription regulation. Our results reveal the structure of an Actinobacteria-unique insert of the RNAPmore » β' subunit. Finally, our analysis reveals the disposition of the N-terminal segment of Msm σA, which may comprise an intrinsically disordered protein domain unique to mycobacteria. The clade-specific features of the mycobacteria RNAP provide clues to the profound instability of mycobacteria RPo compared with E. coli.« less

Structural insights into the mycobacteria transcription initiation complex from analysis of X-ray crystal structures

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

Hubin, Elizabeth A.; Lilic, Mirjana; Darst, Seth A.

The mycobacteria RNA polymerase (RNAP) is a target for antimicrobials against tuberculosis, motivating structure/function studies. Here we report a 3.2 Å-resolution crystal structure of a Mycobacterium smegmatis (Msm) open promoter complex (RPo), along with structural analysis of the Msm RPo and a previously reported 2.76 Å-resolution crystal structure of an Msm transcription initiation complex with a promoter DNA fragment. We observe the interaction of the Msm RNAP α-subunit C-terminal domain (αCTD) with DNA, and we provide evidence that the a CTD may play a role in Mtb transcription regulation. Here, our results reveal the structure of an Actinobacteria-unique insert ofmore » the RNAP β' subunit. Finally, our analysis reveals the disposition of the N-terminal segment of Msm σ A, which may comprise an intrinsically disordered protein domain unique to mycobacteria. The clade-specific features of the mycobacteria RNAP provide clues to the profound instability of mycobacteria RPo compared with E. coli.« less

Time delay and long-range connection induced synchronization transitions in Newman-Watts small-world neuronal networks.

PubMed

Qian, Yu

2014-01-01

The synchronization transitions in Newman-Watts small-world neuronal networks (SWNNs) induced by time delay τ and long-range connection (LRC) probability P have been investigated by synchronization parameter and space-time plots. Four distinct parameter regions, that is, asynchronous region, transition region, synchronous region, and oscillatory region have been discovered at certain LRC probability P = 1.0 as time delay is increased. Interestingly, desynchronization is observed in oscillatory region. More importantly, we consider the spatiotemporal patterns obtained in delayed Newman-Watts SWNNs are the competition results between long-range drivings (LRDs) and neighboring interactions. In addition, for moderate time delay, the synchronization of neuronal network can be enhanced remarkably by increasing LRC probability. Furthermore, lag synchronization has been found between weak synchronization and complete synchronization as LRC probability P is a little less than 1.0. Finally, the two necessary conditions, moderate time delay and large numbers of LRCs, are exposed explicitly for synchronization in delayed Newman-Watts SWNNs.

Time Delay and Long-Range Connection Induced Synchronization Transitions in Newman-Watts Small-World Neuronal Networks

PubMed Central

Qian, Yu

2014-01-01

The synchronization transitions in Newman-Watts small-world neuronal networks (SWNNs) induced by time delay and long-range connection (LRC) probability have been investigated by synchronization parameter and space-time plots. Four distinct parameter regions, that is, asynchronous region, transition region, synchronous region, and oscillatory region have been discovered at certain LRC probability as time delay is increased. Interestingly, desynchronization is observed in oscillatory region. More importantly, we consider the spatiotemporal patterns obtained in delayed Newman-Watts SWNNs are the competition results between long-range drivings (LRDs) and neighboring interactions. In addition, for moderate time delay, the synchronization of neuronal network can be enhanced remarkably by increasing LRC probability. Furthermore, lag synchronization has been found between weak synchronization and complete synchronization as LRC probability is a little less than 1.0. Finally, the two necessary conditions, moderate time delay and large numbers of LRCs, are exposed explicitly for synchronization in delayed Newman-Watts SWNNs. PMID:24810595

[Analysis of characteristics and influence factors of diagnostic delay of endometriosis].

PubMed

Han, X T; Guo, H Y; Kong, D L; Han, J S; Zhang, L F

2018-02-25

Objective: To access the influence factors of diagnostic delay of endometriosis. Methods: We designed a questionnaire of diagnostic delay of endometriosis. From February 2014 to February 2016, 400 patients who had dysmenorrhea and diagnosed with endometriosis by surgery in Peking University Third Hospital were surveyed retrospectively. Time and risk factors of diagnostic delay were analyzed. Results: The diagnostic delay of 400 patients was 13.0 years (0.2-43.0 years), 78.5%(314/400) patients thought pain was a normal phenomenon and didn't see the doctor. Patients who suffered dysmenorrhea at menarche experienced longer diagnostic delay than those who had dysmenorrhea after menarche (18.0 vs 4.5 years; Z= 191.800, P< 0.01) . Patients who suffered aggravating dysmenorrhea experienced shorter delay time than those who suffered stable or relieving dysmenorrhea (11.0 vs 12.5 vs 18.0 years; Z= 8.270, P< 0.05) , with the difference statistically significant, single factor analysis shows. Severe dysmenorrhea, deep infiltration endometriosis (DIE) , family history of dysmenorrhea or endometriosis, previous surgical history of endometriosis, high stage, with infertility, adenomyoma or other symptoms, could help to shorten diagnostic delay with no significant difference ( P> 0.05) . By multiple logistic regression analysis, the results shown that whether have dysmenorrhea at menarche and clinical diagnosis time were the independent factors affecting delayed diagnosis ( P< 0.01) . Conclusions: Diagnostic delay of endometriosis is common and the mean delay time is 13.0 years mainly due to the unawareness of dysmenorrhea. Dysmenorrhea at menarche, clinical diagnosis time and dysmenorrhea intensity are the factors affecting time of diagnostic delay.

LMI designmethod for networked-based PID control

NASA Astrophysics Data System (ADS)

Souza, Fernando de Oliveira; Mozelli, Leonardo Amaral; de Oliveira, Maurício Carvalho; Palhares, Reinaldo Martinez

2016-10-01

In this paper, we propose a methodology for the design of networked PID controllers for second-order delayed processes using linear matrix inequalities. The proposed procedure takes into account time-varying delay on the plant, time-varying delays induced by the network and packed dropouts. The design is carried on entirely using a continuous-time model of the closed-loop system where time-varying delays are used to represent sampling and holding occurring in a discrete-time digital PID controller.

Accurate time delay technology in simulated test for high precision laser range finder

NASA Astrophysics Data System (ADS)

Chen, Zhibin; Xiao, Wenjian; Wang, Weiming; Xue, Mingxi

2015-10-01

With the continuous development of technology, the ranging accuracy of pulsed laser range finder (LRF) is higher and higher, so the maintenance demand of LRF is also rising. According to the dominant ideology of "time analog spatial distance" in simulated test for pulsed range finder, the key of distance simulation precision lies in the adjustable time delay. By analyzing and comparing the advantages and disadvantages of fiber and circuit delay, a method was proposed to improve the accuracy of the circuit delay without increasing the count frequency of the circuit. A high precision controllable delay circuit was designed by combining the internal delay circuit and external delay circuit which could compensate the delay error in real time. And then the circuit delay accuracy could be increased. The accuracy of the novel circuit delay methods proposed in this paper was actually measured by a high sampling rate oscilloscope actual measurement. The measurement result shows that the accuracy of the distance simulated by the circuit delay is increased from +/- 0.75m up to +/- 0.15m. The accuracy of the simulated distance is greatly improved in simulated test for high precision pulsed range finder.

Kalman filters for fractional discrete-time stochastic systems along with time-delay in the observation signal

NASA Astrophysics Data System (ADS)

Torabi, H.; Pariz, N.; Karimpour, A.

2016-02-01

This paper investigates fractional Kalman filters when time-delay is entered in the observation signal in the discrete-time stochastic fractional order state-space representation. After investigating the common fractional Kalman filter, we try to derive a fractional Kalman filter for time-delay fractional systems. A detailed derivation is given. Fractional Kalman filters will be used to estimate recursively the states of fractional order state-space systems based on minimizing the cost function when there is a constant time delay (d) in the observation signal. The problem will be solved by converting the filtering problem to a usual d-step prediction problem for delay-free fractional systems.

Time Delay of CGM Sensors

PubMed Central

Schmelzeisen-Redeker, Günther; Schoemaker, Michael; Kirchsteiger, Harald; Freckmann, Guido; Heinemann, Lutz; del Re, Luigi

2015-01-01

Background: Continuous glucose monitoring (CGM) is a powerful tool to support the optimization of glucose control of patients with diabetes. However, CGM systems measure glucose in interstitial fluid but not in blood. Rapid changes in one compartment are not accompanied by similar changes in the other, but follow with some delay. Such time delays hamper detection of, for example, hypoglycemic events. Our aim is to discuss the causes and extent of time delays and approaches to compensate for these. Methods: CGM data were obtained in a clinical study with 37 patients with a prototype glucose sensor. The study was divided into 5 phases over 2 years. In all, 8 patients participated in 2 phases separated by 8 months. A total number of 108 CGM data sets including raw signals were used for data analysis and were processed by statistical methods to obtain estimates of the time delay. Results: Overall mean (SD) time delay of the raw signals with respect to blood glucose was 9.5 (3.7) min, median was 9 min (interquartile range 4 min). Analysis of time delays observed in the same patients separated by 8 months suggests a patient dependent delay. No significant correlation was observed between delay and anamnestic or anthropometric data. The use of a prediction algorithm reduced the delay by 4 minutes on average. Conclusions: Prediction algorithms should be used to provide real-time CGM readings more consistent with simultaneous measurements by SMBG. Patient specificity may play an important role in improving prediction quality. PMID:26243773

A comparison of control modes for time-delayed remote manipulation

NASA Technical Reports Server (NTRS)

Starr, G. P.

1982-01-01

Transmission time delay in the communication channel of a manual control system is investigated. A time delay can exist in remote manipulation systems, caused by long communication distances or bandwidth limitations. Ferrell 1 conducted the first research in time-delayed manipulation using a two degree-of-freedom manipulator. His subjects, working at time delays of 1.0, 2.1, and 3.2 s, could accomplish tasks even requiring great accuracy. The subjects spontaneously adopted a pattern of moving cautiously, then waiting to see the results of their actions. In experiments with a six degree-of-freedom master-slave manipulator system and time delays of 1.0 to 6 s, Black 2 saw that subjects tried to use the move-and-wait strategy; but there were often difficulties. The subjects seemed to have a problem in holding the master arm stationary while waiting for feedback. Any undesired drifting of the master arm introduced a discrepancy between the positions of the master and slave. This discrepancy was not perceived because of the time delay. The subject would then begin his next move with an inherent error. The difficulty of effectively using the move-and-wait strategy with a master-slave manipulator suggested that rate control might be a more effective control mode with time delay.

TIMEDELN: A programme for the detection and parametrization of overlapping resonances using the time-delay method

NASA Astrophysics Data System (ADS)

Little, Duncan A.; Tennyson, Jonathan; Plummer, Martin; Noble, Clifford J.; Sunderland, Andrew G.

2017-06-01

TIMEDELN implements the time-delay method of determining resonance parameters from the characteristic Lorentzian form displayed by the largest eigenvalues of the time-delay matrix. TIMEDELN constructs the time-delay matrix from input K-matrices and analyses its eigenvalues. This new version implements multi-resonance fitting and may be run serially or as a high performance parallel code with three levels of parallelism. TIMEDELN takes K-matrices from a scattering calculation, either read from a file or calculated on a dynamically adjusted grid, and calculates the time-delay matrix. This is then diagonalized, with the largest eigenvalue representing the longest time-delay experienced by the scattering particle. A resonance shows up as a characteristic Lorentzian form in the time-delay: the programme searches the time-delay eigenvalues for maxima and traces resonances when they pass through different eigenvalues, separating overlapping resonances. It also performs the fitting of the calculated data to the Lorentzian form and outputs resonance positions and widths. Any remaining overlapping resonances can be fitted jointly. The branching ratios of decay into the open channels can also be found. The programme may be run serially or in parallel with three levels of parallelism. The parallel code modules are abstracted from the main physics code and can be used independently.

14 CFR 417.221 - Time delay analysis.

Code of Federal Regulations, 2010 CFR

2010-01-01

... OF TRANSPORTATION LICENSING LAUNCH SAFETY Flight Safety Analysis § 417.221 Time delay analysis. (a) General. A flight safety analysis must include a time delay analysis that establishes the mean elapsed time between the violation of a flight termination rule and the time when the flight safety system is...

14 CFR 417.221 - Time delay analysis.

Code of Federal Regulations, 2011 CFR

2011-01-01

... OF TRANSPORTATION LICENSING LAUNCH SAFETY Flight Safety Analysis § 417.221 Time delay analysis. (a) General. A flight safety analysis must include a time delay analysis that establishes the mean elapsed time between the violation of a flight termination rule and the time when the flight safety system is...

49 CFR 236.831 - Time, delay.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Time, delay. 236.831 Section 236.831 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Time, delay. As applied to an automatic train stop or train control system, the time which elapses...

Lesions Responsible for Delayed Oral Transit Time in Post-stroke Dysphagia.

PubMed

Moon, Hyun Im; Yoon, Seo Yeon; Yi, Tae Im; Jeong, Yoon Jeong; Cho, Tae Hwan

2018-06-01

Some stroke patients show oral phase dysphagia, characterized by a markedly prolonged oral transit time that hinders oral feeding. The aim of this study was to clarify the clinical characteristics and lesions responsible for delayed swallowing. We reviewed 90 patients with stroke. The oral processing time plus the postfaucial aggregation time required to swallow semisolid food was assessed. The patients were divided into two groups according to oral transit time, and we analyzed the differences in characteristics such as demographic factors, lesion factors, and cognitive function. Logistic regression analyses were performed to examine the predictors of delayed oral transit time. Lesion location and volume were measured on brain magnetic resonance images. We generated statistic maps of lesions related to delayed oral phase in swallowing using voxel-based lesion symptom mapping (VLSM). The group of patients who showed delayed oral transit time had significantly low cognitive function. Also, in a regression model, delayed oral phase was predicted with low K-MMSE (Korean version of the Mini Mental Status Exam). Using VLSM, we found the lesion location to be associated with delayed oral phase after adjusting for K-MMSE score. Although these results did not reach statistical significance, they showed the lesion pattern with predominant distribution in the left frontal lobe. Delayed oral phase in post-stroke patients was not negligible clinically. Patients' cognitive impairments affect the oral transit time. When adjusting it, we found a trend that the lesion responsible for delayed oral phase was located in the left frontal lobe, though the association did not reach significance. The delay might be related to praxis function.

The effect of visual-motion time-delays on pilot performance in a simulated pursuit tracking task

NASA Technical Reports Server (NTRS)

Miller, G. K., Jr.; Riley, D. R.

1977-01-01

An experimental study was made to determine the effect on pilot performance of time delays in the visual and motion feedback loops of a simulated pursuit tracking task. Three major interrelated factors were identified: task difficulty either in the form of airplane handling qualities or target frequency, the amount and type of motion cues, and time delay itself. In general, the greater the task difficulty, the smaller the time delay that could exist without degrading pilot performance. Conversely, the greater the motion fidelity, the greater the time delay that could be tolerated. The effect of motion was, however, pilot dependent.

Optimal estimation of parameters and states in stochastic time-varying systems with time delay

NASA Astrophysics Data System (ADS)

Torkamani, Shahab; Butcher, Eric A.

2013-08-01

In this study estimation of parameters and states in stochastic linear and nonlinear delay differential systems with time-varying coefficients and constant delay is explored. The approach consists of first employing a continuous time approximation to approximate the stochastic delay differential equation with a set of stochastic ordinary differential equations. Then the problem of parameter estimation in the resulting stochastic differential system is represented as an optimal filtering problem using a state augmentation technique. By adapting the extended Kalman-Bucy filter to the resulting system, the unknown parameters of the time-delayed system are estimated from noise-corrupted, possibly incomplete measurements of the states.

Opto-VLSI-based photonic true-time delay architecture for broadband adaptive nulling in phased array antennas.

PubMed

Juswardy, Budi; Xiao, Feng; Alameh, Kamal

2009-03-16

This paper proposes a novel Opto-VLSI-based tunable true-time delay generation unit for adaptively steering the nulls of microwave phased array antennas. Arbitrary single or multiple true-time delays can simultaneously be synthesized for each antenna element by slicing an RF-modulated broadband optical source and routing specific sliced wavebands through an Opto-VLSI processor to a high-dispersion fiber. Experimental results are presented, which demonstrate the principle of the true-time delay unit through the generation of 5 arbitrary true-time delays of up to 2.5 ns each. (c) 2009 Optical Society of America

Solar oscillation time delay measurement assisted celestial navigation method

NASA Astrophysics Data System (ADS)

Ning, Xiaolin; Gui, Mingzhen; Zhang, Jie; Fang, Jiancheng; Liu, Gang

2017-05-01

Solar oscillation, which causes the sunlight intensity and spectrum frequency change, has been studied in great detail, both observationally and theoretically. In this paper, owing to the existence of solar oscillation, the time delay between the sunlight coming from the Sun directly and the sunlight reflected by the other celestial body such as the satellite of planet or asteroid can be obtained with two optical power meters. Because the solar oscillation time delay is determined by the relative positions of the spacecraft, reflective celestial body and the Sun, it can be adopted as the navigation measurement to estimate the spacecraft's position. The navigation accuracy of single solar oscillation time delay navigation system depends on the time delay measurement accuracy, and is influenced by the distance between spacecraft and reflective celestial body. In this paper, we combine it with the star angle measurement and propose a solar oscillation time delay measurement assisted celestial navigation method for deep space exploration. Since the measurement model of time delay is an implicit function, the Implicit Unscented Kalman Filter (IUKF) is applied. Simulations demonstrate the effectiveness and superiority of this method.

System for sensing droplet formation time delay in a flow cytometer

DOEpatents

Van den Engh, Ger; Esposito, Richard J.

1997-01-01

A droplet flow cytometer system which includes a system to optimize the droplet formation time delay based on conditions actually experienced includes an automatic droplet sampler which rapidly moves a plurality of containers stepwise through the droplet stream while simultaneously adjusting the droplet time delay. Through the system sampling of an actual substance to be processed can be used to minimize the effect of the substances variations or the determination of which time delay is optimal. Analysis such as cell counting and the like may be conducted manually or automatically and input to a time delay adjustment which may then act with analysis equipment to revise the time delay estimate actually applied during processing. The automatic sampler can be controlled through a microprocessor and appropriate programming to bracket an initial droplet formation time delay estimate. When maximization counts through volume, weight, or other types of analysis exists in the containers, the increment may then be reduced for a more accurate ultimate setting. This may be accomplished while actually processing the sample without interruption.

Tunable delay time and Hartman effect in graphene magnetic barriers

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

Ban, Yue; Wang, Lin-Jun; Chen, Xi, E-mail: xchen@shu.edu.cn

2015-04-28

Tunable group delay and Hartman effect have been investigated for massless Dirac electrons in graphene magnetic barriers. In the presence of magnetic field, dwell time is found to be equal to net group delay plus the group delay contributing from the lateral shifts. The group delay times are discussed in both cases of normal and oblique incidence, to clarify the nature of Hartman effect. In addition, the group delay in transmission can be modulated from subluminality to superluminality by adjusting the magnetic field, which may also lead to potential applications in graphene-based microelectronics.

Causes of delay in door-to-balloon time in south-east Asian patients undergoing primary percutaneous coronary intervention.

PubMed

Sim, Wen Jun; Ang, An Shing; Tan, Mae Chyi; Xiang, Wen Wei; Foo, David; Loh, Kwok Kong; Jafary, Fahim Haider; Watson, Timothy James; Ong, Paul Jau Lueng; Ho, Hee Hwa

2017-01-01

To evaluate causes and impact of delay in the door-to-balloon (D2B) time for patients undergoing primary percutaneous coronary intervention (PPCI). From January 2009 to December 2012, 1268 patients (86% male, mean age of 58 ± 12 years) presented to our hospital for ST-elevation myocardial infarction (STEMI) and underwent PPCI. They were divided into two groups: Non-delay defined as D2B time ≤ 90 mins and delay group defined as D2B time > 90 mins. Data were collected retrospectively on baseline clinical characteristics, mode of presentation, angiographic findings, therapeutic modality and inhospital outcome. 202 patients had delay in D2B time. There were more female patients in the delay group. They were older and tend to self-present to hospital. They were less likely to be smokers and have a higher prevalence of prior MI. The incidence of posterior MI was higher in the delay group. They also had a higher incidence of triple vessel disease. The 3 most common reasons for D2B delay was delay in the emergency department (39%), atypical clinical presentation (37.6%) and unstable medical condition requiring stabilisation/computed tomographic imaging (26.7%). The inhospital mortality was numerically higher in the delay group (7.4% versus 4.8%, p = 0.12). Delay in D2B occurred in 16% of our patients undergoing PPCI. Several key factors for delay were identified and warrant further intervention.

Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions

PubMed Central

Lin, Aijing; Liu, Kang K. L.; Bartsch, Ronny P.; Ivanov, Plamen Ch.

2016-01-01

Within the framework of ‘Network Physiology’, we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain–heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain–heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems. PMID:27044991

Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions

NASA Astrophysics Data System (ADS)

Lin, Aijing; Liu, Kang K. L.; Bartsch, Ronny P.; Ivanov, Plamen Ch.

2016-05-01

Within the framework of `Network Physiology', we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain-heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain-heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems.

Control of amplitude chimeras by time delay in oscillator networks

NASA Astrophysics Data System (ADS)

Gjurchinovski, Aleksandar; Schöll, Eckehard; Zakharova, Anna

2017-04-01

We investigate the influence of time-delayed coupling in a ring network of nonlocally coupled Stuart-Landau oscillators upon chimera states, i.e., space-time patterns with coexisting partially coherent and partially incoherent domains. We focus on amplitude chimeras, which exhibit incoherent behavior with respect to the amplitude rather than the phase and are transient patterns, and we show that their lifetime can be significantly enhanced by coupling delay. To characterize their transition to phase-lag synchronization (coherent traveling waves) and other coherent structures, we generalize the Kuramoto order parameter. Contrasting the results for instantaneous coupling with those for constant coupling delay, for time-varying delay, and for distributed-delay coupling, we demonstrate that the lifetime of amplitude chimera states and related partially incoherent states can be controlled, i.e., deliberately reduced or increased, depending upon the type of coupling delay.

Time domain passivity controller for 4-channel time-delay bilateral teleoperation.

PubMed

Rebelo, Joao; Schiele, Andre

2015-01-01

This paper presents an extension of the time-domain passivity control approach to a four-channel bilateral controller under the effects of time delays. Time-domain passivity control has been used successfully to stabilize teleoperation systems with position-force and position-position controllers; however, the performance with such control architectures is sub-optimal both with and without time delays. This work extends the network representation of the time-domain passivity controller to the four-channel architecture, which provides perfect transparency to the user without time delay. The proposed architecture is based on modelling the controllers as dependent voltage sources and using only series passivity controllers. The obtained results are shown on a one degree-of-freedom setup and illustrate the stabilization behaviour of the proposed controller when time delay is present in the communication channel.

Typical teleoperator time delay profiles, phase 2. [remotely controlled manipulator arms

NASA Technical Reports Server (NTRS)

Wetherington, R. D.; Walsh, J. R.

1974-01-01

The results of the second phase of a study on time delays in communications systems applicable to the teleoperator program are presented. Estimates of the maximum time delays that will be encountered and presents time delay profiles are given for (1) ground control to teleoperator in low earth orbit, (2) ground control to teleoperator in geosynchronous orbit, and (3) low earth orbit control to teleoperator in low earth orbit.

VARIABLE TIME DELAY MEANS

DOEpatents

Clemensen, R.E.

1959-11-01

An electrically variable time delay line is described which may be readily controlled simuitaneously with variable impedance matching means coupied thereto such that reflections are prevented. Broadly, the delay line includes a signal winding about a magnetic core whose permeability is electrically variable. Inasmuch as the inductance of the line varies directly with the permeability, the time delay and characteristic impedance of the line both vary as the square root of the permeability. Consequently, impedance matching means may be varied similariy and simultaneously w:th the electrically variable permeability to match the line impedance over the entire range of time delay whereby reflections are prevented.

Simulator study of the effect of visual-motion time delays on pilot tracking performance with an audio side task

NASA Technical Reports Server (NTRS)

Riley, D. R.; Miller, G. K., Jr.

1978-01-01

The effect of time delay was determined in the visual and motion cues in a flight simulator on pilot performance in tracking a target aircraft that was oscillating sinusoidally in altitude only. An audio side task was used to assure the subject was fully occupied at all times. The results indicate that, within the test grid employed, about the same acceptable time delay (250 msec) was obtained for a single aircraft (fighter type) by each of two subjects for both fixed-base and motion-base conditions. Acceptable time delay is defined as the largest amount of delay that can be inserted simultaneously into the visual and motion cues before performance degradation occurs. A statistical analysis of the data was made to establish this value of time delay. Audio side task provided quantitative data that documented the subject's work level.

Wigner time delay and spin-orbit activated confinement resonances

NASA Astrophysics Data System (ADS)

Keating, D. A.; Deshmukh, P. C.; Manson, S. T.

2017-09-01

A study of the photoionization of spin-orbit split subshells of high-Z atoms confined in C60 has been performed using the relativistic-random-phase approximation. Specifically, Hg@C60 5p, Rn@C60 6p and Ra@C60 5d were investigated and the near-threshold confinement resonances in the j = l - 1/2 channels were found to engender structures in the j = l + 1/2 cross sections via correlation in the form of interchannel coupling. These structures are termed spin-orbit induced confinement resonances and they are found to profoundly influence the Wigner time delay spectrum resulting in time delays of tens or hundreds of attoseconds along with dramatic swings in time delay over small energy intervals. Pronounced relativistic effects in time delay are also found. These structures, including their manifestation in time delay spectra, are expected to be general phenomena in the photoionization of spin-orbit doublets in confined high-Z atoms.

Synchronization in a chaotic neural network with time delay depending on the spatial distance between neurons

NASA Astrophysics Data System (ADS)

Tang, Guoning; Xu, Kesheng; Jiang, Luoluo

2011-10-01

The synchronization is investigated in a two-dimensional Hindmarsh-Rose neuronal network by introducing a global coupling scheme with time delay, where the length of time delay is proportional to the spatial distance between neurons. We find that the time delay always disturbs synchronization of the neuronal network. When both the coupling strength and length of time delay per unit distance (i.e., enlargement factor) are large enough, the time delay induces the abnormal membrane potential oscillations in neurons. Specifically, the abnormal membrane potential oscillations for the symmetrically placed neurons form an antiphase, so that the large coupling strength and enlargement factor lead to the desynchronization of the neuronal network. The complete and intermittently complete synchronization of the neuronal network are observed for the right choice of parameters. The physical mechanism underlying these phenomena is analyzed.

Dissipativity and stability analysis of fractional-order complex-valued neural networks with time delay.

PubMed

Velmurugan, G; Rakkiyappan, R; Vembarasan, V; Cao, Jinde; Alsaedi, Ahmed

2017-02-01

As we know, the notion of dissipativity is an important dynamical property of neural networks. Thus, the analysis of dissipativity of neural networks with time delay is becoming more and more important in the research field. In this paper, the authors establish a class of fractional-order complex-valued neural networks (FCVNNs) with time delay, and intensively study the problem of dissipativity, as well as global asymptotic stability of the considered FCVNNs with time delay. Based on the fractional Halanay inequality and suitable Lyapunov functions, some new sufficient conditions are obtained that guarantee the dissipativity of FCVNNs with time delay. Moreover, some sufficient conditions are derived in order to ensure the global asymptotic stability of the addressed FCVNNs with time delay. Finally, two numerical simulations are posed to ensure that the attention of our main results are valuable. Copyright © 2016 Elsevier Ltd. All rights reserved.

Deep Diving Cetacean Behavioral Response Study MED 09

DTIC Science & Technology

2009-09-30

distribution may be affected by anthropogenic noise. The role of the SPAWAR Systems Center (SSC) Pacific team was to intergrate the interdisiplinary...over 100 hours of data was collected on production sonobuoys for post test ambient noise data. CTD casts were taken at 56 sites, collecting

Determining delayed admission to intensive care unit for mechanically ventilated patients in the emergency department.

PubMed

Hung, Shih-Chiang; Kung, Chia-Te; Hung, Chih-Wei; Liu, Ber-Ming; Liu, Jien-Wei; Chew, Ghee; Chuang, Hung-Yi; Lee, Wen-Huei; Lee, Tzu-Chi

2014-08-23

The adverse effects of delayed admission to the intensive care unit (ICU) have been recognized in previous studies. However, the definitions of delayed admission varies across studies. This study proposed a model to define "delayed admission", and explored the effect of ICU-waiting time on patients' outcome. This retrospective cohort study included non-traumatic adult patients on mechanical ventilation in the emergency department (ED), from July 2009 to June 2010. The primary outcomes measures were 21-ventilator-day mortality and prolonged hospital stays (over 30 days). Models of Cox regression and logistic regression were used for multivariate analysis. The non-delayed ICU-waiting was defined as a period in which the time effect on mortality was not statistically significant in a Cox regression model. To identify a suitable cut-off point between "delayed" and "non-delayed", subsets from the overall data were made based on ICU-waiting time and the hazard ratio of ICU-waiting hour in each subset was iteratively calculated. The cut-off time was then used to evaluate the impact of delayed ICU admission on mortality and prolonged length of hospital stay. The final analysis included 1,242 patients. The time effect on mortality emerged after 4 hours, thus we deduced ICU-waiting time in ED > 4 hours as delayed. By logistic regression analysis, delayed ICU admission affected the outcomes of 21 ventilator-days mortality and prolonged hospital stay, with odds ratio of 1.41 (95% confidence interval, 1.05 to 1.89) and 1.56 (95% confidence interval, 1.07 to 2.27) respectively. For patients on mechanical ventilation at the ED, delayed ICU admission is associated with higher probability of mortality and additional resource expenditure. A benchmark waiting time of no more than 4 hours for ICU admission is recommended.

Microlensing makes lensed quasar time delays significantly time variable

NASA Astrophysics Data System (ADS)

Tie, S. S.; Kochanek, C. S.

2018-01-01

The time delays of gravitationally lensed quasars are generally believed to be unique numbers whose measurement is limited only by the quality of the light curves and the models for the contaminating contribution of gravitational microlensing to the light curves. This belief is incorrect - gravitational microlensing also produces changes in the actual time delays on the ∼day(s) light-crossing time-scale of the emission region. This is due to a combination of the inclination of the disc relative to the line of sight and the differential magnification of the temperature fluctuations producing the variability. We demonstrate this both mathematically and with direct calculations using microlensing magnification patterns. Measuring these delay fluctuations can provide a physical scale for microlensing observations, removing the need for priors on either the microlens masses or the component velocities. That time delays in lensed quasars are themselves time variable likely explains why repeated delay measurements of individual lensed quasars appear to vary by more than their estimated uncertainties. This effect is also a new important systematic problem for attempts to use time delays in lensed quasars for cosmology or to detect substructures (satellites) in lens galaxies.

Long-time behavior for suspension bridge equations with time delay

NASA Astrophysics Data System (ADS)

Park, Sun-Hye

2018-04-01

In this paper, we consider suspension bridge equations with time delay of the form u_{tt}(x,t) + Δ ^2 u (x,t) + k u^+ (x,t) + a_0 u_t (x,t) + a_1 u_t (x, t- τ ) + f(u(x,t)) = g(x). Many researchers have studied well-posedness, decay rates of energy, and existence of attractors for suspension bridge equations without delay effects. But, as far as we know, there is no work about suspension equations with time delay. In addition, there are not many studies on attractors for other delayed systems. Thus we first provide well-posedness for suspension equations with time delay. And then show the existence of global attractors and the finite dimensionality of the attractors by establishing energy functionals which are related to the norm of the phase space to our problem.

Robust outer synchronization between two nonlinear complex networks with parametric disturbances and mixed time-varying delays

NASA Astrophysics Data System (ADS)

Zhang, Chuan; Wang, Xingyuan; Luo, Chao; Li, Junqiu; Wang, Chunpeng

2018-03-01

In this paper, we focus on the robust outer synchronization problem between two nonlinear complex networks with parametric disturbances and mixed time-varying delays. Firstly, a general complex network model is proposed. Besides the nonlinear couplings, the network model in this paper can possess parametric disturbances, internal time-varying delay, discrete time-varying delay and distributed time-varying delay. Then, according to the robust control strategy, linear matrix inequality and Lyapunov stability theory, several outer synchronization protocols are strictly derived. Simple linear matrix controllers are designed to driver the response network synchronize to the drive network. Additionally, our results can be applied on the complex networks without parametric disturbances. Finally, by utilizing the delayed Lorenz chaotic system as the dynamics of all nodes, simulation examples are given to demonstrate the effectiveness of our theoretical results.

Fixed-base simulator study of the effect of time delays in visual cues on pilot tracking performance

NASA Technical Reports Server (NTRS)

Queijo, M. J.; Riley, D. R.

1975-01-01

Factors were examined which determine the amount of time delay acceptable in the visual feedback loop in flight simulators. Acceptable time delays are defined as delays which significantly affect neither the results nor the manner in which the subject 'flies' the simulator. The subject tracked a target aircraft as it oscillated sinusoidally in a vertical plane only. The pursuing aircraft was permitted five degrees of freedom. Time delays of from 0.047 to 0.297 second were inserted in the visual feedback loop. A side task was employed to maintain the workload constant and to insure that the pilot was fully occupied during the experiment. Tracking results were obtained for 17 aircraft configurations having different longitudinal short-period characteristics. Results show a positive correlation between improved handling qualities and a longer acceptable time delay.

Intermittent large amplitude internal waves observed in Port Susan, Puget Sound

NASA Astrophysics Data System (ADS)

Harris, J. C.; Decker, L.

2017-07-01

A previously unreported internal tidal bore, which evolves into solitary internal wave packets, was observed in Port Susan, Puget Sound, and the timing, speed, and amplitude of the waves were measured by CTD and visual observation. Acoustic Doppler current profiler (ADCP) measurements were attempted, but unsuccessful. The waves appear to be generated with the ebb flow along the tidal flats of the Stillaguamish River, and the speed and width of the resulting waves can be predicted from second-order KdV theory. Their eventual dissipation may contribute significantly to surface mixing locally, particularly in comparison with the local dissipation due to the tides. Visually the waves appear in fair weather as a strong foam front, which is less visible the farther they propagate.

A comprehensive review of prehospital and in-hospital delay times in acute stroke care.

PubMed

Evenson, K R; Foraker, R E; Morris, D L; Rosamond, W D

2009-06-01

The purpose of this study was to systematically review and summarize prehospital and in-hospital stroke evaluation and treatment delay times. We identified 123 unique peer-reviewed studies published from 1981 to 2007 of prehospital and in-hospital delay time for evaluation and treatment of patients with stroke, transient ischemic attack, or stroke-like symptoms. Based on studies of 65 different population groups, the weighted Poisson regression indicated a 6.0% annual decline (P<0.001) in hours/year for prehospital delay, defined from symptom onset to emergency department arrival. For in-hospital delay, the weighted Poisson regression models indicated no meaningful changes in delay time from emergency department arrival to emergency department evaluation (3.1%, P=0.49 based on 12 population groups). There was a 10.2% annual decline in hours/year from emergency department arrival to neurology evaluation or notification (P=0.23 based on 16 population groups) and a 10.7% annual decline in hours/year for delay time from emergency department arrival to initiation of computed tomography (P=0.11 based on 23 population groups). Only one study reported on times from arrival to computed tomography scan interpretation, two studies on arrival to drug administration, and no studies on arrival to transfer to an in-patient setting, precluding generalizations. Prehospital delay continues to contribute the largest proportion of delay time. The next decade provides opportunities to establish more effective community-based interventions worldwide. It will be crucial to have effective stroke surveillance systems in place to better understand and improve both prehospital and in-hospital delays for acute stroke care.

Effects of time delay and pitch control sensitivity in the flared landing

NASA Technical Reports Server (NTRS)

Berthe, C. J.; Chalk, C. R.; Wingarten, N. C.; Grantham, W.

1986-01-01

Between December 1985 and January 1986, a flared landing program was conducted, using the USAF Total In-Flight simulator airplane, to examine time delay effects in a formal manner. Results show that as pitch sensitivity is increased, tolerance to time delay decreases. With the proper selection of pitch sensitivity, Level I performance was maintained with time delays ranging from 150 milliseconds to greater than 300 milliseconds. With higher sensitivity, configurations with Level I performance at 150 milliseconds degraded to level 2 at 200 milliseconds. When metrics of time delay and pitch sensitivity effects are applied to enhance previously developed predictive criteria, the result is an improved prediction technique which accounts for significant closed loop items.

Exact synchronization bound for coupled time-delay systems.

PubMed

Senthilkumar, D V; Pesquera, Luis; Banerjee, Santo; Ortín, Silvia; Kurths, J

2013-04-01

We obtain an exact bound for synchronization in coupled time-delay systems using the generalized Halanay inequality for the general case of time-dependent delay, coupling, and coefficients. Furthermore, we show that the same analysis is applicable to both uni- and bidirectionally coupled time-delay systems with an appropriate evolution equation for their synchronization manifold, which can also be defined for different types of synchronization. The exact synchronization bound assures an exponential stabilization of the synchronization manifold which is crucial for applications. The analytical synchronization bound is independent of the nature of the modulation and can be applied to any time-delay system satisfying a Lipschitz condition. The analytical results are corroborated numerically using the Ikeda system.

Time delay induced different synchronization patterns in repulsively coupled chaotic oscillators

NASA Astrophysics Data System (ADS)

Yao, Chenggui; Yi, Ming; Shuai, Jianwei

2013-09-01

Time delayed coupling plays a crucial role in determining the system's dynamics. We here report that the time delay induces transition from the asynchronous state to the complete synchronization (CS) state in the repulsively coupled chaotic oscillators. In particular, by changing the coupling strength or time delay, various types of synchronous patterns, including CS, antiphase CS, antiphase synchronization (ANS), and phase synchronization, can be generated. In the transition regions between different synchronous patterns, bistable synchronous oscillators can be observed. Furthermore, we show that the time-delay-induced phase flip bifurcation is of key importance for the emergence of CS. All these findings may light on our understanding of neuronal synchronization and information processing in the brain.